Vitamin D levels and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor

Background: Suboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCIs). However, very few are known so far on the predictors of high-residual platelet reactivity (HRPR) despite antiplatelet strategies. Increasing attention has been paid in the last years to the role of vitamin D in atherothrombosis. Therefore, the aim of our study was to evaluate the impact of vitamin D levels on platelet function in patients treated with dual antiplatelet therapy (DAPT). Patients treated with DAPT (ASA and clopidogrel or ticagrelor) after a recent acute coronary syndrome (ACS) or elective PCI were scheduled for platelet function assessment at 30–90 days post-discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate®-Roche Diagnostics AG), HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values ≥417 AU*min (for ADP-antagonists). Fasting samples were obtained for main chemistry parameters and vitamin D level assessment.

Our population is represented by 503 patients, who were divided according to vitamin D quartiles (≤9.1; 9.2–14.4; 14.5–21.7; >21.7 ng/ml). Lower vitamin D levels related with age (p = 0.04), diabetic status (p = 0.05), and previous coronary surgery (p = 0.007), therapy with beta-blockers and statins (p = 0.01 and p = 0.02). Vitamin D inversely related to the levels of total cholesterol (p = 0.01), triglycerides (p < 0.001), hemoglobin (p = 0.05), and HbA1c (p < 0.001). Significantly higher platelet reactivity was observed after platelet stimulation with ADP (p = 0.01), but not with other platelet activators. The prevalence of HRPR for ASA was low (1.2%) and not conditioned by Vitamin D levels (adjusted OR[95%CI] = 1.56[0.71–3.5], p = 0.27). HRPR with ADP-antagonists was observed in 26% of patients, and the rate increased with lower vitamin D quartiles (37.3% vs 22.2% vs 24.4% vs 20.2%, p = 0.005, adjusted OR[95%CI] = 1.23[1.02–1.49], p = 0.04).

An absolute increase in HRPR with lower vitamin D levels was similarly observed among patients receiving ticagrelor (adjusted OR[95% CI] = 1.40[0.95–2.06], p = 0.08), and those on clopidogrel (adjusted OR[95%CI] = 1.31[0.99–1.75], p = 0.06).

Thus, lower vitamin D levels are associated with higher platelet reactivity and impaired effectiveness of ADP-antagonists, while not influencing the effectiveness of ASA. Future studies will tell whether vitamin D supplementation can reduce platelet reactivity, overcoming the phenomenon of resistance to antiplatelet agents.     

Ticagrelor versus prasugrel in patients with high on-clopidogrel treatment platelet reactivity after PCI: The ISAR-ADAPT-PF study

Patients with high on-treatment platelet reactivity (HTPR) on clopidogrel are at high risk for adverse cardiovascular events after percutaneous coronary intervention (PCI). The aim of the ISAR-ADAPT-PF study was to assess the antiplatelet efficacy of ticagrelor versus prasugrel in patients with HTPR on clopidogrel. In a prospective and randomized clinical study, 70 patients with HTPR on clopidogrel loading dose (LD) within 24 h post PCI were assigned to receive either ticagrelor [180 mg LD followed by 90 mg maintenance dose (MD) twice daily] or prasugrel (60 mg LD followed by 10 mg MD once daily). The adenosine diphosphate-induced platelet aggregation assessed on the Multiplate analyzer on day 2 after randomization (primary end point) was as follows: the mean difference between the two treatment groups was 6 aggregation units (AU) × min with an upper 95% confidence interval (CI) of 41 AU × min, which was greater than the predefined noninferiority margin of 18 AU × min (P for noninferiority = 0.29). However, no significant differences in absolute platelet reactivity levels between ticagrelor- versus prasugrel-treated patients at that time point were observed (138 ± 100 AU × min vs. 132 ± 64 AU × min, P for superiority = 0.77). In conclusion, neither drug was statistically more effective for inhibition of platelet aggregation in patients with HTPR on clopidogrel post PCI, although the study could not formally demonstrate the assumed noninferiority of ticagrelor versus prasugrel.     

