P2Y12 Inhibitor Monotherapy versus Conventional Dual Antiplatelet Therapy in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: A Meta-Analysis.

P2Y12 inhibitor monotherapy is a feasible alternative treatment for patients after percutaneous coronary intervention (PCI) in the modern era. Clinical trials have shown that it could lower the risk of bleeding complications without increased ischemic events as compared to standard dual antiplatelet therapy (DAPT). However, the efficacy and safety of this novel approach among patients with acute coronary syndrome (ACS) are controversial because they have a much higher risk for recurrent ischemic events. The purpose of this study is to evaluate the efficacy and safety of this novel approach among patients with ACS. We conducted a meta-analysis of randomized controlled trials that compared P2Y12 inhibitor monotherapy with 12-month DAPT in ACS patients who underwent PCI with stent implantation. PubMed, Embase, the Cochrane library database, ClinicalTrials.gov, and other three websites were searched for data from the earliest report to July 2022. The primary efficacy outcome was major adverse cardiovascular and cerebrovascular events (MACCE), a composite of all-cause mortality, myocardial infarction, stent thrombosis, or stroke. The primary safety outcome was major or minor bleeding events. The secondary endpoint was net adverse clinical events (NACE), defined as a composite of major bleeding and adverse cardiac and cerebrovascular events. Five randomized controlled trials with a total of 21,034 patients were included in our meta-analysis. The quantitative analysis showed a significant reduction in major or minor bleeding events in patients treated with P2Y12 inhibitor monotherapy as compared with standard DAPT(OR: 0.59, 95% CI: 0.46-0.75, p < 0.0001) without increasing the risk of MACCE (OR: 0.98, 95% CI: 0.86-1.13, p = 0.82). The NACE was favorable in the patients treated with P2Y12 inhibitor monotherapy (OR: 0.82, 95% CI: 0.73-0.93, p = 0.002). Of note, the overall clinical benefit of P2Y12 inhibitor monotherapy was quite different between ticagrelor and clopidogrel. The incidence of NACE was significantly lower in ticagrelor monotherapy as compared with DAPT (OR: 0.79, 95% CI: 0.68-0.91), but not in clopidogrel monotherapy (OR: 1.14, 95% CI: 0.79-1.63). Both clopidogrel and ticagrelor monotherapy showed a similar reduction in bleeding complications (OR: 0.46, 95% CI: 0.22-0.94; OR: 0.60, 95% CI: 0.44-0.83, respectively). Although statistically insignificant, the incidence of MACCE was numerically higher in clopidogrel monotherapy as compared with standard DAPT (OR: 1.50, 95% CI: 0.99-2.28, p = 0.06). Based on these findings, P2Y12 inhibitor monotherapy with ticagrelor would be a better choice of medical treatment for ACS patients after PCI with stent implantation in the current era.

Tumor endothelial marker 1 is upregulated in heart after cardiac injury and participates in cardiac remodeling.

Tumor endothelial marker 1 (TEM1) is a transmembrane glycoprotein that appears on mesenchymal lineage-derived cells during embryogenesis, but its expression greatly reduces after birth. Re-upregulation of TEM1 is found in tumor angiogenesis, organ fibrosis and wound healing indicating its potential role in tissue remodeling and repair. The expression level and function of TEM1 in adult heart are unknown. In explanted hearts from heart failure (HF) patients received cardiac transplantation, immunofluorescence staining showed TEM1 was expressed in cardiomyocytes (CMs) and cardiac fibroblasts. Bioinformatics analysis showed TEM1 upregulation in mouse heart after coronary ligation. Cardiac TEM1 expression was reconfirmed in mouse HF induced by coronary ligation or doxorubicin injection. TEM1 expression increased in cultured CMs stimulated with mechanical stretch, doxorubicin and hypoxia. Further studies showed recombinant TEM1 (rTEM1) was a functional protein that influenced cell behaviors of CMs. It directly activated Erk and Akt through interaction with PDGF receptor. TEM1lacZ/lacZ mice had less collagen deposition and worse cardiac function than wild type mice. These results indicate that TEM1 expression increases in the heart after cardiac injury and works as a functional protein that participates in cardiac remodeling.

