Repetition of Paclitaxel-Coated Devices for the Treatment of Lower Extremity Artery Disease: Mortality Outcomes and Predictors.

Background: A recent meta-analysis reported late excess mortality in patients treated with paclitaxel-coated devices (PCDs) for symptomatic femoropopliteal disease. However, this finding is controversial. Objectives: To investigate the impact on mortality and predictors of repeat exposure to PCDs in patients with lower extremity peripheral arterial disease (LE-PAD). Methods: We analyzed registry patient-level data from two centers. A total of 214 patients were enrolled, and stratified based on terciles of cumulative dose of paclitaxel. We treated 134 patients with a single PCD exposure and 80 with multiple PCD exposures. We used the follow-up index (FUI) in Kaplan-Meier survival estimates to minimize potential selection bias. We used Cox proportional hazard and splines models to determine the predictors of mortality and assess their relationships with mortality. Results: The mean cumulative dose of paclitaxel was significantly different among groups (6.40 mg vs. 15.06 mg vs. 38.57 mg, p < 0.001). The 5-year FUI (0.93 ± 0.19 vs. 0.94 ± 0.18 vs. 0.95 ± 0.15, p = 0.836) and survival rates were not different (65.4% vs. 51.9% vs. 72.0%, p = 0.148). There was no dose-response association between paclitaxel dosage and death (p = 0.297). The predictors of death were congestive heart failure, stroke, dialysis dependence, neutrophil-lymphocyte ratio (NLR) > 3, age > 71 years, and body mass index (BMI) < 20 kg/m2. Spline model analysis validated the non-linear associations between mortality, age, BMI, and NLR. Conclusions: Repeated PCD exposure for LE-PAD did not result in excess late mortality. Predictors of mortality might change over time, and continuous variables had non-linear relationships with death.

Long-Term Clinical Outcomes of New-Generation Drug-Eluting Stents in Coronary Artery Disease: A Real-World Observational Study.

BACKGROUND: Treating vessels with a very small reference vessel diameter (RVD) in coronary artery disease is challenging. OBJECTIVE: Long-term evaluation of new-generation drug-eluting stents (DESs) for the treatment of coronary lesions with different RVDs. METHODS: From April 2009 to March 2019, 780 patients who underwent single coronary stenting were divided into ≤ 2.25 (very small), 2.5-3.0 (small), and ≥ 3.5 mm (large) DES groups after 1:2:2 propensity score matching. The primary endpoint was target lesion failure (TLF), and the secondary endpoints were major adverse cardiac events (MACEs) and stent thrombosis (ST). RESULTS: During 3 years after new-generation DES implantation, TLF and MACE rates were significantly lower in the very small DES group. The risk of TLF was significantly lower in the very small DES group compared to the small DES group [very small vs. small: TLF, adjusted hazard ratio (HR) = 0.282, p = 0.040]. The risks of MACEs and all-cause mortality were significantly lower in the very small DES group compared to the small DES group (very small vs. small: MACEs, adjusted HR = 0.215, p = 0.001; all-cause mortality, adjusted HR = 0.181, p = 0.005). The cumulative incidence rates of TLF-free (log-rank test p = 0.001) and MACE-free (log-rank test p < 0.001) survival were significantly different among the groups, and the very small DES group had a high event-free survival rate. No cases of ST occurred in any group. CONCLUSIONS: Our results indicate that the use of new-generation DESs for treating coronary lesions in very small vessels is safe and effective.

Feasibility and Mid-Term Outcomes of Drug-Coated Balloon Angioplasty Between Intermittent Claudication and Critical Limb Ischemia in Patients with Femoropopliteal Disease.

