On-clopidogrel Platelet Reactivity Research Articles

Low on-clopidogrel ADP- and TRAP-6-induced platelet aggregation in patients with atrial fibrillation undergoing percutaneous coronary intervention: an observational pilot study

High on-clopidogrel platelet reactivity (HPR) associates with ischemic risk in patients after percutaneous intervention (PCI). This study aimed to evaluate the association of HPR as assessed by multiple electrode aggregometry (MEA) with ischemic, thromboembolic, and bleeding risk in patients with atrial fibrillation (AF) undergoing PCI. Patients with AF and an indication for oral anticoagulation (OAC) were included in this prospective cohort study on day 1–3 after PCI. Platelet aggregation [U] was analyzed by MEA. HPR and low platelet reactivity (LPR) were defined as ADP-induced aggregation ≥ 46 U and ≤ 18 U, respectively. TRAP-6-induced aggregation reference was 94–156 U. The primary outcome was time to all-cause death, myocardial infarction, or stroke at 6 months. The secondary outcome was time to non-major clinically relevant bleedings or major bleedings. 159 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range 72–82) and 111 (70%) were male. Median ADP- and TRAP-induced aggregation were 12 (6–17) and 49 (35–68) U, respectively. 147 (93%) patients had a low overall aggregability. HPR was detected in 2 patients (1%) and 125 (79%) had LPR. ADP-induced aggregation did not significantly associate with the primary outcome (r = 0.081, p = 0.309) but correlated inversely with bleeding risk (r = − 0.201, p = 0.011). HPR status as assessed by MEA among patients with AF after PCI was rare and overall aggregability was low. Conventional cut-off values for HPR might be inappropriate for these patients. ADP-induced aggregation might be helpful to identify patients at risk for bleeding.

Implication of diabetic status on platelet reactivity and clinical outcomes after drug-eluting stent implantation: results from the PTRG-DES consortium

BackgroundDiabetes mellitus (DM) is associated with thrombogenicity, clinically manifested with atherothrombotic events after percutaneous cutaneous intervention (PCI). This study aimed to investigate association between DM status and platelet reactivity, and their prognostic implication in PCI-treated patients.MethodsThe Platelet function and genoType-Related long-term Prognosis-Platelet Function Test (PTRG-PFT) cohort was established to determine the linkage of platelet function test (PFT) with long-term prognosis during dual antiplatelet therapy including clopidogrel in patients treated with drug-eluting stent (DES). We assessed platelet reactivity using VerifyNow and ‘high platelet reactivity (HPR)’ was defined as ≥ 252 P2Y12 reaction unit (PRU). Major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, myocardial infarction, stent thrombosis or stroke.ResultsBetween July 2003 and Aug 2018, DES-treated patients with available PFT were enrolled (n = 11,714). Diabetic patients demonstrated significant higher levels of platelet reactivity (DM vs. non-DM: 225.7 ± 77.5 vs. 213.6 ± 79.1 PRU, P < 0.001) and greater prevalence of HPR compared to non-diabetic patients (38.1% vs. 32.0%, P < 0.001). PRU level and prevalence of HPR were significantly associated with insulin requirement and HbA1c level, as well as diabetic status. DM status and HPR phenotype had a similar prognostic implication, which showed the synergistic clinical impact on MACCE. Association between PRU level and MACCE occurrence seemed higher in diabetic vs. non-diabetic patients. In non-DM patients, HPR phenotype did not significantly increase the risk of MACCE (adjusted hazard ratio [HRadj]: 1.073; 95% confidence interval [CI]: 0.869–1.325; P = 0.511), whereas HPR was an independent determinant for MACCE occurrence among diabetic patients (HRadj: 1.507; 95% CI: 1.193–1.902; P < 0.001).ConclusionThe levels of on-clopidogrel platelet reactivity are determined by diabetic status and the severity of DM. In addition, HPR phenotype significantly increases the risk of MACCE only in diabetic patients.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT04734028.