A three-step stacking capillary electrophoresis of field-amplified sample injection, sweeping, and micellar collapse for determination of dabigatran and its active metabolite in human plasma.

A three-step stacking capillary electrophoresis (CE) composed of field-amplified sample injection, sweeping, and analyte focusing by micellar collapse (FASI-sweeping-AFMC) was developed to determine dabigatran (D) and its major active metabolite, dabigatran acyl-beta-d-glucuronide (DAG), in human plasma. After optimization and validation, this novel approach was further applied to monitor 5 real samples, and the 25.2-186.8 ng mL-1 D could be observed among those. Based on these results, the novel CE stacking strategy was successfully applied for the analysis of D and DAG in human plasma and could be served as a tool for clinical assays.

Comparative Efficacy and Safety of P2Y12 Inhibitor Monotherapy and Dual Antiplatelet Therapy in Patients with and without Diabetes Mellitus Undergoing Percutaneous Coronary Intervention.

Increasing evidence has shown P2Y12 inhibitor monotherapy is a feasible alternative treatment for patients after percutaneous coronary intervention (PCI) with stent implantation in the modern era. However, patients with diabetes mellitus (DM) have a higher risk of ischemic events and more complex coronary artery disease. The purpose of this study is to evaluate the efficacy and safety of this novel approach among patients with DM and those without DM. We conducted a systematic review and meta-analysis of randomized controlled trials that compared P2Y12 inhibitor monotherapy with 12 months of dual antiplatelet therapy (DAPT) in patients who underwent PCI with stent implantation. PubMed, Embase, Cochrane library database, ClinicalTrials.gov, and three other websites were searched for our data from the earliest report to January 2022. The primary efficacy outcome was major adverse cardiovascular and cerebrovascular events (MACCE): a composite of all-cause mortality, myocardial infarction, stent thrombosis, and stroke. The primary safety outcome was major or minor bleeding events. The secondary endpoint was net adverse clinical events (NACE) which are defined as a composite of major bleeding and adverse cardiac and cerebrovascular events. A total of four randomized controlled trials with 29,136 patients were included in our meta-analysis. The quantitative analysis showed a significant reduction in major or minor bleeding events in patients treated with P2Y12 inhibitor monotherapy compared to standard DAPT (OR: 0.68, 95% CI: 0.46-0.99, p = 0.04) without increasing the risk of MACCE (OR: 0.96, 95% CI: 0.85-1.09, p = 0.50). The number of NACE was significantly lower in the patients treated with P2Y12 inhibitor monotherapy (OR: 0.84, 95% CI: 0.72-0.97, p = 0.019). In DM patients, P2Y12 inhibitor monotherapy was associated with a lower risk of MACCE compared to standard DAPT (OR: 0.85, 95% CI: 0.74-0.98, p = 0.02). Furthermore, P2Y12 inhibitor monotherapy was accompanied by a favorable reduction in major or minor bleeding events (OR: 0.80, 95% CI: 0.64-1.05, p = 0.107). In non-DM patients, P2Y12 inhibitor monotherapy showed a significant reduction in major or minor bleeding events (OR: 0.58, 95% CI: 0.38-0.88, p = 0.01), but without increasing the risk of MACCE (OR: 0.99, 95% CI: 0.82-1.19, p = 0.89). Based on these findings, P2Y12 inhibitor monotherapy could significantly decrease bleeding events without increasing the risk of stent thrombosis or myocardial infarction in the general population. The benefit of reducing bleeding events was much more significant in non-DM patients than in DM patients. Surprisingly, P2Y12 inhibitor monotherapy could lower the risk of MACCE in DM patients. Our study supports that P2Y12 inhibitor monotherapy is a promising alternative choice of medical treatment for patients with DM undergoing PCI with stent implantation in the modern era.

