BACKGROUND & AIMS: AIMS:Dual antiplatelet treatment (DAPT) is a cornerstone in the treatment of acute coronary syndrome (ACS) but the optimal treatment duration is unclear. We aimed to evaluate the effect of DAPT duration with clopidogrel and aspirin on the recurrence of ischaemic events and bleeding in a large, unselected ACS population. METHODS AND RESULTS:We performed a prospective, observational cohort study of patients in Sweden (n = 56 440) admitted for ACS, with prescribed DAPT and hospitalized between January 2006 and July 2010. Patients were obtained from the SWEDEHEART register and data were merged with registers from the National Board of Health and Welfare. Depending on dispensed clopidogrel tablets, patients were divided into groups based on DAPT duration with clopidogrel and aspirin (3 months: 84-100 clopidogrel tablets (t); >3 months: >100 t; 6 months: 168-200 t; >6 months: >200 t). For the combined primary endpoint, defined as all-cause death, stroke, or re-infarction, only patients with an uneventful first 3-month period (no death, stroke, re-infarction, bleeding, stent thrombosis, or revascularization) were included. The incidence of the primary endpoint was 45 events per 1000 person-years in the >3 months DAPT group compared with 65 events per 1000 person-years in the 3 months DAPT group [adjusted HR 0.84, 95% CI (0.75; 0.95)]. Bleeding was more common in the >3 months treatment group (adjusted HR 1.56, 95% CI (1.18; 2.07), but the number of events was small. For >6 vs. 6 months DAPT, the adjusted HR for the combined endpoint was 0.75 with 95% CI (0.59; 0.95). CONCLUSION:In this contemporary, large real-life ACS population, DAPT for more than 3 months compared with a shorter duration was associated with a lower risk of death, stroke, or re-infarction. TRIAL REGISTRATION:Clinicaltrials.gov (NCT01623700).

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Aspirin has been associated with adverse heart failure outcomes, probably because of a blunting interaction with angiotensin-converting enzyme (ACE) inhibitors. Therefore, we hypothesized that clopidogrel when compared with aspirin would be associated with a slower progression of heart failure as determined by levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS:In an open-label, randomized, 2-treatment, 2-period crossover study, 18 patients with ischemic heart failure (14 post-myocardial infarction, left ventricular ejection fraction 0.32 +/- 0.08), median age 73, New York Heart Association class II (11 patients) or III (7 patients), all taking ACE inhibitors were included. Patients were randomized to 8 weeks of aspirin 100 mg/day followed by 8 weeks of clopidogrel 75 mg/day, or the reversed sequence. Blood levels of NT-proBNP were measured using sandwich immunoassay. Patients on aspirin experienced an 8-times greater increase in log-transformed values of NT-proBNP compared with patients on clopidogrel (average change 4.757% versus 0.597%; P = .0395 for intervention, P = .4453 for period, P = .4046 for sequence). We observed no change in functional class, 6-minute walking test, creatinine levels, or electrolytes. CONCLUSION:Aspirin is associated with a greater increase in natriuretic peptides (log-transformed NT-proBNP levels), implying that aspirin therapy is associated with a more progressive course of heart failure.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:The interaction among inflammation, Hemostasis, and fibrinolysis plays a major role in the genesis of coronary artery disease (CAD). The aim of the study was to compare the effect of clopidogrel plus aspirin versus aspirin alone on cellular adhesion molecules on leukocytes, soluble adhesion molecules, and molecular markers of coagulation and fibrinolysis in patients with CAD. METHODS:In this randomized, placebo-controlled, and double-blind study, 42 patients with chronic angina pectoris were included. All patients were treated with aspirin (ASA). Twenty-three patients received clopidogrel additionally (75 mg/day with a 300-mg loading dose) for 14 days. Nineteen patients received placebo additionally. Soluble adhesion molecules (sICAM-1, sVCAM-1, sP-selectin), surface expression of CD54, CD11a, CD11b, CD40, CD40L, CD41, CD42b, and CD62L on lymphocytes, monocytes, and neutrophils, and markers of hemostasis and fibrinolysis (TAT, PAP, D-dimers) were measured. RESULTS:In the ASA + clopidogrel group, no change in surface expression of cellular adhesion molecules on leukocytes and on plasma levels of sICAM-1, sVCAM-1, sP-selectin, TAT, PAP, and D-dimers was detectable. CONCLUSIONS:Clopidogrel plus aspirin for 2 weeks did not result in a detectable benefit versus sole aspirin therapy regarding cellular adhesion molecules on leukocytes, plasma markers of coagulation, fibrinolysis, and soluble adhesion molecules in patients with CAD.