Individual long-term variation of platelet reactivity in patients with dual antiplatelet therapy after myocardial infarction

There is a large inter-individual variation in response to clopidogrel treatment, and previous studies have indicated higher risk of thrombotic events in those with high residual platelet reactivity (HPR). Less is known about individual variation over time. The aim of this prospective cohort study was to investigate intra-individual variation in platelet reactivity. Platelet aggregation in whole blood was assessed in 77 patients, at 3 days, 8 days and 6 months after admission for acute myocardial infarction and loading dose of clopidogrel. All patients were treated with aspirin and clopidogrel through 6-month follow-up. We found a significant increase in median ADP-stimulated aggregation from third to eighth day (195 vs. 250 AU*min, p-value = 0.001) but not from day 8 to 6 months (250 vs. 223 AU*min, p-value = 0.666). There was no significant change in the overall rate of HPR (15.6% vs 20.8%, p-value 0.503) or low platelet reactivity (LPR) (37.7% vs 33.8%, p-value = 0.609) from day 8 to 6-month follow-up. In contrast, more than one in four changed HPR status, 15.6% from non-HPR to HPR and 10.4% HPR to non-HPR. A shift in LPR status appeared even more frequent, occurring in about one of three patients. In spite of similar median aggregation and rate of HPR during 6-month follow-up, about one in four of the patients changed HPR status and one in three changed LPR status. This may be important information for a concept of risk stratification based on a single aggregation value early after an acute coronary syndromes.     

低剂量替格瑞洛在冠状动脉慢性完全闭塞性病变PCI后抗血小板治疗的有效性及安全性研究

目的比较小剂量替格瑞洛(120 mg负荷量,序贯60 mg 2/d,口服)与常规剂量氯吡格雷(300 mg负荷量,序贯75 mg 1/d,口服)在冠状动脉慢性完全闭塞性病变(CTO)患者经皮冠状动脉介入治疗(PCI)后抗血小板治疗的有效性与安全性。方法研究共入选357例成功接受PCI的CTO患者,随机分为两组:接受小剂量替格瑞洛组175例和接受氯吡格雷治疗组182例,详细记录患者住院期间及随访1年的主要不良心脑血管事件(MACCE)与出血事件。结果低剂量替格瑞洛组在住院期间MACCE与标准剂量氯吡格雷组无显著差异(2.3%vs.4.4%,P=0.381)。住院期间低剂量替格瑞洛组小出血风险显著低于标准剂量氯吡格雷组(2.3%vs.7.7%,P=0.027),大出血方面均无显著差异(0.6%vs.0.5%,P=1.00)。随访至1年,低剂量替格瑞洛组MACCE显著低于标准剂量氯吡格雷组(2.3%vs.7.1%,P=0.045),其中靶血管再次血运重建(TVR)比例显著低于标准剂量氯吡格雷组(5.1%vs.11.5%,P=0.035)。Kaplan-Meier生存分析显示低剂量替格瑞洛组1年无MACCE生存率显著高于标准剂量氯吡格雷组(P=0.005)。随访至1年,低剂量替格瑞洛组小出血风险显著低于标准剂量氯吡格雷组(4.6%vs.11.0%,P=0.030),大出血方面均无显著差异(1.1%vs.2.2%,P=0.685)。结论中国人CTO患者PCI后接受小剂量替格瑞洛较常规剂量氯吡格雷,可显著降低TVR和复合MACCE事件,同时降低小出血风险。     