Decreased platelet miR-199a-5p level might lead to high on-clopidogrel platelet reactivity in patients with coronary artery disease

Clopidogrel combined with aspirin is widely used in coronary artery disease (CAD) patients, while some patients exhibit high platelet activity when receiving the combined treatment. Current environmental and genetic factors could only explain part of the variability in clopidogrel efficacy. Human platelets harbor abundant miRNAs which might affect clopidogrel efficacy by regulating the expression of key proteins in the clopidogrel antiplatelet signaling pathway. This study aimed to investigate the association between platelet miRNA levels and clopidogrel efficacy. Here we recruited 508 CAD patients who underwent clopidogrel antiplatelet therapy and determined the platelet reactivity index (PRI) to evaluate antiplatelet reactivity responses to clopidogrel. Subsequently, 22 patients with extreme clopidogrel response were selected for platelet small RNA sequencing. Another 41 CAD patients taking clopidogrel were collected to verify the differentially expressed candidate miRNAs. We found the metabolic types of the CYP2C19 enzyme (based on CYP2C19 * 2 and * 3 polymorphisms) could significantly affect the PRI of CAD patients with or without percutaneous coronary intervention (PCI) in Chinese. A total of 43 miRNAs were differentially expressed in the platelets from the 22 extreme clopidogrel response samples, and 109 miRNAs were differentially expressed in the 13 CYP2C19 extensive metabolizers with extreme clopidogrel response. Platelet miR-199a-5p levels were correlated negatively with PRI after clopidogrel therapy. Studies in cultured cells revealed that miR-199a-5p inhibited the expression of VASP, a key effector protein downstream of the P2Y12 receptor. In conclusion, we found the expression of VASP could be inhibited by miR-199a-5p, and decreased platelet miR-199a-5p was associated with high on-clopidogrel platelet reactivity in CAD patients.

Diurnal Oscillations of Fibrinolytic Parameters in Patients with Acute Myocardial Infarction and Their Relation to Platelet Reactivity: Preliminary Insights

There is limited information about diurnal changes in fibrinolysis parameters after acute myocardial infarction (AMI) and their relationship with on-treatment platelet reactivity. The aim of this study was to assess tissue plasminogen activator (t-PA), plasminogen activator inhibitor type-1 (PAI-1), α2-antiplasmin (α2-AP) activity, and plasmin-antiplasmin (PAP) complexes in 30 AMI patients taking dual antiplatelet therapy (DAPT), i.e., acetylsalicylic acid and clopidogrel. Fibrinolytic parameters were assessed at four time points (6 a.m., 10 a.m., 2 p.m., and 7 p.m.) on the third day after AMI using immunoenzymatic methods. Moreover, platelet reactivity was measured using multiple-electrode aggregometry, to assess potential differences in fibrinolytic parameters in low/high on-aspirin platelet reactivity and low/high on-clopidogrel platelet reactivity subgroups of patients. We detected significant diurnal oscillations in t-PA and PAI-1 levels in the whole study group. However, PAP complexes and α2-AP activity were similar at the analyzed time points. Our study reveals a potential impact of DAPT on the time course of fibrinolytic parameters, especially regarding clopidogrel. We suggest the presence of diurnal variations in t-PA and PAI-1 concentrations in AMI patients, with the highest levels midmorning, regardless of platelet reactivity. Significantly elevated levels of PAI-1 during the evening hours in clopidogrel-resistant patients may increase the risk of thrombosis.

Time from blood draw to multiple electrode aggregometry and association with platelet reactivity

Results from multiple electrode aggregometry (MEA) may vary according to pre-analytic factors. This study aimed to analyze the association of time from blood draw to MEA in patients undergoing percutaneous coronary intervention (PCI). In this observational single-center cohort study, platelet aggregation (aggregation units, U) was quantified by MEA (Multiplate Analyzer) after stimulation with adenosine diphosphate (ADP; final concentration [Fc] 6.4 μM), thrombin receptor activating peptide (TRAP; Fc 32 μM), or arachidonic acid (AA; Fc 0.5 mM) in patients treated with ASA and clopidogrel following PCI. High on-clopidogrel platelet reactivity (HPR) was defined as ADP-induced platelet aggregation ≥ 46 U. The manufacturer recommends performing the analysis within 30–180 min after blood draw. Patients were grouped according to the time from blood draw to MEA: 30–180 min, < 30 min, or > 180 min. Platelet function of 273 patients with coronary artery disease undergoing PCI with dual antiplatelet therapy was analyzed. The median age was 72 years (interquartile range, IQR 62–79) and 179 (66%) were male. Median ADP-, TRAP-, and AA-induced aggregation was 25 (IQR 18–36) U, 79 (IQR 63–96) U, and 12 (IQR 7–18) U, respectively. For those analyzed within 30–180 min from blood draw, no significant correlation of time from blood draw to MEA was observed 1) ADP (r = − 0.04, p = 0.51); 2) TRAP (r = − 0.06, p = 0.32); 3) AA (r = − 0.03, p = 0.67). In patients undergoing percutaneous coronary intervention and treated with dual antiplatelet therapy, the time from blood draw to multiple electrode aggregometry does not correlate with ADP- induced aggregation when the measurement occurred within the recommended time interval of 30–180 min after blood draw.