背景与目标：

BACKGROUND & AIMS: :The DAPT score is a recently-proposed decision tool for guiding optimal duration of dual antiplatelet therapy (DAPT). It showed modest accuracy in prior derivation and validation cohorts of patients with ≥12 months DAPT. This study was aimed to evaluate the validity of the DAPT score in a cohort of patients with 6 or 12 months DAPT after implantation of predominantly second-generation drug-eluting stents. We analyzed data of patients enrolled in the ISAR-SAFE trial. Patients were classified into low (<2) or high (≥2) DAPT score groups. Primary ischaemic (all-cause death, myocardial infarction, definite stent thrombosis or stroke) and bleeding (TIMI major or minor) outcomes were analyzed in the low and high DAPT score groups. Data of 3976 patients were available for DAPT score calculation. 2407 patients (60.5 %) were classified in the low DAPT score group and 1569 patients (39.5 %) in the high DAPT score group. In the low DAPT score group there were no significant differences between 6 and 12 months DAPT regarding ischaemic (1.0 % vs. 1.4 %, HR=0.74, 95 % CI, 0.35-1.57; p=0.43) or bleeding outcomes (0.3 % vs. 0.8 %, HR=0.44, 95 % CI, 0.13-1.42; p=0.17). In the high DAPT score group there were also no significant differences between 6 and 12 months DAPT regarding ischaemic (1.9 % vs. 1.8 %, HR=1.02, 95 % CI, 0.49-2.14; p=0.96) or bleeding (0.3 % vs. 0.5 %, HR=0.51, 95 % CI, 0.09-2.78; p=0.44) outcomes. In conclusion, the DAPT score failed to show a differential treatment effect in patients receiving 6 or 12 months DAPT after contemporary drug-eluting stent implantation.

背景与目标： : DAPT评分是最近提出的用于指导双重抗血小板治疗 (DAPT) 最佳持续时间的决策工具。在 ≥ 12个月DAPT的患者的先前推导和验证队列中，它显示出适度的准确性。这项研究旨在评估DAPT评分在植入主要是第二代药物洗脱支架后6或12个月的DAPT患者队列中的有效性。我们分析了参加ISAR-SAFE试验的患者的数据。患者分为低 (<2) 或高 (≥ 2) DAPT评分组。在低和高DAPT评分组中分析了原发性缺血性 (全因死亡，心肌梗塞，明确的支架血栓形成或中风) 和出血 (TIMI主要或次要) 结局。3976例患者的数据可用于DAPT评分计算。低DAPT评分组2407例 (60.5   %)，高DAPT评分组1569例 (39.5   %)。在低DAPT评分组中，DAPT在缺血 (1.0   % vs. 1.4   %，HR = 0.74，95   % CI，0.35-1.57; p = 0.43) 或出血结果 (0.3   % vs. 0.8   %，HR = 0.44，95  % CI，0.13-1.42; p = 0.17)。在高DAPT评分组中，在缺血 (1.9   % vs. 1.8   %，HR = 1.02，95   % CI，0.49-2.14; p = 0.96) 或出血 (0.3   % vs. 0.5   %，HR = 0.51，95% CI，0.09-2.78; p = 0.44) 结果。总之，在当代药物洗脱支架植入后接受6或12个月DAPT的患者中，DAPT评分未能显示出不同的治疗效果。