BACKGROUND: The efficacy of drug-coated balloons (DCBs) in critical limb ischemia (CLI) is unclear. To investigate the clinical characteristics and outcomes of DCBs in symptomatic femoropopliteal disease between patients with intermittent claudication (IC) and CLI. METHODS: Data were retrospectively collected from three centers in Taiwan on patients who received DCBs for femoropopliteal lesions between March 2013 and June 2017. We compared the clinical characteristics and outcomes regarding binary restenosis, amputation-free survival (AFS), and major adverse limb events (MALEs) between groups. Cox proportional hazards analysis was used to identify predictors of outcome endpoints. RESULTS: We enrolled a total of 200 affected limbs in 174 patients, including 83 limbs in 71 patients with IC and 117 limbs in 103 patients with CLI. Compared to the patients with claudication, those with CLI were older and had higher proportions of medical comorbidities, tissue inflammation, poor runoff, and vessel calcification. The 3-year rates of freedom from binary restenosis (57% vs. 59%, p = 0.781), and MALEs (77% vs. 67%, p = 0.507) were similar between the two groups. However, the 3-year AFS was significantly higher in the IC group compared to the CLI group (91% vs. 73%, p = 0.001). Lesion length and severe calcification independently predicted binary restenosis, and restenotic lesion predicted MALEs. Age, congestive heart failure, and dialysis were independently associated with AFS. CONCLUSIONS: Despite advanced limb ischemia and comorbidities, the mid-term outcomes in surviving CLI patients were similar to those in the IC patients after treatment with DCBs for femoropopliteal disease.

Elevated Neutrophil-to-Lymphocyte Ratio Predicts Intermediate-Term Outcomes in Patients Who Have Advanced Chronic Kidney Disease with Peripheral Artery Disease Receiving Percutaneous Transluminal Angioplasty.

BACKGROUND: Inflammation plays an important role in the pathogenesis of cardiovascular disease in patients with advanced chronic kidney disease (CKD). Neutrophil-to-lymphocyte ratio (NLR), an inflammatory biomarker, has not been evaluated in patients who have advanced CKD with peripheral artery disease (PAD) undergoing percutaneous transluminal angioplasty (PTA), especially in Taiwan. METHODS: We retrospectively evaluated 148 advanced CKD (creatinine clearance rate ≤ 30 mL/min/1.73 m2) identified from a prospective registry in our hospital (303 PTA cases in total). Kaplan-Meier analysis with log-rank test was used to study event-free survival, and all univariables (p value < 0.1) were put into multivariate Cox regression analysis. RESULTS: During the mean follow-up time of 8.6 ± 7.8 months, 35.1% of the cases achieved primary composite endpoint (all-cause mortality or major amputation), 25.5% underwent death from any cause, and 14.9% underwent major or minor amputation. Rutherford grade 6, either NLR or NLR ≥ 3.76, and a history of hypertension had a positively prognostic impact on the occurrence of primary composite endpoint, whereas higher albumin level (≥ 3.0 mg/dL) and technical success had a significantly protective effect. History of hypertension, either NLR or NLR ≥ 3.76, and age were associated with all-cause mortality. In addition, Rutherford 6, higher albumin level (≥ 3.0 mg/dL), technical success, NLR, and age could predict the occurrence of major amputation. CONCLUSIONS: NLR, but not C-reactive protein or platelet-lymphocyte ratio, is an important prognostic predictor of all major clinical outcomes in patients with advanced CKD and PAD receiving PTA. Further studies are warranted to establish a better strategy and healthcare program in this clinical setting.

Pluripotent Stem Cell Therapy in Ischemic Cardiovascular Disease.

UNLABELLED: Stem cell therapy has been viewed as a promising therapeutic strategy in ischemic cardiovascular disease for almost a decade. Although many progenitor/stem cells obtained from patients have been investigated, and are alleged to be suitable for autologous transplantation, their therapeutic application has been limited by their inability to yield a sufficient number of stem cells, as well as impaired regeneration capacity from ageing and cardiovascular risk factors. Pluripotent stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have the capacity for functional multi-lineage differentiation and properties of self-renewal and immortality, and can generate clinically relevant amounts of stem cells. The regeneration capacity of these cells is not affected by ageing. Patient-specific pluripotent stem cells, iPSCs, can be established by epigenetically reprogramming somatic fibroblasts. iPSCs and iPSC-derived stem cells share similar phenotypes and gene expressions of ESCs and ESC-derived stem cells. Transplantation of pluripotent stem cell-derived endothelial cells, mural cells, cardiomyocytes, or cardiovascular progenitor cells contribute to neovascularization and cardiomyogenesis with better limb perfusion and recovery of myocardial contractility in the preclinical studies. Several strategies have been developed to enhance the efficacy of reprogramming and engrafting, and improve graft survival, proliferation, and electromechanical coupling by tissue engineering. However, the therapeutic application of ESCs and derivatives is limited by ethical concerns. Before wide clinical application of these cells in regeneration therapy occurs, substantial effort should be undertaken to discover the most promising cell type and derivatives, the best protocol regarding cell preparation, reprogramming and differentiation, and the most efficacious methods to avoid adverse effects. KEY WORDS: Embryonic stem cells; Induced pluripotent stem cells; Limb ischemia; Myocardial infarction.