Soluble tumor endothelial marker 1 in heart failure with reduced ejection fraction: A pilot study.

Background: Tumor endothelial marker 1 (TEM1/CD248) is a transmembrane protein that expresses in mesenchymal lineage derived cells during embryogenesis and becomes undetectable in normal adults after birth. Re-expression of TEM1 is found in organ fibrosis, wound healing and cardiac remodeling indicating its potential role in heart failure (HF). The purpose of this study is to explore the role of soluble TEM1 (sTEM1) in patients with HF with reduced ejection fraction. Methods: We examined endomyocardial biopsy specimens from three HF patients and blood samples from 48 patients admitted for acute decompensated HF (age 72 years, men 61.7%). The expression of TEM1 in cardiac tissue and concentrations of sTEM1 in plasma were evaluated. Cultured rat cardiomyocytes (H9c2) and human cardiac fibroblasts (HCF) were stimulated with hypoxia or transforming growth factor beta (TGF-ß) to observe the release of sTEM1 into culture media. The conditioned media of hypoxia-stimulated H9c2 cells was harvested and added into cultured cardiac fibroblast to evaluate its biological effect. Results: Immunofluorescence study of biopsy specimens from three HF patients showed TEM1 expression in cardiomyocytes and cardiac fibroblasts. The plasma level of sTEM1 was significantly higher in patients (0.90 ± 0.23 vs. 0.33 ± 0.10 ng/mL, p = 0.032) with LVEF ≤ 35% compared with those with LVEF 36-49%. The sTEM1 levels had correlations with HF biomarkers of cardiac fibrosis, including growth differentiation factor-15 (GDF-15) and galectin-3. There was a significant increase in sTEM1 levels in the cultured media of H9c2 and HCF after being stressed with hypoxia or TGF-ß. The conditioned media derived from hypoxia-stimulated H9c2 cells significantly increased cell proliferation of cardiac fibroblasts. This effect was partially reversed by anti-TEM1 antibody. Conclusion: This pilot study demonstrated that cardiac TEM1 expression was upregulated in HF. The levels of sTEM1 were significantly higher in HF patients with LVEF ≤ 35% and correlated with other biomarkers of cardiac fibrosis. In vitro study proved that functional sTEM1 was released into cultured media after stressing cardiomyocytes and HCF.

Effect of aspirin treatment duration on clinical outcomes in acute coronary syndrome patients with early aspirin discontinuation and received P2Y12 inhibitor monotherapy.

Recent clinical trials showed that short aspirin duration (1 or 3 months) in dual antiplatelet therapy (DAPT) followed by P2Y12 inhibitor monotherapy reduced the risk of bleeding and did not increase the ischemic risk compared to 12-month DAPT in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). However, it is unclear about the optimal duration of aspirin in P2Y12 inhibitor monotherapy. The purpose of this study was to evaluate the influence of aspirin treatment duration on clinical outcomes in a cohort of ACS patients with early aspirin interruption and received P2Y12 inhibitor monotherapy. From January 1, 2014 to December 31, 2018, we included 498 ACS patients (age 70.18 ± 12.84 years, 71.3% men) with aspirin stopped for various reasons before 6 months after PCI and received P2Y12 inhibitor monotherapy. The clinical outcomes between those with aspirin treatment ≤ 1 month and > 1 month were compared in 12-month follow up after PCI. Inverse probability of treatment weighting was used to balance the covariates between groups. The mean duration of aspirin treatment was 7.52 ± 8.10 days vs. 98.05 ± 56.70 days in the 2 groups (p<0.001). The primary composite endpoint of all-cause mortality, recurrent ACS or unplanned revascularization and stroke occurred in 12.6% and 14.4% in the 2 groups (adjusted HR 1.19, 95% CI 0.85-1.68). The safety outcome of BARC 3 or 5 bleeding was also similar (adjusted HR 0.69, 95% CI 0.34-1.40) between the 2 groups. In conclusion, patients with ≤ 1 month aspirin treatment had similar clinical outcomes to those with treatment > 1 month. Our results indicated that ≤ 1-month aspirin may be enough in P2Y12 inhibitor monotherapy strategy for ACS patients undergoing PCI.