BACKGROUND & AIMS: BACKGROUND:Clopidogrel is activated by CYP2C19, which also metabolizes proton pump inhibitors (PPI). As proton pump inhibitors are metabolized to varying degrees by CYP2C19, we hypothesized that the reported negative omeprazole-clopidogrel drug interaction may not be a class effect. METHODS:Responsiveness to clopidogrel was assessed by the vasodilator-stimulated phosphoprotein phosphorylation (VASP) assay and aggregometry (Multiplate Analyzer) in 300 patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). RESULTS:The mean platelet reactivity index (PRI, assessed by the VASP assay) was nearly the same in patients with (n = 226; PRI = 51%) or without PPI treatment (n = 74; PRI = 49%; P = .724). Likewise, the adenosine diphosphate-induced platelet aggregation did not differ significantly between patients with or without PPI treatment (45 vs. 41 U; P = .619). Similarly, there was no difference in the PRI or the adenosine diphosphate-induced platelet aggregation between patients with pantoprazole (n = 152; PRI = 50%; aggregation = 47 U), esomeprazole (n = 74; PRI = 54%; aggregation = 42 U), or without PPI (n = 74; PRI = 49%; aggregation = 41 U; P = .382). CONCLUSION:In contrast to the reported negative omeprazole-clopidogrel drug interaction, the intake of pantoprazole or esomeprazole is not associated with impaired response to clopidogrel.

背景与目标：

BACKGROUND & AIMS: CONTEXT:Recent studies of drug-eluting intracoronary stents suggest that current antiplatelet regimens may not be sufficient to prevent late stent thrombosis. OBJECTIVE:To assess the association between clopidogrel use and long-term clinical outcomes of patients receiving drug-eluting stents (DES) and bare-metal stents (BMS) for treatment of coronary artery disease. DESIGN, SETTING, AND PATIENTS:An observational study examining consecutive patients receiving intracoronary stents at Duke Heart Center, a tertiary care medical center in Durham, NC, between January 1, 2000, and July 31, 2005, with follow-up contact at 6, 12, and 24 months through September 7, 2006. Study population included 4666 patients undergoing initial percutaneous coronary intervention with BMS (n = 3165) or DES (n = 1501). Landmark analyses were performed among patients who were event-free (no death, myocardial infarction [MI], or revascularization) at 6- and 12-month follow-up. At these points, patients were divided into 4 groups based on stent type and self-reported clopidogrel use: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. MAIN OUTCOME MEASURES:Death, nonfatal MI, and the composite of death or MI at 24-month follow-up. RESULTS:Among patients with DES who were event-free at 6 months (637 with and 579 without clopidogrel), clopidogrel use was a significant predictor of lower adjusted rates of death (2.0% with vs 5.3% without; difference, -3.3%; 95% CI, -6.3% to -0.3%; P = .03) and death or MI (3.1% vs 7.2%; difference, -4.1%; 95% CI, -7.6% to -0.6%; P = .02) at 24 months. However, among patients with BMS (417 with and 1976 without clopidogrel), there were no differences in death (3.7% vs 4.5%; difference, -0.7%; 95% CI, -2.9% to 1.4%; P = .50) and death or MI (5.5% vs 6.0%; difference, -0.5%; 95% CI, -3.2% to 2.2%; P = .70). Among patients with DES who were event-free at 12 months (252 with and 276 without clopidogrel), clopidogrel use continued to predict lower rates of death (0% vs 3.5%; difference, -3.5%; 95% CI, -5.9% to -1.1%; P = .004) and death or MI (0% vs 4.5%; difference, -4.5%; 95% CI, -7.1% to -1.9%; P<.001) at 24 months. However, among patients with BMS (346 with and 1644 without clopidogrel), there continued to be no differences in death (3.3% vs 2.7%; difference, 0.6%; 95% CI, -1.5% to 2.8%; P = .57) and death or MI (4.7% vs 3.6%; difference, 1.0%; 95% CI, -1.6% to 3.6%; P = .44). CONCLUSIONS:The extended use of clopidogrel in patients with DES may be associated with a reduced risk for death and death or MI. However, the appropriate duration for clopidogrel administration can only be determined within the context of a large-scale randomized clinical trial.