Podocalyxin-Like Protein 1 Regulates Pluripotency through the Cholesterol Biosynthesis Pathway.

Deciphering signaling mechanisms critical for the extended pluripotent stem cell (EPSC) state and primed pluripotency is necessary for understanding embryonic development. Here, a membrane protein, podocalyxin-like protein 1 (PODXL) as being essential for extended and primed pluripotency, is identified. Alteration of PODXL expression levels affects self-renewal, protein expression of c-MYC and telomerase, and induced pluripotent stem cell (iPSC) and EPSC colony formation. PODXL is the first membrane protein reported to regulate de novo cholesterol biosynthesis, and human pluripotent stem cells (hPSCs) are more sensitive to cholesterol depletion than fibroblasts. The addition of exogenous cholesterol fully restores PODXL knockdown-mediated loss of pluripotency. PODXL affects lipid raft dynamics via the regulation of cholesterol. PODXL recruits the RAC1/CDC42/actin network to regulate SREBP1 and SREBP2 maturation and lipid raft dynamics. Single-cell RNA sequencing reveals PODXL overexpression enhanced chimerism between human cells in mouse host embryos (hEPSCs 57%). Interestingly, in the human-mouse chimeras, laminin and collagen signaling-related pathways are dominant in PODXL overexpressing cells. It is concluded that cholesterol regulation via PODXL signaling is critical for ESC/EPSC.

Off-label reduced-dose apixaban does not reduce hemorrhagic risk in Taiwanese patients with nonvalvular atrial fibrillation: A retrospective, observational study.

ABSTRACT: East Asians are reportedly at high risk of anticoagulant-related bleeding; therefore, some physicians prefer to prescribe low-dose direct oral anticoagulants (DOACs). Little is known about the therapeutic effectiveness and safety of off-label reduced-dose apixaban in East Asians with nonvalvular atrial fibrillation (AF). We aimed to investigate the effectiveness and safety of off-label reduced-dose apixaban in Taiwanese patients with nonvalvular AF.This retrospective cohort study enrolled 1073 patients with nonvalvular AF who took apixaban between July 2014 and October 2018 from 4 medical centers in southern Taiwan. The primary outcomes included thromboembolic events (stroke/transient ischemic attack or systemic embolism), major bleeding, and all-cause mortality.Among all patients, 826 (77%) patients were classified as the "per-label adequate-dose" treatment group (i.e., consistent with the Food and Drug Administration label recommendations) while 247 (23%) patients were the "off-label reduced-dose" treatment group. The mean follow-up period was 17.5 ±â€Š13 months. The "off-label reduced-dose" group did not have a lower major bleeding rate than the "per-label adequate-dose" group (4.8% vs 3.8%, adjusted hazard ratio [HR] 1.20, 95% confidence interval [CI] 0.69-2.09), but had a nonsignificantly higher incidence of thromboembolic events (4.23% vs 3.05%, adjusted HR: 1.29, 95% CI: 0.71-2.34).An off-label reduced-dose apixaban treatment strategy may not provide incremental benefits or safety for Taiwanese patients with nonvalvular AF.

Rosiglitazone reduces plasma levels of inflammatory and hemostatic biomarkers and improves global endothelial function in habitual heavy smokers without diabetes mellitus or metabolic syndrome.