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

Abstract

Managing bleeding in patients receiving P2Y₁₂ inhibitors is challenging. Few data are available regarding the efficacy of platelet transfusion in patients treated with prasugrel or ticagrelor. The aim of this study was to evaluate the minimal amount of platelet supplementation (in terms of ratio of non-inhibited platelets to inhibited platelets) necessary to restore platelet reactivity in platelet-rich plasma (PRP) of patients treated with aspirin and a prasugrel or ticagrelor loading dose for an acute coronary syndrome. PRP samples from patients were mixed ex vivo with increasing proportions of pooled PRP from healthy volunteers. Platelet reactivity was challenged with adenosine diphosphate (ADP), arachidonic acid, collagen or thrombin receptor activating peptide using light transmission aggregometry. The primary endpoint was the proportion of patient samples recovering an ADP-induced maximal aggregation (ADP-Agg_max) value above 40%. In patients treated with prasugrel (n?=?32), ADP-Agg_max increased progressively with supplements of pooled PRP, with an average increase of 7.9% (95% CI [7.1; 8.8], p?<?0.001) per each 20% increase in the ratio of non-inhibited platelets to inhibited platelets. A ratio of 60% was associated with 90% of patients reaching the primary endpoint. In patients treated with ticagrelor (n?=?15), ADP-Agg_max did not significantly increase with any level of supplements. In conclusions, ex vivo addition of non-inhibited platelets significantly improved ADP-Agg_max in patients treated with prasugrel with a dose-dependent effect. There was no evidence of such a reversal in patients treated with ticagrelor. These results suggest that platelet transfusion may be more effective in blunting bleeding in patients treated with prasugrel, than those treated with ticagrelor.     

Evidence of platelet sensitization to ADP following discontinuation of clopidogrel therapy in patients with stable coronary artery disease

Epidemiological studies have linked clopidogrel discontinuation with an increased incidence of ischemic events. This has led to the hypothesis that clopidogrel discontinuation may result in a pharmacological rebound. We evaluated the impact of clopidogrel discontinuation on platelet function. Platelet aggregation was measured by light transmission aggregometry (LTA) in response to adenosine diphosphate (ADP) 0.5, 1, 1.5, 2.5, 5 and 10?µM and by VerifyNow® P2Y₁₂, in 37 clinically stable coronary artery disease (CAD) patients scheduled to discontinue clopidogrel treatment, and 37 clinically stable CAD patients not taking clopidogrel. Platelet function was assessed the day before clopidogrel cessation and 1, 3, 7, 14, 21 and 28 days after. Clopidogrel had been initiated a median of 555 days (ranging from 200 to 2280 days) before the treating cardiologist recommended its discontinuation. All participants were taking aspirin, most commonly 80?mg daily although a minority was prescribed 325?mg daily. Following clopidogrel discontinuation, VerifyNow® P2Y₁₂ did not detect any rebound platelet activity, but ADP-induced LTA showed platelet sensitization to ADP, particularly at low ADP levels. Increased platelet activity was detectable seven days after clopidogrel cessation and remained higher than in controls 28 days after discontinuation. No clinical event occurred in any of the participants during the 28 days following clopidogrel cessation. In conclusion, platelet sensitization to ADP as a consequence of chronic clopidogrel administration may partially explain the recrudescence of ischemic events following clopidogrel discontinuation in otherwise stable coronary artery patients.     

Differences in platelet aggregation in coronary sinus and aortic blood in patients with coronary artery disease: Effect of propranolol

Platelet aggregation was studied in aortic and coronary sinus blood samples obtained from 18 patients with coronary artery disease (CAD). Using epinephrine and ADP as aggregating agents, platelet aggregation was lower in coronary venous blood than in aortic blood. In nine patients on long-term propranolol therapy, platelet aggregation was lower in both aortic and coronary venous blood compared to the nine patients not taking propranolol. Four other subjects without angiographic evidence of coronary disease exhibited no difference in platelet aggregation in aortic and coronary sinus blood. These data suggest that platelet aggregation is lower in the coronary venous blood of certain patients with coronary disease and chronic propranolol treatment may reduce aggregation in both aortic and coronary sinus blood.     