Thrombelastography Compared with Multiple Impedance Aggregometry to Assess High On-Clopidogrel Reactivity in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

Background: High on-clopidogrel platelet reactivity (HPR) following percutaneous coronary intervention (PCI) is associated with increased ischemic risk. It is unclear whether conventional definitions of HPR apply to patients with concomitant oral anticoagulation (OAC). This study aimed to compare the performance of multiple platelet aggregometry (MEA) and thrombelastography (TEG) to detect HPR in patients with atrial fibrillation (AF) and indication for an OAC. Methods: In this observational single-center cohort study, MEA and TEG were performed in patients with AF with an indication for OAC on day 1 to 3 after PCI. The primary outcome was HPR as assessed by MEA (ADP area under the curve ≥ 46 units [U]) or TEG (MAADP ≥ 47 mm), respectively. The secondary exploratory outcomes were a composite of all-cause death, myocardial infarction (MI) or stroke and bleeding, as defined by the International Society on Thrombosis and Hemostasis, at 6 months. Results: Platelet function of 39 patients was analyzed. The median age was 78 (interquartile range [IQR] was 72–82) years. 25 (64%) patients were male, and 19 (49%) presented with acute coronary syndrome. All patients received acetylsalicylic acid and clopidogrel prior to PCI. Median (IQR) ADP-induced aggregation, MAADP, TRAP-induced aggregation, and MAthrombin were 9 (6–15) U, 50 (43–60) mm, 54 (35–77) U and 65 (60–67) mm, respectively. The rate of HPR was significantly higher if assessed by TEG compared with MEA (25 [64%] vs. 1 [3%]; p < 0.001). Within 6 months, four (10%) deaths, one (3%) MI and nine (23%) bleeding events occurred. Conclusion: In patients with AF undergoing PCI, the rates of HPR detected by TEG were significantly higher compared with MEA. Conventional cut-off values for HPR as proposed by consensus documents may need to be re-evaluated for this population at high ischemic and bleeding risk. Further studies are needed to assess the association with outcomes.

Impact of On-Clopidogrel Platelet Reactivity on Incidence of Peri-Interventional Bleeding in Patients Undergoing Transcatheter Aortic Valve Implantation.

Dual anti-platelet therapy (DAPT) with clopidogrel and acetylsalicylic acid (ASA) has previously been recommended after transcatheter aortic valve implantation (TAVI) and is still the standard of care in patients who underwent coronary stent placement within 3 months prior to TAVI. This study sought to evaluate whether on-treatment platelet reactivity is a predictor for the occurrence of bleeding events after TAVI. This study enrolled 484 patients undergoing TAVI from November 2013 until April 2018. Patients were either on long-term DAPT with clopidogrel and ASA or received loading doses of both drugs before TAVI, reflecting the standard of care at the time of the patient’s enrollment. Platelet reactivity was determined by multi-electrode impedance aggregometry before TAVI, at days 1 and 5 thereafter. Peri-interventional bleeding was assessed up to 5 days following TAVI and coded according to BARC-classification. Bleeding events were seen in 199 (41.1%) patients. The most frequent were BARC 2 bleeding cases (24.2%), followed by BARC 1 (6.0%), BARC 3b (5.2%), and BARC 3a (4.5%) cases. Low on-clopidogrel platelet reactivity before TAVI was present in 243 patients, of which 44.4% had a bleeding event. In contrast, the incidence of bleeding was 30.5% in the 95 patients with high on-clopidogrel platelet reactivity. Multivariate logistic regression analysis identified low/normal/high on-clopidogrel platelet reactivity (OR: 0.533; CI: 0.309–0.917; p = 0.023) and use of oral anticoagulation (OR: 1.766; CI: 1.209–2.581; p = 0.003) as strongest predictors for peri-interventional bleeding events. These findings support current recommendations advocating against the routine use of dual antiplatelet therapy following TAVI.

Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial

BackgroundHigh on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown. ObjectiveThe purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated. Design, participants and interventionThis was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone. Main outcome measuresThe primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3. ResultsA total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/μL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups. ConclusionSTDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only. Trial registrationThis study was registered on www.chictr.org.cn: ChiCTR-IPR-16009785.

Platelet Function and Genotype after DES Implantation in East Asian Patients: Rationale and Characteristics of the PTRG-DES Consortium.

PurposePlatelet function test (PFT) results and genotype hold unique prognostic implications in East Asian patients. The aim of the PTRG-DES (Platelet function and genoType-Related long-term proGnosis in Drug-Eluting Stent-treated Patients with coronary artery disease) consortium is to assess the clinical impact thereof on long-term clinical outcomes in Korean patients with coronary artery disease during dual antiplatelet therapy (DAPT) including clopidogrel.Materials and MethodsSearching publications on the PubMed, we reviewed clopidogrel treatment studies with PFT and/or genotype data for potential inclusion in this study. Lead investigators were invited to share PFT/genotype results, patient characteristics, and clinical outcomes to evaluate relationships among them.ResultsNine registries from 32 academic centers participated in the PTRG-DES consortium, contributing individual patient data from 13160 patients who underwent DES implantation between July 2003 and August 2018. The PTRG-PFT cohort was composed of 11714 patients with available VerifyNow assay results. Platelet reactivity levels reached 218±79 P2Y12 reaction units (PRU), and high on-clopidogrel platelet reactivity based on a consensus-recommended cutoff (PRU >208) was observed in 55.9%. The PTRG-Genotype cohort consisted of 8163 patients with candidate genotypes related with clopidogrel responsiveness. Of those with cytochrome P450 (CYP) 2C19 genotype, frequencies of carrying one and two loss-of-function allele (s) (*2 or *3) were 47.9% (intermediate metabolizers) and 14.2% (poor metabolizers), respectively.ConclusionThe PTRG-DES consortium highlights unique values for on-clopidogrel platelet reactivity and CYP2C19 phenotype that may be important to developing optimal antiplatelet regimens in East Asian patients.Trial RegistrationClinicalTrials.gov Identifier: NCT04734028.

Abstract 11448: Time from Blood Draw to Multiple Electrode Aggregometry and Association with On-Clopidogrel Platelet Reactivity

Background: Guidelines consider platelet function testing to guide dual antiplatelet therapy (DAPT) de-escalation in selected patients. On-clopidogrel platelet reactivity as measured by multiple electrode aggregometry (MEA) varies according to patients′ characteristics but may also depend on pre-analytic factors. Purpose: This study aimed to analyze the association of time from blood draw to MEA results in patients undergoing percutaneous coronary intervention (PCI). Methods: In this observational single center cohort study, in patients undergoing PCI, all patients received DAPT with ASA and clopidogrel. Platelet aggregation (aggregation units, U) was quantified by MEA (Multiplate Analyzer) after stimulation with adenosine diphosphate (ADP; 6.4 μM in patients treated with ASA and clopidogrel following PCI. High on-clopidogrel platelet aggregation (HPR) was defined as ≥46 U. The manufacturer recommends performing the analysis within 30-180 min after blood draw. Thus, patients were grouped according to the time from blood draw to MEA: 1) 30-180 min 2) &lt;30 min 3) &gt;180 min. Results: Platelet function of 273 patients with coronary artery disease undergoing PCI with DAPT were analyzed. The median age was 72 years (interquartile range, IQR 62-79) and 179 (66%) were male. Median ADP-induced aggregation was 25 (IQR 18-36) U. HPR was observed in 34 patients (12%). Median time to MEA was 65 (IQR 45-113) min and 245 measurements (90%) were performed within 30-180 min as recommend by the manufacturer of the aggregometer. Compared with measurements performed within the manufacturers′ recommendations (25 [IQR 18-36] U, median ADP-induced aggregation was not significantly different if performed outside these recommendations (&lt;30min: 24 [IQR 20-28] U, p=0.54; &gt;180min: 25 [IQR 21-40] U, p=0.31). For those analyzed within 30-180 min from blood draw, no relevant correlation of time from blood draw to MEA with ADP-induced platelet aggregation was observed (r= - 0.04; p=0.51). Conclusion: In patients undergoing percutaneous coronary intervention and treated with dual antiplatelet therapy, the time from blood draw to multiple electrode aggregometry does not correlate with ADP-induced aggregation.