BACKGROUND/PURPOSE: Thiazolidinediones have anti-atherothrombotic effects in diabetic patients. However, the effects of rosiglitazone on inflammatory and hemostatic markers, as well as global endothelial function in non-diabetic smokers are unknown. METHODS: Twenty-seven healthy male heavy smokers without metabolic syndrome were enrolled in this double-blind, controlled study. Fourteen subjects received 4 mg/day rosiglitazone for 8 weeks (group R) and 13 subjects received placebo (group C). Changes in the reflection index (Delta RI) of beta-agonist-induced endothelium-dependent vasodilatation by photoplethysmography and plasma biomarkers were measured before and after treatment. RESULTS: Matrix metalloproteinase-9, fibrinogen, and high-sensitivity C-reactive protein were reduced significantly in group R after treatment as compared with the baseline [84.1 (45.6 139.0) vs. 123.9 (58.4 141.8) ng/mL, p = 0.03; 2914 (2400-3553) vs. 3220 (2542-3940) mg/L, p = 0.04; and 3.4 (2.2 5.1) vs. 5.5 (4.1 6.8) mg/L, p = 0.009, respectively]. Delta RI was improved markedly in group R as compared with the baseline [13.5 (4.2 65.1) vs. 2.5 (-10.6 to 9.3)%; p = 0.024]. These biomarkers and Delta RI did not differ significantly in the group C. There were no significant changes in fasting plasma glucose, insulin, homeostasis model assessment index, and lipid profile in both groups R and group C. CONCLUSION: Rosiglitazone significantly reduces plasma levels of inflammatory and hemostatic biomarkers, and restores global endothelial dysfunction, independently from insulin sensitization, in healthy smokers.

Peak systolic velocity ratio derived from quantitative vessel analysis for restenosis after femoropopliteal intervention: a multidisciplinary review from Endovascular Asia.

With technological improvements in the endovascular armamentarium, there have been tremendous advances in catheter-based femoropopliteal artery intervention during the last decade. However, standardization of the methodology for assessing outcomes has been underappreciated, and unvalidated peak systolic velocity ratios (PSVRs) of 2.0, 2.4, and 2.5 on duplex ultrasonography have been arbitrarily but routinely used for assessing restenosis. Quantitative vessel analysis (QVA) is a widely accepted method to identify restenosis in a broad spectrum of cardiovascular interventions, and PSVR needs to be validated by QVA. This multidisciplinary review is intended to disseminate the importance of QVA and a validated PSVR based on QVA for binary restenosis in contemporary femoropopliteal intervention.

Failure mode and bimodal restenosis of drug-coated balloon in femoropopliteal intervention.

BACKGROUND: Pattern of DCB restenosis and associated outcomes in facing complex femoropopliteal lesions remain uncertain. METHODS: Data were retrospectively collected from dual centers in Taiwan on patients who underwent treatment with DCBs for femoropopliteal lesions between 2013 and 2016. The restenosis pattern was categorized by the index-treated length. Clinical outcomes and time to DCB restenosis were retrospectively analyzed. Cox proportional hazards model identified restenosis predictors. RESULTS: We recruited a total of 164 patients (91 men; median age 73 years) into the final analysis. The mean lesion length was 204.0 ±â€¯109.2 mm. Of them, 45% total occlusions, 28% severe calcification and 15% in-stent restenosis were treated. Fifty-five patients have DCB restenosis (28 focal and 27 diffuse-occlusive patterns) over a 55-month follow-up. The median restenosis time emerged as a bimodal pattern with a significant difference between the diffuse-occlusive and focal restenosis group (225 vs. 484 days, P = 0.01). The 1-year patency rate after reintervention for DCB restenosis also was different between both restenosis group (29% vs. 65%, P = 0.017). The anticipated timing of escape for diffuse-occlusive or focal restenosis was 687 and 1068 days, respectively. Independent factors were lesion length (P = 0.049) for diffuse-occlusive restenosis and lumen gain of the popliteal artery for focal restenosis (P = 0.034). CONCLUSIONS: This study demonstrated time to DCB failure emerged as a bimodal pattern of distribution and associations of restenosis pattern to subsequent outcomes after the repeated intervention. Exemption from late catchup restenosis required 3-year observation instead of the 1-year mark for conventional treatment.

Blockade of soluble epoxide hydrolase attenuates post-ischemic neuronal hyperexcitation and confers resilience against stroke with TrkB activation.