Dynamic platelet adhesion in patients with an acute coronary syndrome: The effect of antiplatelet therapy

Platelet adhesion and aggregation are key functions leading to thrombus formation. The effect of aspirin, clopidogrel, and ticagrelor on platelet aggregation has been well established, however, there is limited data on the effect of these drugs on platelet adhesion. We therefore evaluated the effect of these drugs on platelet adhesion in acute coronary syndrome (ACS) patients. Citrated blood was collected from 50 ACS patients loaded with 325 mg of aspirin (baseline) and at 5 days after the administration of aspirin 100 mg/day and clopidogrel (600 mg loading dose, 75 mg/day) (n = 26) or ticagrelor (180 mg loading dose, 90 mg × 2/day) (n = 24). High on-treatment platelet reactivity (HTPR) to clopidogrel was estimated by vasodilator stimulated phosphoprotein (VASP) phosphorylation assay. Platelet adhesion to collagen was studied for 6 min under high shear stress and was evaluated using the time to platelet recruitment (TPR), the perimeter and average area of each adherent object, number of adherent objects, and the total percent of surface coverage (SC%). Six ACS patients exhibited HTPR to clopidogrel and excluded from the platelet adhesion assays. TPR and SC% values were similar among patient groups at baseline and controls. However, all other adhesion parameters were different in ACS patients, indicating the formation of more aggregates in regard to controls. At 5 days post-treatment with either clopidogrel or ticagrelor, the TPR values were increased and the SC% values were reduced to a similar extent compared with baseline. However, significant differences were observed in the ticagrelor group in the perimeter, number of adherent objects, and the average area of each adherent object indicating a more potent inhibition of adherence-induced platelet aggregation than clopidogrel. In conclusion, aspirin does not affect platelet adherence to collagen, whereas clopidogrel and ticagrelor inhibit to a similar extent dynamic platelet adhesion at 5 days post-treatment in ACS patients. However, ticagrelor exhibits a greater inhibitory effect on reducing adhesion-induced platelet aggregation.     

Association between plasma inflammatory markers and morphology of coronary artery lesion in patients with coronary artery disease

The atherosclerotic plaque vulnerability may be related to inflammation,immunity,metabolism and blood clotting.One of the key factors affecting plaque stability is inflammatory reaction.This study was to investigate the relationship between vulnerability of coronary artery plaque evaluated with coronary angiography (CAG),intravascular ultrasound (IVUS) and the levels of plasma inflammatory markers.Methods Fifty-eight consecutive patients with acute coronary syndrome who had coronary lesion of a single vessel were divided into 3 groups based on angiographic morphology of the lesions:type Ⅰ lesion group (n =16),type Ⅱ lesion group (n =25) and type Ⅲ lesion group (n =17).The control group consisted of 17 patients with stable angina.Plasma levels of high sensitivity C reaction protein (hs-CRP),matrix metalloproteinase (MMP,including MMP-2 and MMP-9),CD40 ligand (CD40L) and pregnancy associated plasma protein-A (PAPP-A) were measured by ELISA.A subgroup of 28 patients (including 18 ACS patients and 10 stable angina control patients) who underwent IVUS study,were analyzed.Results The plasma levels of MMP-2,MMP-9 and PAPP-A in type Ⅱ lesion group were significantly higher than those in other groups (all P＜0.05).In type Ⅱ lesion group,linear correlation analyses showed significant positive correlation between levels of hs-CRP and MMP-2 (r=0.508);MMP-2 and MMP-9,CD40L,PAPP-A (r=0.647,0.704 and 0.751,respectively);MMP-9 and CD40L,PAPP-A (r=0.491 and 0.639,respectively);CD40L and PAPP-A (r=0.896).IVUS subgroup analysis showed that the area of plaques and plaque burden in culprit lesion,the incidence of high-risk plaques,remodeling index (RI) and positive remodeling percentage in ACS patients were significantly greater than those in control subgroup (P=0.000,0.037,0.028,0.015 and 0.040,respectively).Compared with control subgroup,the plasma levels of hs-CRP,MMP-2,MMP-9 and PAPP-A were markedly elevated (P=0.033,0.000,0.000 and 0.027,respectively).Conclusions CAG and IVUS combined with study on plasma levels of inflammation mediators are helpful in judging the vulnerability of coronary artery plaques.(J Geriatr Cardiol 2008;5:207-211)     

Homocysteine levels and platelet reactivity in coronary artery disease patients treated with ticagrelor