背景与目标：

BACKGROUND & AIMS: BACKGROUND/AIMS:Acute ST-segment elevation of myocardial infarction (STEMI) is the most severe type of acute coronary syndrome (ACS). Particular attention has been focused on studying the pathogenesis of STEMI, and how to prevent thrombosis, reduce inflammatory reaction, stabilize plaques and improve vascular endothelial functions to preserve the survived myocardium. This study aimed to compare the anti-inflammatory endothelium-protective effects, clinical prognosis, and relevant bleeding risks of ticagrelor versus clopidogrel in patients with STEMI who underwent urgent percutaneous coronary intervention (PCI) and provide certain experimental evidence and a theoretical basis for the selection of safe and effective drugs and their proper dosage, thereby further guiding clinical medication. METHODS:We sequentially enrolled 193 patients (104 males and 89 females) admitted to hospital due to acute STEMI. These patients underwent urgent PCI between December 2013 and May 2015 and met the inclusion criteria. They were assigned (1: 1) into two groups according to different treatments, 97 patients in the ticagrelor group (treatment group), and 96 patients in the clopidogrel group (control group). Levels of hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), and endothelial cell-specific molecule 1 (ESM-1) taken at admission and 24 h, 4 days, and 7 days after administration, as well as the correlation between the levels of IL-6, hs-CRP, and ESM-1, were determined in the two groups. At the same time, the effects of treatment with ticagrelor and clopidogrel on the efficacy endpoint events (ischemic and safety) were explored. RESULTS:No statistically significant difference was found in the levels of hs-CRP, IL-6, or ESM-1 at admission between the two groups (P> 0.05); Their levels were significantly elevated 24 h after administration, with statistical differences between two groups (P< 0.05). Furthermore, a downward trend with statistically significant differences was found on Day 4 and Day 7 (P< 0.05); ESM-1 levels increased along with increases of hs-CRP and IL-6 levels, indicating ESM-1 was positively correlated with hs-CRP (r=0.523, P< 0.001) and IL-6 (r=0.431, P< 0.001); and the occurrence rates of ischemic endpoint events at 30 days were lower in the treatment group than in the control group. The occurrence of safety endpoint events was higher than in the control group; however, no statistically significant difference was found (P> 0.05). CONCLUSIONS:Compared with clopidogrel, ticagrelor appears to rapidly reduce the prevalence of inflammatory reactions and stabilize the functions of vascular endothelium to improve the stability of atherosclerotic plaque and decrease the occurrence rate of thrombosis as well as ischemic outcome events without any obvious increase in the risk of bleeding in patients with acute STEMI receiving urgent PCI. This renders it a potential drug for clinical practice. At the same time, measurement of ESM-1, a new biological marker for vascular endothelial function disorder, could possibly become a simple, effective, and practical new method for clinical evaluation of risk stratification of patients with acute STEMI at admission.