Abstract 11338: On-Clopidogrel Platelet Reactivity in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention and Association with Patient Characteristics

Introduction: On-clopidogrel platelet reactivity (PR) is associated with thrombotic and bleeding risk in patients undergoing percutaneous coronary intervention (PCI). Patient-related factors affect the level of PR. Patients with atrial fibrillation (AF) undergoing PCI are treated concomitantly with oral anticoagulants (OAC) potentially interacting with platelet function. This study aimed to investigate the association of PR with demographic and clinical characteristics in these patients. Methods: In this single-centre prospective observational cohort study, patients with AF with an indication for OAC were enrolled during hospitalization after PCI with clopidogrel. TRAP- and ADP- induced PR (TRAP 32 μM, ADP 6.4 μM) were assessed by multiple electrode aggregometry. ADP-induced PR was normalized to TRAP-induced PR (r-ADP-agg). Results: 159 patients were enrolled between May 2020 and May 2021. The median age was 78 years (interquartile range, IQR 72-82), 112 (70%) were male and 39 (25%) presented with ACS. 68 (43%) presented with chronic kidney disease (CKD), defined as GFR&lt;60. 54 (34%) patients received apixaban, 6 (4%) dabigatran, 18 (11%) edoxaban, 74 (47%) rivaroxaban and 4 (3%) marcumar. 128 (81%) patients received clopidogrel loading. Median ADP-induced PR was 12 U (IQR 6-17); median r-ADP-agg was 24% (IQR 14-39). ADP-induced PA is significantly correlated with age (r=-0.22; p=0.035) and platelet count (r=0.22; p=0.006). Compared to the patients without CKD,patients with CKD had a significantly lower ADP-induced PA (median 8 [IQR 10] vs. median 13 [IQR 10]; p&lt;0.001) and r-ADP-agg. (median 20 [IQR 25] vs median 28 [IQR 24]; p=0.003).In a multivariable linear regression, ADP-induced PR was significantly associated with age (r=-0.177, CI:-0.481 to -0.018, p=0.035), immature platelet count (r=0.178, CI: 0.003 to 0.729, p=0.048), and diabetes mellitus (r=0.21, CI: 1.192 to 9.087, p=0.011). CKD was associated with both: lower ADP-PR (r=-0.262, CI:-9.962 to -2.396, p=-0.002) and lower r-ADP-agg (r=-0.253, CI:-9.962 to -2.396, p=0.003). Conclusions: In this patient cohort the association of on-clopidogrel PR as assessed by multiple electrode aggregometry with patient related factors was weak and most pronounced for chronic kidney disease.

Association of lipoprotein(a) with intrinsic and on-clopidogrel platelet reactivity

Lipoprotein(a) [Lp(a)] is an independent, genetically determined, and causal risk factor for cardiovascular disease. Laboratory data have suggested an interaction of Lp(a) with platelet function, potentially caused by its interaction with platelet receptors. So far, the potential association of Lp(a) with platelet activation and reactivity has not been proven in larger clinical cohorts. This study analyzed intrinsic platelet reactivity before loading with clopidogrel 600 mg and on-treatment platelet reactivity tested 24 h following loading in patients undergoing elective coronary angiography. Platelet reactivity was tested by optical aggregometry following stimulation with collagen or adenosine diphosphate as well as by flow cytometry. Lp(a) levels were directly measured in all patients from fresh samples. The present analysis included 1912 patients. Lp(a) levels ranged between 0 and 332 mg/dl. There was a significant association of rising levels of Lp(a) with a higher prevalence of a history of ischemic heart disease (p < 0.001) and more extensive coronary artery disease (p = 0.001). Results for intrinsic (p = 0.80) and on-clopidogrel platelet reactivity (p = 0.81) did not differ between quartiles of Lp(a) levels. Flow cytometry analyses of expression of different platelet surface proteins (CD41, CD62P or PAC-1) confirmed these findings. Correlation analyses of levels of Lp(a) with any of the tested platelet activation markers did not show any correlation. The present data do not support the hypothesis of an interaction of Lp(a) with platelet reactivity.

A Combination of Aspirin and Clopidogrel Predict More Favorable Dynamics of Platelet Reactivity versus Clopidogrel Alone in the Acute Phase of Minor Stroke.