Background and aimRecurrent atherothrombotic events have been reported in certain higher risk subsets of patients even with ticagrelor, a potent first-line antiplatelet agent for the management of patients with acute coronary syndrome (ACS). Hyperhomocysteinemia is a known determinant of platelet function abnormalities. Therefore, the aim of our study was to evaluate the impact of homocysteine (Hcy) levels on platelet reactivity in patients receiving Ticagrelor.Methods and resultsPatients with ACS undergoing percutaneous coronary revascularization and on dual antiplatelet therapy with ASA + Ticagrelor (90mg/twice a day) were scheduled for platelet function assessment 30–90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min).We included 432 patients, divided according to Hcy tertiles. Higher Hcy levels were associated with age, renal failure, creatinine levels and use diuretics (p < 0.001).Patients with higher Hcy levels displayed a higher platelet reactivity at COL test (p = 0.002), and ADP test (p = 0.04), with a linear relationship between Hcy and platelet aggregation after stimulation with collagen (r = 0.202, p < 0.001), thrombin receptor peptide (r = 0.104, p = 0.05) and ADP (r = 0.145, p = 0.006).However, Hcy levels did not significantly affect the rate of HRPR with Ticagrelor (9.9% vs 13.7% vs 10.7%, p = 0.89; adjusted OR [95% CI] = [0.616–1.51], p = 0.99).ConclusionsAmong patients with ACS, despite the elevated platelet reactivity associated to hyperhomocysteinemia, DAPT with ticagrelor could overcome such phenomenon, achieving an adequate platelet inhibition in the majority of the patients.     

老年与中年急性冠脉综合征患者不同双联抗血小板方案疗效与出血风险比较

目的比较≥75岁老年急性冠脉综合征(ACS)患者与60岁中年ACS患者"阿司匹林+替格瑞洛"与"阿司匹林+氯吡格雷"两种双联抗血小板治疗(DAPT)方案的疗效与出血风险。方法连续入选2014年3月至2015年5月于解放军总医院心血管内科住院治疗的ACS患者、年龄60岁及≥75岁,并进行血栓弹力图(T7EG)检查的患者416例,分为:(1)年龄60岁阿司匹林+氯吡格雷(60C组),(2)年龄≥75岁阿司匹林+氯吡格雷(≥75C组),(3)年龄60岁阿司匹林+替格瑞洛(60T组),(4)年龄≥75岁阿司匹林+替格瑞洛(≥75T组),随访1年,比较各组主要不良心血管事件(MACE)及出血情况。结果各组MACE事件发生率、TEG检测的最大振幅(MA)值、花生四烯酸抑制率(AA-IPA)差异均无统计学意义(P0.05);相同年龄段"阿司匹林+替格瑞洛"患者二磷酸腺苷抑制率(ADP-IPA)高于"阿司匹林+氯吡格雷"(P0.05),但"阿司匹林+替格瑞洛"在两个年龄段的ADP-IPA差异无统计学意义(P=0.828),≥75C组ADP-IPA较60C组低(P=0.011);相同年龄段"阿司匹林+替格瑞洛"患者出血事件发生率高于"阿司匹林+氯吡格雷"患者(P0.05),但多为I型非致命性出血;"阿司匹林+替格瑞洛"在不同年龄段出血事件发生率差异无统计学意义(P=0.392)。应用Cox回归分析MACE危险因素:血糖(B=0.111,RR=1.117,95%CI:1.014~1.231,P=0.025),eGFR(B=-0.023,RR=0.977,95%CI:0.961~0.993,P=0.005),心率(B=0.040,RR=1.041,95%CI:1.013~1.070,P=0.004)。应用logistic回归分析出血事件危险因素:DAPT方案(B=3.527,OR=34.025,95%CI:9.560~121.101,P0.001),性别(B=1.126,OR=3.085,95%CI:1.083~8.788,P=0.035)。结论在本研究中"阿司匹林+替格瑞洛"的临床疗效不优于"阿司匹林+氯吡格雷",且I型出血风险增高;中、老年人口服"阿司匹林+替格瑞洛"的出血风险无差异。     

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

Residual high on-treatment platelet reactivity (HTPR) despite dual antiplatelet therapy (DAPT) has emerged as a predictor of major ischemic events in patients undergoing percutaneous coronary interventions (PCIs), especially after an acute cardiovascular event. However, its determinants are still poorly defined. Therefore, the aim of the present study was to evaluate the role of the percentage of reticulated platelets on HTPR in patients on DAPT with ASA (100–160 mg) and prasugrel (10 mg).