背景与目标：

BACKGROUND & AIMS: Clinical Question:Among patients at high risk for or with established cardiovascular disease (ie, history of peripheral artery disease, stroke, or coronary artery disease without a coronary stent), is the addition of clopidogrel to aspirin associated with lower risk of mortality and cardiovascular events compared with aspirin alone? Bottom Line:Clopidogrel plus aspirin is associated with a reduced risk for myocardial infarction and ischemic stroke and an increased risk for major bleeding compared with aspirin alone among patients at high risk for or with an established cardiovascular disease but without a coronary stent. However, combined therapy is not associated with lower mortality.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Dual antiplatelet therapy (DAP) is necessary to prevent thromboembolic events during carotid stenting, stent-assisted coil embolization, and implant of flow diverters (FD). However, DAP in the acute phase may be challenging. An intravenous alternative, cangrelor, has rapid onset, short plasma half-life, and more reliable antiplatelet action for acute interventions. The study objective was to evaluate feasibility and safety of IV cangrelor during acute neuroendovascular surgery procedures. METHODS:We performed a retrospective analysis of our database of patients treated with stent-assisted coil embolization, FD placement for aneurysmal subarachnoid hemorrhage (aSAH), or stenting for acute internal carotid artery (ICA) occlusion where IV cangrelor was used. Morbidity, mortality, incidence of thromboembolic events, hemorrhages, and 90-day outcomes were reported. RESULTS:Ten patients were found in our database from June 2018 through January 2019. Four patients had aSAH, four had middle cerebral artery strokes with tandem lesions, one had an ICA occlusion, and one had a vertebral artery aneurysm. One of the ten patients experienced a thrombotic event. One patient developed new post-procedural bleeding and two had worsening intracranial hemorrhage. Five patients were discharged home in stable condition, two to acute rehabilitation, one to a nursing facility, and two others expired (likely the result of the severe and evolving strokes). Of the eight who were discharged, six (75%) had a good 90-day functional outcome (modified Rankin Scale 0-2). CONCLUSION:Acute administration of IV cangrelor with or without oral ticagrelor is a feasible antiplatelet treatment option for acute neuroendovascular procedures.

背景与目标：

BACKGROUND & AIMS: :Ticagrelor has been promoted to reduce the rate of definite stent thrombosis compared to clopidogrel from the The Platelet Inhibition and Patient Outcomes (PLATO) trial. However, several issues prevent this statement from being accurate, (1) stent thrombosis was an exploratory endpoint in PLATO--cases were retrospectively and prospectively adjudicated, (2) Sampling/ascertainment bias most likely lead to these conclusions, (3) Stent thromboses were not confirmed by an angiographic core lab (a requirement by the ARC definition for 'definite stent thrombosis'), (4) The integrity of the mortality and MI data from the PLATO trial have recently been challenged. A statement that ticagrelor reduces definite stent thrombosis versus clopidogrel cannot be justified.

背景与目标： : 从血小板抑制和患者结果 (PLATO) 试验中，与氯吡格雷相比，替格瑞洛已被推广以降低确定的支架内血栓形成率。然而，有几个问题阻碍了这一说法的准确性，(1) 支架血栓形成是PLATO的探索性终点-病例是回顾性和前瞻性裁决的，(2) 抽样/确定偏差最有可能导致这些结论，(3) 血管造影核心实验室未确认支架血栓形成 (ARC定义对 “确定的支架血栓形成” 的要求)，(4) PLATO试验的死亡率和MI数据的完整性最近受到挑战。与氯吡格雷相比，替格瑞洛减少明确的支架内血栓形成的说法是不合理的。

BACKGROUND & AIMS: :The risk for gastrointestinal bleeding from dual antiplatelet therapy (DAPT) with new antiplatelets (prasugrel/ticagrelor) compared to clopidogrel is unclear. AIM:To determine the risk and type of major (gastrointestinal bleeding requiring hospitalization) and minor (anemia and iron deficiency) gastrointestinal events with different types of DAPT. METHODS:Retrospective observational cohort study of patients who started DAPT after percutaneous coronary intervention. Follow-up was censored after 12 months of DAPT, when a major gastrointestinal event occurred, or when DAPT was discontinued. RESULTS:Among 1,327 patients (54.03% were treated with clopidogrel-based DAPT, 38.13% with ticagrelor-based DAPT, and 7.84% with prasugrel-based DAPT), 29.5% had at least one gastrointestinal event. Patients taking clopidogrel-DAPT were older, with more comorbidities, and higher gastrointestinal risk compared to those taking other DAPT regimens. Adjusted hazard ratios (HRs) showed no between-group differences in the risk for major (clopidogrel vs. new antiplatelets: HR 0.996; 95% confidence interval 0.497-1.996) and minor (HR 0.920; 0.712-1.189) gastrointestinal events. Most patients received proton pump inhibitors while on DAPT (93.3%) and after withdrawal (83.2%). CONCLUSION:Prasugrel- or ticagrelor-based DAPT was not associated with increased gastrointestinal bleeding risk when compared to clopidogrel-DAPT. New antiplatelets do not necessarily need to be restricted to patients with low gastrointestinal risk.

