Efficacy and Safety of Prolonged Dual Antiplatelet Therapy after Percutaneous Coronary Intervention in Acute Coronary Syndrome Patients.

Objective: It remains controversial whether to extend the course of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). We conducted a study to investigate the benefits and risks of applying DAPT for different durations after PCI in acute coronary syndromes (ACS) patients in China. What's more, we explored the efficacy of extended DAPT regimen based on ticagrelor. Methods: This single-center prospective cohort study used data obtained from the PHARM-ACS Patient Registration Database. We included all patients who were discharged between April and December 2018. All patients had at least 18 months of follow-up. Patients were divided into two groups according to the duration of DAPT: a 1-year group and a >1-year group. Potential bias between the two groups was adjusted for by propensity score matching using logistic regression. The primary outcomes were major adverse cardiovascular and cerebrovascular events (MACCE), defined as a composite of death, myocardial infarction, and stroke occurring from 12 months after discharge to follow-up visit. The safety endpoint was any significant bleeding event (BARC ≥ 2). Results: Of 3,205 patients enrolled, 2,201 (68.67%) had DAPT prolonged beyond one year. A total of 2,000 patients were successfully propensity score-matched; patients who received DAPT > 1-year (n = 1000), compared with DAPT = 1-year patients (n = 1000), had a similar risk of MACCE (adjusted HR 0.23, 95% CI 0.05-1.10) and significant bleeding events (adjusted HR 0.63, 95% CI 0.32-1.24). The DAPT > 1-year group had a higher risk of revascularization (adjusted HR 3.36, 95% CI 1.64-6.87). Conclusion: Prolonged DAPT may not be of sufficient benefit to ACS patients within 12-18 months after the index PCI to offset the increased risk of significant bleeding events.

Clinical Outcomes of Individualized Antiplatelet Therapy Based on Platelet Function Test in Patients After Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis.

ABSTRACT: Platelet function test (PFT) is universally used to assess platelet reactivity to antiplatelet drugs in patients after percutaneous coronary intervention (PCI). However, it remains controversial whether individualized antiplatelet therapy guided by PFT can improve the prognosis in patients after PCI. This meta-analysis was conducted to explore the efficacy and safety of individualized antiplatelet therapy guided by PFT in patients after PCI. Studies that compared PFT-guided antiplatelet therapy with standard antiplatelet therapy were researched. The risks of major adverse cardiovascular and cerebrovascular events (MACCE) and major bleeding events were assessed. Pooled odds ratios (ORs) with 95% CIs were obtained. Finally, a total of 16,835 patients from 22 studies met the criteria and were included in the meta-analysis. Compared with standard antiplatelet therapy, individualized antiplatelet therapy guided by PFT significantly decreased the risk of MACCE (OR: 0.58, 95% CI: 0.43-0.77) in patients after PCI. There was no significant difference in major bleeding events (OR: 0.85, 95% CI: 0.70-1.05, P = 0.13). This study identified that PFT-guided individualized antiplatelet therapy could reduce the incidence of MACCE without increasing the risk of hemorrhage in patients after PCI.

Metformin and the risk of neurodegenerative diseases in patients with diabetes: A meta-analysis of population-based cohort studies.

AIMS: The association between metformin use and neurodegenerative disease (ND) onset remains controversial. In this systematic review and meta-analysis, we aimed to determine the relationship between metformin use and ND risk based on data from population-based cohort studies. METHODS: Articles were systematically searched in PubMed, EMBASE and Cochrane Library databases. Pooled relative risks (RRs) with 95% CIs were obtained using a random-effects model. Subgroup analyses, sensitivity analyses and meta-regression were performed to identify the sources of heterogeneity and strengthen the results. RESULTS: Twelve population-based cohort studies involving 194,792 participants (94,462 metformin users and 100,330 metformin non-users) were eligible for inclusion in this meta-analysis. The pooled RR of NDs reached 0.77 (95% CI 0.67-0.88) when comparing metformin users with non-users. The effects were more prominent in long-term metformin users (≥4 years) (RR 0.29, 95% CI 0.13-0.44) and studies from Asian countries (RR 0.69, 95% CI 0.64-0.74). The effect estimates were stable when stratified by subtypes of NDs, study designs, and control definitions (p for interaction >0.05). Meta-regression did not identify the coefficients as the sources of heterogeneity (all p > 0.05). CONCLUSIONS: This systematic review and meta-analysis found that metformin use, especially long-term use, was associated with lower ND risk. However, because there was substantial heterogeneity among studies, high-quality randomized controlled trials are still needed to confirm this finding.