P2Y12 Inhibitor Monotherapy after Percutaneous Coronary Intervention: Is It Safe to Abandon Aspirin?

Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor for 6-12 months is the current standard treatment for patients after percutaneous coronary intervention (PCI). However, the optimal DAPT duration is still under debate. A novel strategy with P2Y12 inhibitor monotherapy after PCI has been proposed recently. This strategy shortens the duration of DAPT to 1 to 3 months, followed by monotherapy with a P2Y12 inhibitor instead of aspirin. It has been tested in several clinical trials with promising results. In this article, we reviewed the relevant clinical trial data and the scientific rationale of P2Y12 inhibitor monotherapy with laboratory evidence of platelet inhibition. An early aspirin-free strategy with P2Y12 inhibitor monotherapy seems feasible in some of the patients after PCI.

Impact of the Dual Antiplatelet Therapy Score on Clinical Outcomes in Acute Coronary Syndrome Patients Receiving P2Y12 Inhibitor Monotherapy.

Background: Dual antiplatelet therapy (DAPT) score is used to stratify ischemic and bleeding risk for antiplatelet therapy after percutaneous coronary intervention (PCI). This study assessed the association between the DAPT score and clinical outcomes in acute coronary syndrome (ACS) patients who were treated with P2Y12 inhibitor monotherapy. Methods: A total of 498 ACS patients, with early aspirin discontinuation for various reasons and who received P2Y12 inhibitor monotherapy after PCI, were enrolled during the period from January 1, 2014 to December 31, 2018. The efficacy and safety between those with low (<2) and high (≥2) DAPT scores were compared during a 12-month follow-up after PCI. Inverse probability of treatment weighting was used to balance the covariates between the two groups. The primary endpoint was a composite outcome of all-cause mortality, recurrent ACS or unplanned revascularization, and stroke within 12 months. The safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding. Results: The primary composite endpoint occurred in 11.56 and 14.38% of the low and high DAPT score groups, respectively. Although there was no significant difference in the primary composite endpoint between the two groups in the multivariate Cox proportional hazards models, the risk of recurrent ACS or unplanned revascularization was significantly higher in the high DAPT score group (adjusted hazard ratio [HR]: 1.900, 95% confidence interval [CI]: 1.095-3.295). The safety outcome for BARC 3 or 5 bleeding was similar between the two groups. Conclusions: Our results indicate that ACS patients receiving P2Y12 monotherapy with high DAPT score had an increased risk of recurrent ACS or unplanned revascularization.

Effects of Lipids and Lipoproteins on Mesenchymal Stem Cells Used in Cardiac Tissue Regeneration.

Mesenchymal stem cells (MSCs) have two characteristics of interest for this paper: the ability to self-renew, and the potential for multiple-lineage differentiation into various cells. MSCs have been used in cardiac tissue regeneration for over a decade. Adult cardiac tissue regeneration ability is quite low; it cannot repair itself after injury, as the heart cells are replaced by fibroblasts and lose function. It is therefore important to search for a feasible way to repair and restore heart function through stem cell therapy. Stem cells can differentiate and provide a source of progenitor cells for cardiomyocytes, endothelial cells, and supporting cells. Studies have shown that the concentrations of blood lipids and lipoproteins affect cardiovascular diseases, such as atherosclerosis, hypertension, and obesity. Furthermore, the MSC lipid profiles, such as the triglyceride and cholesterol content, have been revealed by lipidomics, as well as their correlation with MSC differentiation. Abnormal blood lipids can cause serious damage to internal organs, especially heart tissue. In the past decade, the accumulated literature has indicated that lipids/lipoproteins affect stem cell behavior and biological functions, including their multiple lineage capability, and in turn affect the outcome of regenerative medicine. This review will focus on the effect of lipids/lipoproteins on MSC cardiac regenerative medicine, as well as the effect of lipid-lowering drugs in promoting cardiomyogenesis-associated MSC differentiation.