Inhibition and deletion of soluble epoxide hydrolase (sEH) has been suggested to ameliorate infarction in experimental ischemic stroke possibly via vasoactive epoxyeicosatrienoic acids. However, it is unknown whether the neuroprotective mechanisms involve alteration of post-ischemic neuronal transmission and neurotrophic signaling. We used a permanent middle cerebral artery occlusion (MCAO) model in adult wild-type mice with the sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA) post-treatment and in sEH knockout (sEH KO) mice. We found that sensorimotor recovery was significantly enhanced after MCAO in both AUDA-treated and sEH KO mice, with decreased sEH activity and brain infarction. Decreased post-ischemic long-term potentiation (iLTP) was observed in an ex vivo hippocampal oxygen-glucose deprivation model. Tropomyosin receptor kinase B (TrkB) activation, rather than glutamate receptor alteration, was consistently found after the different manipulations. Immunohistochemistry further revealed peri-infarct neuronal TrkB activation and microvasculature augmentation in AUDA-treated and sEH KO mice, suggesting parallel neurovascular enhancement. Mechanistically, pretreatment with a selective TrkB antagonist ANA12 countered the effect of iLTP attenuation induced by sEH deletion ex vivo and abolished the infarct reduction in vivo. Together, the neuroprotective effects of sEH inhibition and gene deletion can both be mediated partially via enhancement of TrkB signaling which attenuated post-ischemic neuroexcitation and neurological deficits.

Impacts of Cross-Linkers on Biological Effects of Mesoporous Silica Nanoparticles.

Chemically synthesized cross-linkers play decisive roles in variable cargos attached to nanoparticles (NPs). Previous studies reported that surface properties, such as the size, charge, and surface chemistry, are particularly important determinants influencing the biological fate and actions of NPs and cells. Recent studies also focused on the relationship of serum proteins with the surface properties of NPs (also called the protein corona), which is recognized as a key factor in determining the cytotoxicity and biodistribution. However, there is concern that cross-linkers conjugated onto NPs might induce undesirable biological effects. Cell responses induced by cross-linkers have not yet been precisely elucidated. Herein, using mesoporous silica nanoparticles (MSNs) the surfaces of which were separately conjugated with four popular heterobifunctional cross-linkers, i.e., N-[α-maleimidoacetoxy]succinimide ester (AMAS), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and maleimide poly(ethylene glycol) succinimidyl carboxymethyl ester (MAL-PEG-SCM), we investigated cross-linker-conjugated MSNs to determine whether they can cause cytotoxicity, or enhance reactive oxygen species (ROS) generation, nuclear factor (NF)-κB activation, and p-p38 or p21 protein expressions in RAW264.7 macrophage cells. Furthermore, we also separately conjugated two biomolecules containing TAT peptides and bovine serum albumin (BSA) as model systems to study their cell responses in detail. Finally, in vivo mice studies evaluated the biodistribution and blood assays (biochemistry and complete blood count) of PEG-derivative NPs, and results suggested that TAT peptides caused significant white blood cell (WBC)-related cell and platelet abnormalities, as well as liver and kidney dysfunction compared to BSA when conjugated onto MSNs. The results showed that attention to cross-linkers should be considered an issue in the surface modification of NPs. We anticipate that our results could be helpful in developing biosafety nanomaterials.

Effect of cilostazol on plasma levels of proprotein convertase subtilisin/kexin type 9.

The protein complex proprotein convertase subtilisin/kexin type 9 (PCSK9) serves as an important target for the prevention and treatment of atherosclerosis and lipid homeostasis. This study investigated the effect of cilostazol on plasma PCSK9 concentrations. We performed a post hoc analysis of two prospective, double-blind, randomized controlled trials including 115 patients of whom 61 received cilostazol 200 mg/day and 54 received placebo for 12 weeks. Linear regression analysis was performed to determine the associations between several parameters and changes in PCSK9 levels. Use of cilostazol, but not placebo, significantly increased plasma PCSK9 concentrations, high-density lipoprotein cholesterol levels, and number of circulating endothelial progenitor cells (EPCs), and decreased triglyceride levels with a trend toward an increase in total cholesterol (TC) levels. A reduction in hemoglobin A1C and an increase in plasma vascular endothelial growth factor and adiponectin levels with cilostazol treatment were also found. Changes in the number of circulating EPCs were positively correlated and the TC concentrations were inversely correlated with changes in the PCSK9 levels. After adjusting for changes in levels of TC and numbers of circulating EPCs and history of metabolic syndrome, use of cilostazol remained independently associated with changes in plasma PCSK9 levels. In conclusion, cilostazol treatment was significantly and independently associated with an increase in plasma PCSK9 levels in patients with peripheral artery disease or at a high risk of cardiovascular disease regardless of background statin use and caused an improvement in some metabolic disorders and levels of vasculo-angiogenic biomarkers.