背景与目标：

BACKGROUND & AIMS: OBJECTIVES:The purpose of this study was to compare the effects of ticagrelor versus clopidogrel on health-related quality of life in the PLATelet inhibition and patient Outcomes (PLATO) trial. BACKGROUND:The PLATO trial showed that ticagrelor was superior to clopidogrel for the prevention of cardiovascular death, myocardial infarction, or stroke in a broad population of patients with acute coronary syndromes. METHODS:HRQOL in the PLATO study was measured at hospital discharge, 6-month visit, and end of treatment (anticipated at 12 months) by using the EuroQol five-dimensional (EQ-5D) questionnaire. All patients who had an EQ-5D questionnaire assessment at discharge from the index hospitalization (n = 15,212) were included in the study. Patients who died prior to the end-of-treatment visit were assigned an EQ-5D questionnaire value of 0. RESULTS:The EQ-5D questionnaire value at discharge among 7631 patients assigned to ticagrelor was 0.847 and among 7581 patients assigned to clopidogrel was 0.846 (P = 0.71). At 12 months, the mean EQ-5D questionnaire value was 0.840 for ticagrelor and 0.832 for clopidogrel (P = 0.046). Excluding patients who died resulted in mean EQ-5D questionnaire values of 0.864 among ticagrelor patients and 0.863 among clopidogrel patients (P = 0.69). CONCLUSIONS:In patients hospitalized with acute coronary syndromes with or without ST-segment elevation, treatment with ticagrelor was associated with a lower mortality but otherwise no difference in quality of life relative to treatment with clopidogrel. The improved survival and reduction in cardiovascular events with ticagrelor are therefore obtained with no loss in quality of life.

背景与目标：

BACKGROUND & AIMS: :Clopidogrel plus aspirin is considered the antiplatelet treatment of choice in patients with acute coronary syndrome, whether or not they are undergoing a percutaneous coronary intervention (PCI). The same treatment is mandatory in all patients undergoing a PCI with stent implantation. Clopidogrel is a pro-drug that needs metabolic activation through a cytochrome P450-dependent pathway, with an extensive involvement of the CYP 2C19 isoenzyme. Proton pump inhibitors (PPIs) reduce the risk of gastrointestinal bleeding in patients receiving dual antiplatelet therapy. In the past two years some scientific evidences have suggested a possible negative interference of PPIs on antiplatelet effect of clopidogrel because of the competitive inhibition of the CYP 2C19 isoenzyme. Few studies testing platelet reactivity in patients receiving both clopidogrel and a PPI have demonstrated a reduced inhibitory effect of the association on platelet aggregation. Moreover, results from retrospective observational studies have shown a higher incidence of major cardiovascular events in patients receiving both clopidogrel and PPIs. These data have not been confirmed neither by the only prospective randomized study comparing clopidogrel plus omeprazole with clopidogrel alone, nor by the retrospective analysis of the TRITON TIMI 38 trial, where PPIs did not affect the clinical outcome of patients given clopidogrel or prasugrel. Nevertheless both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have discouraged the concomitant use of clopidogrel and PPIs. Important questions concerning a true interference between the two classes of drugs still remain unanswered and need to be addressed by adequately powered studies.

