Mechanism of Improving Aspirin Resistance: Blood-Activating Herbs Combined With Aspirin in Treating Atherosclerotic Cardiovascular Diseases

Atherosclerotic thrombotic disease continues to maintain a high morbidity and mortality rate worldwide at present. Aspirin, which is reckoned as the cornerstone of primary and secondary prevention of atherosclerotic cardiovascular diseases (ASCVDs), has been applied in clinics extensively. However, cardiovascular events continue to occur even though people utilize aspirin appropriately. Therefore, the concept of aspirin resistance (AR) was put forward by scholars, which is of great significance for the prediction of the clinical outcome of diseases. The pathogenesis of AR may be incorporated with low patient compliance, insufficient dose, genetic polymorphism, increased platelet transformation, inflammation, and the degenerative changes and calcification of platelets. The improvement of AR in the treatment of ASCVDs has gradually become a research hot spot in recent years. Traditional Chinese medicine (TCM) regards individuals as a whole and treats them from a holistic view, which has been found to have advantages in clinical studies on the treatment of AR. Many kinds of blood-activating TCM have the effect of improving AR. The potential mechanism for the improvement of AR by blood-activating herbs combined with aspirin was explored. The combination of blood-activating herbs and aspirin to improve AR is likely to turn into a hot topic of research in the future.

Glycemic Control and Aspirin Resistance in Patients Taking Low-Dose Aspirin for Pre-eclampsia Prevention

Objectives To assess the association between aspirin and glycemic control in diabetic, pregnant patients, and the risk for aspirin resistance in those with poor glycemic control across gestation taking low-dose aspirin (LDA) for pre-eclampsia (PEC) prevention. Study Design We performed a secondary analysis of samples collected during the Maternal-Fetal Medicine Units trial of LDA for PEC prevention. A subset of insulin-controlled diabetic patient samples on placebo or 60 mg aspirin daily were evaluated. Glycosylated hemoglobin was measured at randomization, mid-second trimester, and third trimester time points. Thromboxane B2 (TXB2) measurements were previously assessed as part of the original study. Primary outcome was the effect of LDA on glycosylated hemoglobin levels compared with placebo across gestation. Results Levels of glycosylated hemoglobin increased across gestation in the placebo group (2,067.7 [interquartile range, IQR: 1,624.6–2,713.5 µg/mL] vs. 2,461.9 [1,767.0–3,209.9 µg/mL] vs. 3,244.3 [2,691.5–4,187.0 µg/mL]; p < 0.01) compared with no difference in levels of glycosylated hemoglobin across gestation in the LDA group (2,186.4 [IQR: 1,462.3–3,097.7 µg/mL] vs. 2,337.1 [1,327.7–5,932.6 µg/mL] vs. 2,532.9 [1,804.9–5,511.8 µg/mL]; p = 0.78). Higher levels of glycosylated hemoglobin were associated with increased TXB2 levels prior to randomization (r = 0.67, p < 0.05). Incomplete TXB2 was higher in pregnancies with increasing levels of glycosylated hemoglobin compared with those with decreasing levels of glycosylated hemoglobin across gestation (69.2 vs. 18.1%, p = 0.02). Conclusion LDA exposure may be beneficial to glycemic control in this patient population. Additionally, poor glycemic control is associated with a higher level of TXB2 in diabetic pregnant patients on LDA. Higher doses of aspirin may be required in these patients to prevent development of PEC. Key Points