Background: The combined use of clopidogrel and aspirin is recommended for the short-term (21 days) therapy of minor stroke or transient ischemic attack. Previous studies have demonstrated its efficacy and superiority over treatment with a single antiplatelet agent. However, there is insufficient support for the advantages of such therapy based on platelet function testing. We aimed to compare the effect of the concomitant use of clopidogrel and aspirin versus clopidogrel alone on the dynamics of platelet reactivity over time to determine the appropriate antiplatelet treatment strategy for minor strokes. Methods: We enrolled 74 ischemic stroke subjects, including 38 minor strokes. Platelet reactivity was assessed by impedance aggregometry (Multiplate Analyzer) 48 and 96 h after a first 75 mg dose of clopidogrel, using the acetylsalicylic acid platelet inhibition (ASPI) test and the adenosine diphosphate (ADP) test. Dual antiplatelet therapy was strictly reserved only to minor strokes, as the other strokes received clopidogrel alone in the secondary prevention. The dynamics of platelet reactivity refer to the difference between two assessments, and a decrease in values over time was considered favorable. Results: The incidence of clopidogrel non-responsiveness was 64.8%, and this was similar in the group of minor strokes and the group of more disabling strokes. We indicated diabetes mellitus as an independent predictor of high on-clopidogrel platelet reactivity (Odds ratio OR 5.69 95% Confidence Interval CI 1.13–41.26, p = 0.0386). Among minor strokes treated with dual antiplatelet therapy, in relation to clopidogrel, we reported a trend toward more favorable dynamics of platelet reactivity over time compared to the group using clopidogrel alone (p = 0.0652 vs. p = 0.3384, respectively). We identified five predictors (sex, female; small-vessel disease; no diabetes; no hyperlipidemia; and no alcohol abuse) related to a significant decrease in platelet reactivity over time with respect to clopidogrel. No significant dynamics of platelet reactivity when using aspirin were found. Conclusions: Our findings, based on the favorable dynamics of platelet reactivity over time in relation to clopidogrel, confirm the usefulness of dual antiplatelet therapy in minor strokes and support the continuation of the secondary prevention with clopidogrel alone rather than aspirin, particularly among identified beneficiaries of such a strategy.

Clinical significance of high on-treatment platelet reactivity in patients with prolonged clopidogrel therapy.

Background/AimsProlonged dual antiplatelet therapy (DAPT) with aspirin and clopidogrel beyond 1 year has been shown to reduce ischemic events at the expense of increased bleeding. However, limited data are available on the clinical significance of platelet reactivity (PR) at 1 year.MethodsWe retrospectively identified 331 patients who underwent percutaneous coronary intervention (PCI) and assessed the on-clopidogrel PR using VerifyNow P2Y12 assay at 1 year in a single center. Two hundred eleven patients were on DAPT for > 1 year. The relationship between high on-treatment platelet reactivity (HPR) at 1 year and clinical outcomes beyond 1 year, as well as the longitudinal change in PR was analyzed.ResultsAt 1 year, 135 (64%) patients showed HPR and 76 (36%) did not. There was a significant increase in ischemic endpoint events, including cardiovascular death, non-fatal myocardial infarction, and stroke/transient ischemic attack in patients with compared to without HPR at 1 year (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.06 to 6.77; p = 0.036). However, the incidence of any Bleeding Academic Research Consortium bleeding was significantly lower in the HPR group (HR, 0.11; 95% CI, 0.02 to 0.65; p = 0.015). In the longitudinal analysis, PR significantly decreased from post-load to 1 year after index PCI in the non-HPR group. Conversely, the HPR group showed high PR from baseline through 1 year.ConclusionsHPR at 1 year may be a useful surrogate for predicting ischemic and bleeding events in patients on prolonged DAPT. Patients with and without HPR at 1 year showed different patterns of longitudinal change in PR.