Plasma Levels of Proprotein Convertase Subtilisin/Kexin Type 9 Are Elevated in Patients With Peripheral Artery Disease and Associated With Metabolic Disorders and Dysfunction in Circulating Progenitor Cells.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in cholesterol homeostasis, inflammation, and oxidative stress. This study investigated the association of plasma PCSK9 levels with the presence and severity of peripheral artery disease (PAD) and with parameters of endothelial homeostasis. METHODS AND RESULTS: A post hoc analysis of 2 randomized trials (115 patients, 44 with PAD and 71 without atherosclerotic disease) was conducted. Patients with PAD had significantly higher plasma PCSK9 levels than those without (471.6±29.6 versus 302.4±16.1 ng/mL, P<0.001). Parameters for glucose homeostasis, endothelial progenitor cell functions, apoptotic circulating endothelial cell counts, and plasma levels of vascular endothelial growth factor-A165 and oxidized low-density lipoprotein were correlated with PCSK9 concentration. By multivariable linear regression analysis, presence of PAD, plasma glucose or hemoglobin A1c levels, apoptotic circulating endothelial cell counts, and vascular endothelial growth factor-A165 concentration were found to be associated with PCSK9 levels after multivariable adjustment. Patients with extensive involvement of PAD or with severe PAD had significantly higher PCSK9 levels than those without PAD. Computed tomographic angiography showed that the numbers of chronic total occlusion sites and vessels involved were positively associated with PCSK9 levels in patients with PAD (r=0.40, P=0.01, and r=0.36, P=0.02, respectively). CONCLUSION: PCSK9 levels were significantly higher in patients with PAD, especially those with advanced PAD. Further large-scale studies examining the effect of PCSK9-targeting therapies or the modification of PCSK9 levels on cardiovascular outcomes in this clinical setting are warranted. CLINICAL TRIAL REGISTRATION: Cohort 1: URL: ClinicalTrials.gov. Unique identifier: NCT01952756; cohort 2: URL: ClinicalTrials.gov. Unique identifier: NCT02194686.

Cilostazol Enhances Mobilization of Circulating Endothelial Progenitor Cells and Improves Endothelium-Dependent Function in Patients at High Risk of Cardiovascular Disease.

This is the first study to investigate the vasculoangiogenic effects of cilostazol on endothelial progenitor cells (EPCs) and flow-mediated dilatation (FMD) in patients at high risk of cardiovascular disease (CVD). This double-blind, placebo-controlled study included 71 patients (37 received 200 mg/d cilostazol and 34 received placebo for 12 weeks). Use of cilostazol, but not placebo, significantly increased circulating EPC (kinase insert domain receptor(+)CD34(+)) counts (percentage changes: 149.0% [67.9%-497.8%] vs 71.9% [-31.8% to 236.5%], P = .024) and improved triglyceride and high-density lipoprotein cholesterol levels (P = .002 and P = .003, respectively). Plasma levels of vascular endothelial growth factor (VEGF)-A165 and FMD significantly increased (72.5% [32.9%-120.4%] vs -5.8% [-46.0% to 57.6%], P = .001; 232.8% ± 83.1% vs -46.9% ± 21.5%, P = .003, respectively) in cilostazol-treated patients. Changes in the plasma triglyceride levels significantly inversely correlated with the changes in the VEGF-A165 levels and FMD. Cilostazol significantly enhanced the mobilization of EPCs and improved endothelium-dependent function by modifying some metabolic and angiogenic markers in patients at high risk of CVD.