Platelet reactivity and the reticulated platelets fraction (immature platelets fraction [IPF]) were assessed at 30–90 days after an acute coronary syndrome. Aggregation was assessed by multiple-electrode aggregometry. HTPR was defined as ADP test > 417 AU × min.

Our population is represented by 180 ACS patients undergoing stent implantation, divided according to median values of IPF (< or ≥ 2.8%). Higher IPF values were associated to lower platelet count (p < 0.001) and a higher rate of active smokers (p = 0.02). No difference was observed in terms of mean platelet reactivity, with different activating stimuli. The prevalence of HTPR on prasugrel did not significantly differ in patients with IPF < or ≥ 2.8% (8%vs. 11.8%, p = 0.46; adjusted OR [95% CI] = 1.89 [0.66–5.4], p = 0.24).

Our study showed that in patients treated with prasugrel after PCI for ACS, the immature platelet fraction influences neither platelet reactivity nor the rate of HTPR.     

血小板微小RNA-223和微小RNA-21对冠心病患者经皮冠状动脉介入治疗后氯吡格雷抵抗的预测价值

目的探讨血小板微小RNA(miR)-223和miR-21对冠心病患者经皮冠状动脉介入治疗(PCI)后氯吡格雷抵抗的预测价值。方法根据血小板抑制率,将119例行PCI的冠心病患者分为氯吡格雷反应正常组(正常组)67例和氯吡格雷抵抗组(抵抗组)52例。比较两组患者的血小板miR-23和miR-21水平。采用多元logistic回归分析评估发生氯吡格雷抵抗的影响因素。采用Pearson相关分析评估血小板miR-223、miR-21水平与血小板抑制率的相关性。采用受试者工作特征(ROC)曲线评估血小板miR-223和miR-21水平对发生氯吡格雷抵抗的预测价值。结果抵抗组患者血小板miR-223和miR-21水平高于正常组(P<0.05)。多元logistic回归分析结果显示,血小板miR-223和miR-21水平升高是冠心病患者PCI后发生氯吡格雷抵抗的独立危险因素(P<0.05)。Pearson相关分析结果显示,行PCI的冠心病患者血小板miR-223和miR-21水平与血小板抑制率均呈负相关(P<0.05)。血小板miR-223和miR-21预测冠心病患者PCI后发生氯吡格雷抵抗的ROC曲线下面积(AUC)分别为0.69(95%CI 0.53~0.78)、0.64(95%CI 0.51~0.69);血小板miR-223联合miR-21的AUC为0.85(95%CI 0.77~0.94)。结论PCI后发生氯吡格雷抵抗的冠心病患者血小板miR-223和miR-21水平升高,且与血小板抑制率呈负相关,可用于预测氯吡格雷抵抗的发生风险。     

替格瑞洛对不稳定型心绞痛患者经皮冠状动脉介入术围手术期血小板反应性及短期预后的影响

目的探讨替格瑞洛对不稳定型心绞痛患者经皮冠状动脉介入术(PCI)围手术期血小板反应性及短期预后的影响。方法入选不稳定型心绞痛患者424例,随机分为2组:(1)替格瑞洛组(n=212):给予替格瑞洛治疗(负荷剂量180 mg,维持剂量90 mg,每天2次,口服);(2)氯吡格雷组(n=212):给予氯吡格雷治疗(负荷剂量300 mg,维持剂量75 mg,每天1次,口服)。2组均成功接受PCI术,支架均选择国产Firebird雷帕霉素药物洗脱支架。观察2组患者PCI术围手术期血小板反应性及心肌损伤标志物心肌肌钙蛋白I(cTnI)及PCI术后90天不良事件发生情况。结果 2组患者PCI术后cTnI水平比较差异无统计学意义(P0.05)。替格瑞洛组患者花生四烯酸及二磷酸腺苷诱导的血小板聚集率均低于氯吡格雷组(P0.05);替格瑞洛组患者二磷酸腺苷诱导的血小板高反应性比例低于氯吡格雷组(P0.05)。替格瑞洛组PCI术后90天内患者再发心肌缺血发生率低于氯吡格雷组(5.19%比16.04%,P0.05)。出血事件两组比较差异无统计学意义(P0.05)。结论替格瑞洛并不降低PCI术后心肌损伤的发生,但较氯吡格雷能发挥更强的抗血小板作用,减少术后再发心肌缺血事件发生率,并不增加出血风险。     