Clopidogrel versus Ticagrelor in CYP2C19 Loss-of-Function Allele Noncarriers: A Real-World Study in China.

OBJECTIVE: This article compares the clinical outcomes of clopidogrel and ticagrelor in patients with acute coronary syndrome (ACS) without cytochrome P450 (CYP)2C19 loss-of-function (LOF) alleles and investigates whether clopidogrel could be an alternative P2Y12 inhibitor without increasing the risk of ischemic events. METHODS: Patients were divided into the clopidogrel-treated group and the ticagrelor-treated group. Inverse probability of treatment weighting (IPTW) calculated by propensity scores was used to adjust confounding covariates. The primary outcome was major adverse cardiovascular or cerebrovascular events (MACCEs) within 12 months. The secondary outcomes were MACCEs plus unstable angina, and clinically significant bleeding events. RESULTS: Finally, 2,199 patients were included. Of them, 1,606 were treated with clopidogrel, and 593 were treated with ticagrelor. The mean age of the original cohort was 59.92 ± 9.81 years. During the 12-month follow-up period, MACCEs occurred in 89 patients (4.0%). No significant differences were observed in MACCEs (IPTW-adjusted hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.65-1.18), MACCEs plus unstable angina (IPTW-adjusted HR, 1.20; 95% CI, 0.91-1.59), or clinically significant bleeding events (IPTW-adjusted HR, 0.81; 95% CI, 0.53-1.23) between the clopidogrel- and ticagrelor-treated groups. CONCLUSION: In patients with ACS without CYP2C19 LOF alleles, clopidogrel was not associated with a higher risk of MACCEs when compared with ticagrelor. The main findings of this study support use of clopidogrel in CYP2C19 LOF noncarriers as an alternative P2Y12 inhibitor, which may reduce medical expenses and adverse reactions caused by more potent P2Y12 inhibitors in these patients.

Personalized Antiplatelet Therapy Based on CYP2C19 Genotypes in Chinese ACS Patients Undergoing PCI: A Randomized Controlled Trial.

Background: The clinical benefits of cytochrome P450 (CYP) 2C19 genotype-guided antiplatelet therapy in Asians remain unclear. In this study, we aimed to investigate the clinical outcomes of pharmacogenomic antiplatelet therapy in Chinese patients. Methods: Patients with acute coronary syndrome planning to undergo percutaneous coronary intervention were eligible for this study and were randomly divided into a genotype-guided treatment (GT) group and routine treatment (RT) group, with a ratio of 2:1. Patients in the GT group underwent CYP2C19 genotyping (*2 and *3 alleles), and the results were considered in selecting P2Y12 receptor inhibitors. Patients in the RT group were treated with P2Y12 receptor inhibitors according to their clinical characteristics. The primary endpoint was a composite of major adverse cardiovascular or cerebrovascular events (MACCE). The secondary endpoint was significant bleeding events. Results: Finally, 301 patients were enrolled; 75.1% were men and the mean age was 59.7 ± 9.8 years. In total, 281 patients completed the follow-up procedure. The primary endpoint occurred in 16 patients, 6 patients in the GT group and 10 in the RT group. The GT group showed lower MACCE rates than the RT group (6/189 vs. 10/92, 3.2 vs. 10.9%, hazard ratio: 0.281, 95% confidence interval: 0.102-0.773, P = 0.009). There was no statistically difference in significant bleeding events between the GT and RT groups (4.2 vs. 3.3%, hazard ratio: 1.315, 95% confidence interval: 0.349-4.956, P = 0.685). Conclusion: Personalized antiplatelet therapy that is based on CYP2C19 genotypes could decrease MACCE within a 12-month period in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention. Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2000034352.

Danthron attenuates experimental atherosclerosis by targeting foam cell formation.