Impact of on-clopidogrel platelet reactivity on incidence of peri-interventional bleeding in patients undergoing transcatheter aortic valve implantation

Abstract Background Transcatheter aortic valve implantation (TAVI) has become clinical routine for patients at intermediate to high risk for surgical aortic valve replacement. The optimal antithrombotic strategy following TAVI is still not well defined. Antithrombotic treatment is administered to prevent hypo-attenuated leaflet thickening, valve thrombosis, or ischemic stroke. However, most of these patients are also at high risk for bleeding. Current guidelines recommend dual antiplatelet therapy although the clinical evidence is limited. Methods This analysis enrolled patients undergoing TAVI from 11/2013 until 04/2018. Patients were either on long-term dual antiplatelet therapy with clopidogrel and aspirin or received a loading dose 300 to 600mg of clopidogrel and 400mg aspirin before TAVI. Platelet reactivity was determined by multi-electrode impedance aggregometry after stimulation with arachidonic acid and adenosine diphosphate (ADP) before TAVI as well as at day 1 and 5 thereafter. Peri-interventional bleeding was assessed up to 5 days following TAVI and coded according to BARC-classification. Results The present analysis included 484 patients (median age 83 [79–86] years; female sex 54.5%). There were 199 (41.1%) patients with a bleeding event. Most frequent were BARC 2 bleedings in 117 (24.2%) cases followed by BARC 1 (6.0%), BARC 3b in 25 (5.2%) and BARC 3a in 22 (4.5%) cases. On-clopidogrel platelet reactivity tested after stimulation with ADP was significantly lower in patients with bleeding events as compared to patients without bleeding (Figure). No differences were observed in arachidonic acid-induced platelet reactivity as marker for aspirin-efficacy between both groups over time. Multivariate logistic regression analysis identified on-clopidogrel platelet reactivity and use of oral anticoagulation as strongest independent predictors for bleeding events. Conclusion On-clopidogrel platelet reactivity is an independent predictor for peri-interventional bleeding in patients undergoing TAVI. Taken together with previous data indicating no association of on-clopidogrel platelet reactivity with peri-interventional ischemic events, the present data question the need for a strong peri-interventional dual antiplatelet therapy in patients undergoing TAVI. Funding Acknowledgement Type of funding source: None

Association of Lipoprotein(a) levels with intrinsic and on-clopidogrel platelet reactivity

Abstract Background Lipoprotein(a) [Lp(a)] is an independent, genetic, and causal risk factor for premature cardiovascular disease (CVD). Laboratory data have suggested an interaction of Lp(a) with platelet function, potentially caused by its structural similarity to plasminogen. So far, the potential association of Lp(a) with platelet activation and reactivity has not been well established in larger clinical cohorts. Methods This secondary analysis of the EXCELSIOR study analyzed intrinsic platelet reactivity before loading with clopidogrel 600mg and on-treatment platelet reactivity tested 24 hours following loading in patients undergoing elective coronary angiography. Platelet reactivity was tested by optical aggregometry as final aggregation after 5 min following stimulation with 5μM ADP. Platelet reactivity was also assessed by flow cytometry (expression of CD62P and PAC1) following stimulation with ADP and TRAP. Levels of Lp(a) on admission of each patient were immediately measured from fresh samples in a central laboratory. Results The present analysis included 2046 patients. Levels of Lp(a) ranged between 0 and 332 mg/dl. Results for intrinsic (p=0.80) and on-clopidogrel platelet reactivity (p=0.81) did not differ between quartiles of Lp(a) levels (Figure). Flow cytometry analyses confirmed these findings. Conclusion The present data do not support the hypothesis of an interaction of Lp(a) with platelet function. This finding might be important to define the safety of evolving therapeutic options for lowering Lp(a). Funding Acknowledgement Type of funding source: None

Beta-amyloid and mitochondrial-derived peptide-c are additive predictors of adverse outcome to high-on-treatment platelet reactivity in type 2 diabetics with revascularized coronary artery disease