Antiplatelet Effect of Aspirin in Ischemic Stroke: A Hospital-based Study

Introduction: Aspirin is widely used for the treatment of stroke. Therefore aspirin resistance can lead to a significant increase in the burden of stroke. Platelet aggregation studies can evaluate platelet function, and this may help to detect anti-platelet resistance. Methods: This is a hospital-based study of the antiplatelet effect of aspirin in ischemic stroke, during a duration of one year. All first-time ischemic stroke patients >18 years of age were included. Platelet aggregometry test was done by LTA (Light transmission optical aggregometer), after starting the patients on oral aspirin. Results: A total of 113 ischemic stroke patients were included for the antiplatelet effect of the aspirin study. Aspirin resistance was found in 18.58% of patients. Patients with aspirin resistance had higher mortality, and less improvement on follow-up, as compared to aspirin-sensitive patients. They had more incidence of smoking, alcohol abuse, diabetes mellitus, and dyslipidemia, as compared to the aspirin-sensitive group. The results reveal that there is a non-statistically significant trend in both mortality and prognosis between the two study groups compared: aspirin-resistant versus aspirin-sensitive patients. Conclusion: Aspirin resistance can lead to loss of functional improvement and more mortality than aspirin-sensitive patients. However, further study for drug interactions, adequate risk factor control, the genetic profile of the population is needed, to come to a definite conclusion.

Genetic Polymorphism of ITGA2 C807T Collagen Receptor Encoding Gene of Aspirin Therapy among Javanese-Indonesian Healthy Respondents

BACKGROUND: Aspirin is an antiplatelet drug commonly administered as primary and secondary prophylaxis to prevent thromboembolic events. However, there has been a common incidence of aspirin resistance that leads to a recurrent cerebrovascular disease. One of the causes of such event is the genetic polymorphisms of the integrin alpha-2 (ITGA2) gene that encodes the glycoprotein Ia (GPIa) receptor in the pharmacodynamics of aspirin. AIM: This study analyzed the genetic polymorphism of ITGA2 as the GPIa collagen receptor encoding gene of aspirin therapy among healthy Javanese, the largest ethnic group in Indonesia. METHODS: This cross-sectional study involved 100 respondents who met the inclusion criteria with their blood sample taken for DNA isolation. Identification of genetic polymorphism in the target SNPs was done using the PCR-RFLP method with 5’-CCTTAAAGCTACCGGCCCATGT-3’ forward primer and 5’-TTGGCCTATTAGCACCAAAACTTACC-3’ reverse primer as well as Hpy188Irestriction enzyme to fragment the target at position 244 in the C base. RESULTS: This study found that the dominant genotype and allele were CT (51%) and C (66.5%), respectively. CONCLUSION: The allele frequency of ITGA2 gene in this study was similar to that of the populations in other Asian countries. Further research regarding the effects of ITGA2 C807T polymorphism on the pharmacodynamics of aspirin as an antiplatelet is recommended to minimize atherothrombotic events and examine its interactions as a biomarker of the risk and prognosis of some cancer types.

Antithrombotic effect of different acetylsalicylic acid drug formulations: is there a difference?

To date, a sufficient volume of clinical studies has been accumulated that have demonstrated a reduced antiplatelet effect of enteric-coated (EC) lowdose acetylsalicylic acid (ASA). Delayed and incomplete absorption from the intestinal alkaline medium, which significantly reduces the bioavailability of drug, is considered the main reason for laboratory aspirin resistance (pseudoresistance) to EC ASA. This phenomenon is of particular importance for patients with acute coronary syndrome, when a quick effect is required, as well as for patients with diabetes and obesity due to additional causes of increased platelet activity, on the one hand, and reduced bioavailability of ASA, on the other. Given the issue of efficacy, the dubious gastroprotective effect and the more pronounced damaging effect on the mucous membrane of small intestine, the use of EC ASA should be avoided, especially in patients with a multifactorial risk of insufficient response to therapy. A good alternative is buffered ASA, which quickly dissolves and is partially absorbed directly in the stomach, having antiplatelet activity comparable to simple ASA and a similar aspirin resistance, is associated with a lower risk of aspirin-induced enteropathy in comparison with ES ASA. In addition, according to a number of small studies and retrospective analyzes, buffered ASA is less likely to cause damage to gastric mucosa compared to EC ASA.