Efficacy and safety of ticagrelor versus clopidogrel in acute coronary syndrome in Taiwan: A multicenter retrospective pilot study.

BACKGROUND: The efficacy and safety of ticagrelor compared with clopidogrel in acute coronary syndrome has not previously been evaluated in an Eastern Asian population, which is recognized to have a different response to P2Y12 antagonists compared with the Caucasian population in real-life situations. METHODS: A multicenter retrospective pilot study was performed to evaluate 928 consecutive patients with acute coronary syndrome, receiving aspirin and one P2Y12 antagonist (324 ticagrelor or 604 clopidogrel). Using propensity score matching, 448 patients were selected and divided into two equal groups. Kaplan-Meier analysis was used to study patient survival and event-free status using the log-rank test. Independent covariates were identified using univariate in a multivariate Cox proportional hazard model. RESULTS: In the overall cohort, significant differences were observed for certain variables between the two groups. During the mean 164.3 (±116.4)-day follow-up in the overall cohort, ticagrelor treatment had no significant effect on the primary efficacy endpoint (myocardial infarction, stroke, or vascular death); however, in the matched cohort, ticagrelor showed a lower incidence of primary endpoint (hazard ratio: 0.56; 95% confidence interval: 0.30-1.04; p = 0.07) and stroke (hazard ratio: 0.15; 95% confidence interval: 0.02-1.24; p = 0.08) with marginal statistical significance, and a similar bleeding rate. The protective effect of ticagrelor treatment was consistent for all subgroups. More patients treated with ticagrelor experienced dyspnea (21.0% vs. 11.6%, p = 0.007), and P2Y12 antagonist treatment was consequently discontinued. CONCLUSION: Ticagrelor treatment could provide a marginally favorable effect at the expense of an increased risk of dyspnea in real-life situations. This pilot study provides a scientific basis to call for a larger, suitably powered Phase 4 prospective or observational study in this ethnic population.

Impact of routine coronary catheterization in low extremity artery disease undergoing percutaneous transluminal angioplasty: study protocol for a multi-center randomized controlled trial.

BACKGROUND: The prevalence of significant obstructive coronary artery disease with complex lesions is high in patients who have low extremity artery disease (LEAD). However, intermediate- or long-term cardiovascular prognosis of LEAD patients undergoing percutaneous transluminal angioplasty (PTA) remains poor. Accordingly, prophylactic coronary revascularization may modify short- and long-term cardiovascular outcomes of LEAD patients receiving PTA. Because myocardial ischemic symptoms are often masked in LEAD and the accuracy of non-invasive stress tests is usually limited, a high-quality randomized controlled trial aimed at the investigation of the prognostic role of coronary evaluation strategies before PTA is warranted. METHODS/DESIGN: The proposed study is designed as a prospective, multi-center, open-label, superiority, randomized controlled trial. The study is conducted in high-volume centers for PTA and coronary revascularization in Taiwan. To meet the inclusion criteria, the patients must be at least 20 years old, have known LEAD, and have been admitted for elective PTA. We plan to enroll 450 participants who are randomly allocated to a routine group (routine coronary angiography without a previous non-invasive stress test before PTA) and a selective group (selective coronary angiography based on the results of non-invasive stress tests before PTA) with 1:1 ratio. Besides, we expect to enroll about 250 additional participants, who are not willing to be randomly assigned, in the registration group. The choice of revascularization procedure depends on the operator's or cardiovascular team's suggestion and the patient's decision. Clinical follow-up will be performed 30 days after PTA and every 6 months until the end of the 1-year follow-up for the last randomly assigned participant. The primary endpoint is the composite major adverse cardiac event on long-term follow-up. Pre-specified secondary and other endpoints are also evaluated. Those assessing biomarkers and clinical endpoints are all blinded after assignment to interventions. DISCUSSION: The results of the trial will, for the first time, support better decision-making for coronary evaluation before PTA in LEAD. If favorable, routine coronary angiography followed by revascularization will improve cardiovascular outcomes in LEAD patients undergoing PTA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02169258 (registered on 21 June 2014); registry name: Routine Coronary Catheterization in Low Extremity Artery Disease Undergoing Percutaneous Transluminal Angioplasty (PIROUETTE-PTA).