Abstract Background and aims Increased b-amyloid and decreased Mitochondrial-derived peptide (MOTS-c), are reported in diabetes. We investigated their additive value to high on-clopidogrel platelet reactivity (HPR) for adverse outcome in type 2 diabetics after recent revascularization. Patients and methods In 121 type II diabetics, treated with clopidogrel and aspirin, (93 males, mean age 67.2 years) we measured: a). maximum platelet aggregation to adenosine diphosphate (ADP) by Light Transmission Aggregometry (LTAmax), b) Malondialdehyde (MDA), as oxidative stress marker, c) MOTS-c, d) b-amyloid blood levels. Cardiac death and acute coronary syndromes (MACE) were recorded during 2 years of follow-up. Results Out of 121 patients, 32 showed HPR (LTAmax &amp;gt;48%,). At baseline, HPR was associated with b-amyloid &amp;gt;51 pg/ml (p=0.006) after adjusting clinical variables, HbA1c, MOTS-c, MDA and medication. During follow-up, 22 patients suffered a MACE. HPR, b-amyloid &amp;gt;51 pg/ml and MOTS-c&amp;lt;167 ng/ml were predictors of MACE (relative risk 3.1, 3.5 and 3.8 respectively, p&amp;lt;0.05) after adjusting for confounders and medication. There was significant interaction between HPR and b-amyloid or MOTS-c for the prediction of MACE (p&amp;lt;0.05). Patients with HPR and b-amyloid&amp;gt;51mg/dl or HPR and MOTS-c concentration&amp;lt;167 ng/ml had a 4-fold higher risk for MACE than patients without these predictors (relative risk 4.694 and 4.447 respectively p&amp;lt;0.01). The above results were confirmed in an external validation cohort of 90 patients with diabetes and CAD. Conclusions Increased b-amyloid or low MOTS-c are additive predictors to high on-clopidogrel platelet reactivity for adverse outcome in diabetics with CAD during 2-years follow- up. Funding Acknowledgement Type of funding source: None

Clopidogrel Dosing: Current Successes and Emerging Factors for Further Consideration

This review aimed to evaluate the clinical success of clopidogrel dosing based on CYP2C19 genotype and to identify the relevant additional factors that may be useful for consideration by the clinician when dosing individuals with clopidogrel. The results indicated that genotype-guided dosing in individuals with acute coronary syndrome undergoing percutaneous coronary intervention is frequently practiced, although the advantages remain controversial. Demographic factors, such as age, ethnicity, and some comorbidities, such as diabetes mellitus, can potentially contribute to further refinement of clopidogrel dosage but additional clinical studies to guide these practices are required. Drugs that are CYP2C19 or CYP3A4 inhibitors may reduce the effectiveness of clopidogrel and should be carefully considered during co-administration. In particular, as stated in the clopidogrel label, concomitant use with strong or moderate CYP2C19 inhibitors, such as omeprazole, should be avoided. Increased exposure and response to clopidogrel has been observed in smokers. Noteworthy, a very recent study has shown that smoking cessation in clopidogrel patients may result in reduced response and carries the risk of high on-clopidogrel platelet reactivity. Recent studies have shown clinically significant increases in exposure to CYP2C8 substrates (repaglinide, dasabuvir, and desloratadine) and a CYP2B6 substrate (s-sibutramine) following co-administration with clopidogrel, indicating that therapeutic strategies with clopidogrel should avoid these drugs.

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss‐of‐function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate‐induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e−33). After correction for CYP2C19*2 no other single‐nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e−09, 4.53e−08, and 2.60e−10, respectively). CYP2C19*2 is the strongest genetic determinant of on‐clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.

High on-clopidogrel platelet reactivity in ischaemic stroke or transient ischaemic attack: Systematic review and meta-analysis

ObjectivesTo assess the prevalence of high on-clopidogrel platelet reactivity (HCPR) in patients with ischaemic stroke or transient ischaemic attack (IS/TIA), their outcome and genetic basis of on-treatment response variability in IS/TIA patients. MethodsWe conducted a comprehensive search of PubMed and EMBASE from their inceptions to March 9, 2019. Studies that reported absolute numbers/percentages of HCRP at any time point after IS/TIA onset evaluated with any type of platelet function tests, clinical outcomes and genotyping data were included. ResultsAmong 21 studies of 4312 IS/TIA patients treated with clopidogrel, the pooled prevalence of HCPR was 28% (95%CI: 24–32%; high heterogeneity: I2 = 88.2%, p < 0.001). Heterogeneity degree diminished across groups defined by the HCPR testing method. Clopidogrel non-responder IS/TIA patients had poorer outcome compared to responders (RR = 2.09, 95%CI: 1.61–2.70; p = 0.036; low heterogeneity across studies: I2 = 27.4%, p = 0.210). IS/TIA carriers of CYP2C19*2 or CYP2C19*3 loss of function alleles had a higher risk of HCPR compared to wild type (RR = 1.69, 95%CI: 1.47–1.95; p < 0.001; I2 = 0.01%, p = 0.475). ConclusionsThis systematic review shows a high prevalence of clopidogrel resistance in IS/TIA and poor outcome in these patients. CYP2C19 polymorphisms may potentially influence clopidogrel resistance.