背景与目标： : 氯吡格雷联合阿司匹林被认为是急性冠状动脉综合征患者的首选抗血小板治疗，无论他们是否正在接受经皮冠状动脉介入治疗 (PCI)。所有接受支架置入PCI的患者都必须接受相同的治疗。氯吡格雷是一种需要通过细胞色素P450-dependent途径代谢激活的前体药物，广泛参与CYP 2C19同工酶。质子泵抑制剂 (PPIs) 可降低接受双重抗血小板治疗的患者的胃肠道出血风险。在过去的两年中，一些科学证据表明，由于CYP 2C19同工酶的竞争性抑制，ppi可能对氯吡格雷的抗血小板作用产生负面干扰。在接受氯吡格雷和PPI的患者中测试血小板反应性的研究很少表明该关联对血小板聚集的抑制作用降低。此外，回顾性观察性研究的结果表明，在接受氯吡格雷和ppi的患者中，主要心血管事件的发生率更高。这些数据既没有被唯一一项比较氯吡格雷联合奥美拉唑和单独氯吡格雷的前瞻性随机研究证实，也没有被TRITON TIMI 38试验的回顾性分析证实，在该试验中，ppi不影响接受氯吡格雷或普拉格雷的患者的临床结局。然而，美国食品药品监督管理局 (FDA) 和欧洲药品管理局 (EMEA) 都不鼓励氯吡格雷和ppi的同时使用。关于两类药物之间真正干扰的重要问题仍然没有答案，需要通过有足够动力的研究来解决。

BACKGROUND & AIMS: :Transcatheter aortic valve replacement (TAVR) causes early acquired thrombocytopenia on postoperative Days 1 and 2 in 30-50% of patients. While usually transient and rarely severe, early acquired thrombocytopenia is strongly associated with 30-day and 1-year post-TAVR outcomes, including mortality. Observation from a prospective registry suggests pretreatment with the P2Y12 receptor inhibitor clopidogrel before TAVR reduces the frequency and magnitude of early acquired thrombocytopenia. If a protective effect of clopidogrel pretreatment on early thrombocytopenia can be confirmed, then further study to determine if this translates into improved TAVR outcomes is warranted.

背景与目标： : 经导管主动脉瓣置换术 (TAVR) 在30-50% 例患者的术后第1天和第2天引起早期获得性血小板减少症。早期获得性血小板减少症通常是短暂的，很少严重，但与TAVR后30天和1年的结局 (包括死亡率) 密切相关。前瞻性注册表的观察结果表明，在TAVR之前使用P2Y12受体抑制剂氯吡格雷进行预处理可降低早期获得性血小板减少症的频率和幅度。如果可以确认氯吡格雷预处理对早期血小板减少症的保护作用，则需要进一步研究以确定这是否转化为改善的TAVR结局。

BACKGROUND & AIMS: BACKGROUND:Clopidogrel (CLP) suffers from extensive first pass metabolism results in a negative impact on its oral systemic bioavailability. Cubosomes are Lyotropic Liquid Crystalline (LLC) nano-systems comprising monoolein, a steric stabilizer and an aqueous system, it considered a promising carrier for different pharmaceutical compounds. Box-Behnken Design (BBD) is an efficient tool for process analysis and optimization skipping forceful treatment combinations. OBJECTIVE:The study was designed to develop freeze-dried clopidogrel loaded LLC (cubosomes) for enhancement of its oral bioavailability. METHODS:A 33 BBD was adopted, the studied independent factors were glyceryl monooleate (GMO lipid phase), Pluronic F127 (PL F127steric stabilizer) and polyvinyl alcohol powder (stabilizer). Particle Size (PS), Polydispersity Index (PDI) and Zeta Potential (ZP) were set as independent response variables. Seventeen formulae were prepared in accordance with the bottom up approach and in-vitro evaluated regarding PS, PDI and ZP. Statistical analysis and optimization were achieved using design expert software®, then the optimum suggested formula was prepared, in-vitro revaluated, freeze-dried with 3% mannitol (cryoprotectant), solid state characterized and finally packed in hard gelatin capsule for comparative in-vitro release and in-vivo evaluation to Plavix®. RESULTS:Results of statistical analysis of each individual response revealed a quadratic model for PS and PDI where a linear model for ZP. The optimum suggested formula with desirability factor equal 0.990 consisting of (200 mg GMO, 78.15 mg PL F127 and 2% PVA). LC/MS/MS study confirmed significant higher Cmax, AUC0-24h and AUC0-∞ than that of Plavix®. CONCLUSION:The results confirm the capability of developed carrier to overcome the low oral bioavailability.

背景与目标：