P2Y12 Inhibitor Monotherapy with Clopidogrel Versus Ticagrelor in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

BACKGROUND: P2Y12 inhibitor monotherapy is an alternative antiplatelet strategy in patients undergoing percutaneous coronary intervention (PCI). However, the ideal P2Y12 inhibitor for monotherapy is unclear. METHODS AND RESULTS: We performed a multicenter, retrospective, observational study to compare the efficacy and safety of monotherapy with clopidogrel versus ticagrelor in patients with acute coronary syndrome (ACS) undergoing PCI. From 1 January 2014 to 31 December 2018, 610 patients with ACS who received P2Y12 monotherapy with either clopidogrel (n = 369) or ticagrelor (n = 241) after aspirin was discontinued prematurely were included. Inverse probability of treatment weighting was used to balance covariates between the groups. The primary endpoint was the composite of all-cause mortality, recurrent ACS or unplanned revascularization, and stroke within 12 months after discharge. Overall, 84 patients reached the primary endpoint, with 57 (15.5%) in the clopidogrel group and 27 (11.2%) in the ticagrelor group. Multivariate adjustment in Cox proportional-hazards models revealed a lower risk of the primary endpoint with ticagrelor than with clopidogrel (adjusted hazard ratio (aHR): 0.67, 95% confidence interval (CI): 0.49-0.93). Ticagrelor significantly reduced the risk of recurrent ACS or unplanned revascularization (aHR: 0.46, 95% CI: 0.28-0.75). No significant difference in all-cause mortality and major bleeding events was observed between the 2 groups. CONCLUSIONS: Among patients with ACS undergoing PCI who cannot complete course of dual antiplatelet therapy, a significantly lower risk of cardiovascular events was associated with ticagrelor monotherapy than with clopidogrel monotherapy. The major bleeding risk was similar in both the groups.

The effects of secondary prevention after coronary revascularization in Taiwan.

BACKGROUND: Secondary prevention therapy for patients with coronary artery disease using an antiplatelet agent, ß-blocker, renin-angiotensin system blocker (RASB), or statin plays an important role in the reduction of coronary events after coronary artery bypass grafting (CABG) surgery or percutaneous coronary intervention (PCI). We analyzed the status and effects of secondary prevention after coronary revascularization in Taiwan. METHODS: This national population-based cohort study was conducted by analyzing the Longitudinal Health Insurance Database 2000 from the National Health Insurance Research Database of Taiwan. Patients who underwent CABG or PCI from 2004 to 2009 were included in the analysis. The baseline characteristics of the patients and ACC/AHA class I medication use at 12 months were analyzed. The primary endpoints were a composite of major adverse cardiac and cerebrovascular events. RESULTS: A total of 5544 patients comprising 895 CABG and 4649 PCI patients were evaluated. CABG patients had more comorbidities and a higher rate of major adverse event during the follow-up period. However, use of antiplatelet agents and RASB at 12 months was significantly lower in CABG patients than in PCI patients (44.2% vs. 50.9% and 38.6% vs. 48.9%, both p < 0.01). Age, diabetes, and chronic kidney disease were independent risk factors while statin use was a protective factor for the primary endpoints in both PCI and CABG groups. CONCLUSION: There is still much room to improve class I medication use in secondary prevention for patients after revascularization in Taiwan. Statin could be an effective treatment to improve the outcomes.