Efficacy and Mechanism of Panax Notoginseng in the Secondary Prevention for Stroke Patients with "Antiplatelet Drug Resistance"

Background Cerebral stroke is common and associated with high rates of mortality, disability, and recurrence while the chance of complete recovery is low. It adversely affects human physical and mental health and represents the leading cause of death in China. Aspirin is the cornerstone of secondary prevention of cerebral stroke. However, recurrence of stroke cannot be completely prevented by regular oral administration of aspirin due to aspirin resistance, which is an independent risk factor for stroke recurrence. In this instance, several strategies have been taken, including dose incrementation, frequency increaseof drug administration, combination with other antiplatelet drugs, or replacing it with new antiplatelet drugs. However, these measures have led to several other undesirable outcomes, including gastrointestinal tract stimulation, increased risk of bleeding, higher cost, and poor patient compliance to treatment.let aggregation, but its efficacy and mechanism in the secondary prevention Numerous studies have confirmed that Panax notoginseng has the effect of anti-plateof cerebral stroke among patients with aspirin resistance have not been ascertained. Method/Design: This is a two-center, triple-blinded, randomized, controlled, and optimal efficiency trial. A total of 120 patients aged 45–65 years old with semi-resistance to antiplatelet drugs treated in the secondary prevention clinics for cerebral stroke in the Shaanxi Traditional Chinese Medicine Hospital and Xi'an Hospital of Traditional Chinese Medicine from October 2020 to June 2022 will be recruited. Patients are randomly divided into the experimental group and control group at the ratio of 1:1, with 60 cases in each group. The blood pressure, blood glucose, and blood lipid are controlled within the normal range as the basic standards of treatment. The experimental group is given aspirin enteric coated tablets 100 mg/day + Panax Notoginseng Powder (3 g/day, oral administrationafter dissolved), while the control group is given aspirin enteric coated tablets 100 mg/day + placebo (Panax Notoginseng Powder 0.03 g + malt powder/day, oral administration after dissolved). Measurements on the platelet aggregation rate, thromboxane A2 (TXA2), prostacyclin (PGI2), adenosine diphosphate (ADP), and changes of the coagulation index of the two groups are performed on the day-14 and day-30. The efficacy, mechanism, and safety of Panax notoginseng in the treatment of patients with aspirin resistance will be evaluated. The data are analyzed and the mean and confidence interval (CI) of 95% level are calculated by the SPSS 21.0 software. The intention-to-treat (ITT) analysis is used to account for the missing data or dropouts. Descriptive analyses are performed on the baseline population data. Repeated ANOVA (general linear model) is used to compare the differences ofkey indicators (platelet aggregation rate, thromboxane A2, prostacyclin, ADP) between the two groups.For the secondary indicators (coagulation function), two independent samples t-test and Wilcoxon rank-sum test are used. P < 0.05 is considered a statistically significant difference between the two groups. Conclusion This study aims is to explore the efficacy and mechanism of Panax notoginseng in the secondary prevention for stroke patients with aspirin resistance. The results will provide evidence-based practice for traditional Chinese medicine, and also shed light on how it may influence the secondary prevention of cerebral stroke. Trial registration: The trial has been registered with the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx,) on 24th October 2020, with the registration number ChiCTR2000037833.