NEW FINDINGS: What is the central question of this study? Does danthron alleviate experimental atherosclerosis by inhibiting the formation of foam cells? What are the main findings and their importance? Danthron improved serum lipid profiles and significantly reduced the atherosclerotic plaque areas and lipid accumulation in the aortic root of ApoE-/- mice. Danthron inhibited foam cell formation in oxidized low-density lipoprotein-induced RAW264.7 macrophages. Furthermore, danthron exerted its function in atherosclerosis at least partly through activating the AMP-activated protein kinase-sirtuin 1 signalling pathway. These findings suggest that danthron has the potential to alleviate atherosclerosis. ABSTRACT: Danthron, an ingredient isolated from Rheum palmatum L., has been revealed to reduce lipid accumulation in vitro. This study aimed to discover the effects of danthron on the development of atherosclerosis and to delineate the underlying mechanisms. For in vivo studies, male ApoE-/- mice were fed a high-fat diet and orally treated with danthron (30 or 60 mg/kg/day) for 12 weeks. For in vitro studies, RAW264.7 cells were induced by oxidized low-density lipoprotein (ox-LDL, 50 µg/ml) for 48 h and subsequently administered danthron at appropriate concentrations for 24 h. AMP-activated protein kinase (AMPK) inhibitor compound C was added to ox-LDL-stimulated RAW264.7 cells 2 h before danthron administration to confirm the role of the AMPK signalling pathway in the regulation by danthron of foam cell formation. We found that danthron improved serum lipid profiles, and significantly reduced atherosclerotic plaque areas and lipid accumulation in the aortic root of atherosclerotic mice. Moreover, danthron upregulated the mRNA and protein expression of ATP-binding cassette transporter A1 (ABCA1), ABCG1 and liver X receptor α (LXRα), which play a crucial role in lipid metabolism, and activated the AMPK-sirtuin 1 (SIRT1) pathway. In an in vitro study, danthron inhibited foam cell formation in ox-LDL-induced RAW264.7 macrophages with an increase in the expression of ABCA1, ABCG1 and LXRα as well as activation of the AMPK-SIRT1 pathway. Furthermore, compound C abolished the effects of danthron on lipid accumulation and the protein expression of ABCA1/G1 and LXRα in vitro. Our results highlight that danthron possesses potential benefits in alleviating experimental atherosclerosis by targeting foam cell formation by activating the AMPK-SIRT1 signalling pathway.

Impact of Implementing CYP2C19 Genotype-Guided Antiplatelet Therapy on P2Y12 Inhibitor Selection and Clinical Outcomes in Acute Coronary Syndrome Patients After Percutaneous Coronary Intervention: A Real-World Study in China.

Background: CYP2C19 loss-of-function (LOF) alleles reduce the effectiveness of clopidogrel in patients undergoing percutaneous coronary intervention for acute coronary syndrome. However, the clinical impact of implementing CYP2C19 gene-guided pharmacotherapy is unclear, especially among the Chinese population. The purpose of this study was to evaluate P2Y12 receptor inhibitor selection and clinical outcomes upon implementation of CYP2C19 genotype-guided pharmacotherapy in current clinical practice. Methods: This was a single-center observational cohort study. Adult percutaneous coronary intervention patients who received CYP2C19 genetic testing (*2, *3, *17 alleles) were included. Ticagrelor was recommended for patients with a LOF allele. Factors related to P2Y12 inhibitor selection were determined by logistic regression. The primary endpoint was major cardiac or cerebrovascular adverse events (MACCE) within 12 months. MACCE and clinically significant bleeding events (BARC ≥2) in the LOF-clopidogrel group, non-LOF-clopidogrel group, and non-LOF-ticagrelor group were compared with those in the LOF-ticagrelor group. The inverse probability of treatment weighting (IPTW) was adjusted in a Cox regression analysis to eliminate confounding factors. Results: Among 1,361 patients, 826 (60.7%) had a LOF allele. Patients with a LOF allele were more likely to be prescribed ticagrelor (multivariate-adjusted OR 1.349; 95% CI 1.040 to 1.751; p = 0.024). The MACCE rate was higher in the LOF-clopidogrel group than in the LOF-ticagrelor group (7.8 vs. 4.0%; log-rank p = 0.029; IPTW-adjusted HR 2.138; 95% CI 1.300-3.515). Compared with the LOF-ticagrelor group, the non-LOF-clopidogrel group showed no significant difference in MACCE rate (5.8 vs. 4.0%; log-rank p = 0.272; IPTW-adjusted HR 1.531; 95% CI 0.864-2.714). Among the patients treated with ticagrelor, there was no significant difference in the MACCE rate between the LOF group and non-LOF group (4.3 vs. 4.0%; log-rank p = 0.846; IPTW-adjusted HR 1.184; 95% CI 0.582-2.410). There was no significant difference in the incidence of clinically significant bleeding events among the four groups. Conclusion: This study confirms that efficiently returned CYP2C19 genotype results did partially guide cardiologists to prescribe ticagrelor for patients with a LOF allele, and that clopidogrel had a higher risk of MACCE than ticagrelor in these patients, which provides support for the implementation of CYP2C19 gene-guided antiplatelet therapy in clinical practice.