Platelet reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor in comparison to clopidogrel: a retrospective pharmacodynamic analysis

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor is a mainstay of the prevention of stent thrombosis following percutaneous coronary intervention (PCI). In the 2015 European guidelines for the management of acute coronary syndrome (ACS), prasugrel (PRA) and ticagrelor (TICA) combined with aspirin are recommended as first-line therapy. Clopidogrel (CLO) is recommended as an alternative medication for patients with contradictions to these new drugs.

This single-center study analyzed the platelet function of 809 ACS patients undergoing PCI and treatment with DAPT. The platelet response to ADP was determined using Multiplate® analyzer at a median of 3 days after PCI in 254 patients treated with PRA (loading dose [LD] 60 mg, 10 mg qd), 162 patients receiving TICA (LD 180 mg, D 90 mg bid), and 393 CLO-treated patients (LD 600 mg, 75 mg qd). An aggregation >468 arbitrary units (AU)*min was defined as “high on-treatment platelet reactivity” (HPR), <188 AU*min as “low on-treatment platelet reactivity” (LPR).

Platelet response in PRA-treated patients was lower compared to CLO or TICA (median; interquartile range: PRA 220 [163–275] AU*min vs. CLO 268 [186–387] AU*min, p < 0.001 vs. TICA 245 [190–320] AU*min, p = 0.001). Only 1.6% of PRA patients were stratified as HPR and 34.6% as LPR, while in the TICA group 1.9% fulfilled the criteria of HPR and 24.1% criteria of LPR. Sixteen percent of CLO patients were stratified as HPR and 26.2% as LPR.

In a real-world cohort of ACS patients following PCI, PRA results in more potent inhibition of platelet function compared to CLO and TICA. TICA achieves a consistent antiplatelet effect with reduced rates of HPR and LPR in relation to CLO.     

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.     

Intra-individual variability in clopidogrel responsiveness in coronary artery disease patients under long term therapy

Clopidogrel responsiveness (CR) following a loading dose (LD) predicts thrombotic events after percutaneous coronary interventions (PCI). Some of the mechanisms involved in large inter-individual variability in CR may be varied. We therefore postulated that there may be an intra-individual variability in CR. Two hundred and one patients receiving long-term therapy with aspirin and clopidogrel after drug-eluting stents PCI were prospectively included in this monocentre study along with any patient re-admitted within 12 months post-PCI. Platelet reactivity (PR) inhibition was assessed by the vasodilator phosphoprotein (VASP) index following a 600 mg loading dose of clopidogrel on each admission to determine CR (VASP 1 during the first admission and VASP 2 during re-admission). DeltaVASP = VASP 2 –VASP 1 was used to study intra-individual variability in CR. We observed that the response to a 600 mg LD of clopidogrel was poorly correlated within an individual (kappa = 0.33; p < 0.001 (n = 201)). Although most patients had increased platelet inhibition at the time of readmission, 35.3% of patients exhibited a decreased platelet inhibition despite chronic clopidogrel therapy and a 600 mg reload. Quartiles analysis of DeltaVASP demonstrated that insulin-treated diabetes was associated with decreased CR over time (p = 0.03). In addition to the large inter-individual variability in clopidogrel responsiveness, there is large intra-individual variability. Decreased clopidogrel responsiveness despite long-term clopidogrel therapy could be a trigger for recurrent thrombotic events.