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

Purpose: Calcium channel blockers (CCBs) do not reduce the risk of initial or recurrent myocardial infarction (MI) in patients diagnosed with stable coronary artery disease (CAD). The aim of this current study was to evaluate the association between CCBs and aspirin resistance in patients with CAD. Methods: Patients with stable CAD who were regularly taking aspirin (75-100 mg qd) for at least one month prior to enrollment in the study were included. The VerifyNow system was used for platelet function testing with high on-aspirin platelet reactivity (HAPR) defined as aspirin reaction units (ARU) >550. We compared patients treated with CCBs versus control group. Results: 503 patients with CAD were included in this study, 88 were treated with CCBs; Mean age (67.9±9.7 in the CCB group vs 66.5±11.4 in the control group, p=0.288), gender (77.3 male vs. 82.9%, p=0.214) and rates of diabetes mellitus (34.7 vs. 36.9%, p=.121) were similar. Rates of hypertension were higher in the CCB group (83.9 vs. 63.5%, p<0.01), but rates of past MI were lower (47.1 vs. 59.7%, p=0.039). The mean ARU was 465.4P70.0 for patients treated with CCBs versus 445.2u60.0 in controls (p=0.006). Similarly, 15.9% of CCB patients demonstrated HAPR compared to 7.0% (p=0.006). In a multivariate analysis, the administration of CCBs was independently associated with HAPR (OR- 1.72, 95% CI 1.04 – 8.91, p=0.047). Conclusions: Usage of CCBs is positively correlated with aspirin resistance. These findings may suggest an adverse pharmacologic effect of CCBs among patients with stable CAD treated with aspirin.

A Pilot Study Of Aspirin Resistance In Obstructive Sleep Apnea Patients

Purpose: Obstructive sleep apnea (OSA) leads to endothelial dysfunction and platelet hyperactivity, which arelinked to increased risk of cardiovascular disease and implicated in the development of aspirin resistance. We hypothesized that aspirin resistance is prevalent among OSA patients and aimed to explore effects of continuous positive airway pressure (CPAP) therapy on aspirin responsiveness. Methods: In Phase 1, prevalence of aspirin resistance was determined cross-sectionally in a group of OSA patients (n=59) on daily low-dose aspirin (81 mg) taken before entering the study, for primary or secondary prevention. In Phase 2, aspirin responsiveness before and after initiation of CPAP therapy was compared and stratified by endothelial function in a cohort of aspirin-naïve patients with newly diagnosed OSA (n=18). Results: In Phase 1, prevalence of aspirin resistance was 17%; most patients (56%) were on CPAP therapy. In Phase 2, initiation of CPAP therapy was associated with significant improvement in endothelial function (p=0.03). The mean pre-CPAP aspirin resistance units (ARU) was 569 (SD=75). In subjects with endothelial dysfunction (44%), the mean decrease after initiation of CPAP therapy was 43 ARU (SD=81, p=0.18). In contrast, subjects with normal endothelial function experienced the mean decrease of 8 ARU (SD=116, p=0.83). Conclusion: Aspirin resistance may be prevalent among OSA patients. After initiation of CPAP therapy, we observed a trend towards improvement in aspirin responsiveness among patients with endothelial dysfunction. The role of endothelial dysfunction and aspirin resistance should be explored in further studies that focus on the effect of CPAP on cardiovascular outcomes.

Genetic aspects of aspirin resistance in patients with cerebrovascular pathology

Введение. Цереброваскулярные заболевания (ЦВЗ) и нарушения мозгового кровообращения (НМК) остаются одной из основных причин смерти во всем мире. Доказана генетическая составляющая возникновения НМК, генетические полиморфизмы могут изменять ответ на фармакологические агенты. Ацетилсалициловая кислота (АСК) — «золотой стандарт» антиагрегантного лечения ЦВЗ. С начала XXI века в мировой науке накопились факты о недостаточном эффекте АСК, в связи с чем возник термин аспиринорезистентность. Цель исследования: оценка вклада гемореологических и генетических факторов в возникновение феномена аспиринорезистентности у пациентов с ЦВЗ. Материалы и методы. В настоящее проспективное рандомизированное контролируемое наблюдательное исследование были включены 186 пациентов с ЦВЗ в возрасте 45–75 лет. Все пациенты получали 75 мг АСК ежедневно. Наряду с комплексным клиническим обследованием, оценкой когнитивного статуса и приверженности к лечению, проводилась лабораторная оценка функции тромбоцитов, развернутый биохимический анализ крови, идентификация полиморфизмов A842G гена циклооксигеназы 1-го типа (ЦОГ-1) (rs 10306114), С50Т ЦОГ-1 (rs3842787) и А1676G ЦОГ-1 (rs1330344). Статистическая обработка выполнена с использованием программ IBM SPSS Statistics. Результаты. Выявлена положительная взаимосвязь между уровнем агрегации тромбоцитов (АТ) с аденозиндифосфатом (АТ-АДФ) и адреналином и (АТ-адр) и пробой АСК in vitro (r = 0,722 и r = 0,689; р < 0,001). Обнаружена отрицательная взаимосвязь между АТ-АДФ и баллом по Монреальской шкале оценки когнитивных функций (англ. Montreal Cognitive Assessment, MoCA) и приверженностью к лечению (r = –0,845; p = 0,001). На основании анализа АТ все обследованные были подразделены на АСК-нечувствительных (группа 1, n = 100) и АСК-чувствительных (группа 2, n = 86). В группе АСК-нечувствительных наблюдалось больше пациентов, несущих хотя бы один аллель G полиморфизма гена ЦОГ-1 rs1330344 по сравнению с пациентами в группе ACK-чувствительных (60,4% против 47,7%; p < 0,01). Наличие rs1330344 часто ассоциировано с сахарным диабетом 2-го типа (отношение шансов = 3,749; 95% доверительный интервал = 1,937–7,254; p = 0,001). Полиморфизм ЦОГ-1 C50T (rs3842787) по данным логистической регрессии связан с АТ-Адр (r = 0,845; р < 0,001). Заключение. Среди причин аспиринорезистентности у пациентов с ЦВЗ следует учитывать генетические аспекты. Background. Cerebrovascular disease (CVD) and stroke remain one of the leading causes of death worldwide. The genetic component of stroke has been proven; genetic polymorphisms can alter the response to pharmacological agents. Acetylsalicylic acid (ASA) is the “gold standard” for antiplatelet treatment of CVD. Since the beginning of the XXI century, the world science has accumulated facts about the insufficient effect of ASA, so the term aspirin resistance appeared. Objectives: to assess hemorheological and genetic factors to the occurrence of the phenomenon of aspirin resistance in patients with CVD. Patients/Methods. This prospective randomized controlled observational study included 186 patients with CVD, aged 45–75 years. All patients received 75 mg ASA daily. Clinical examination, assessment of cognitive status and compliance to treatment, a laboratory assessment of platelet function, a detailed biochemical blood test, identifi cation of A842G polymorphisms of type 1 cyclooxygenase (COX-1) gene (rs 10306114), C50T COX-1 (rs3842787) and A1676G COX-1 (rs3842787) and A1676G COX-1 (rs1330344) were performed. Statistics was carried out using the IBM SPSS Statistics software. Results. The positive correlation was found between platelet aggregation (РА) with adenosine diphosphate (РА-ADP) and adrenaline (РА-Аdr) and an in vitro test with ASA (r = 0.722 and r = 0.689; p < 0.001). A negative correlation was found between РА-ADP and the Montreal Cognitive Assessment (MoCA) score for compliance to treatment (r = –0,845; p = 0,001). Based on the analysis of PA, all examined patients were divided into ASA-insensitive (group 1, n = 100) and ASA-sensitive (group 2, n = 86). In the ASA-insensitive group, there were more patients carrying at least one G allele of the COX-1 gene rs1330344 polymorphism compared with patients in the ACK-sensitive group (60.4% versus 47.7%; p < 0.01). The presence of rs1330344 is often associated with type 2 diabetes mellitus (OR = 3.749; 95% СI = 1.937–7.254; p = 0.001). C50T polymorphism of COX-1 (rs3842787) according to logistic regression is associated with AT-Adr (r = 0.845; p < 0.001). Conclusions. Genetic aspects should be considered among the causes of aspirin resistance in patients with CVD.