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. 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. 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. 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.

Background: Proprotein convertase subtilisin/kexin type 9 ( PCSK 9) is involved in cholesterol homeostasis, inflammation, and oxidative stress. This study investigated the association of plasma PCSK 9 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 PCSK 9 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 PCSK 9 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 PCSK 9 levels after multivariable adjustment. Patients with extensive involvement of PAD or with severe PAD had significantly higher PCSK 9 levels than those without PAD. Computed tomographic angiography showed that the numbers of chronic total occlusion sites and vessels involved were positively associated with PCSK 9 levels in patients with PAD ( r =0.40, P =0.01, and r =0.36, P =0.02, respectively). Conclusion: PCSK 9 levels were significantly higher in patients with PAD , especially those with advanced PAD . Further large‐scale studies examining the effect of PCSK 9‐targeting therapies or the modification of PCSK 9 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.

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. 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. 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. 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).

Cilostazol is an anti-platelet agent with vasodilatory activity that acts by increasing intracellular concentrations of cAMP. Recent reports have suggested that cilostazol may promote angiogenesis. In the present study, we have investigated the effect of cilostazol in promoting angiogenesis and vasculogenesis in a hindlimb ischaemia model and have also examined its potential mechanism of action in vitro and in vivo. We found that cilostazol treatment significantly increased colony formation by human early EPCs (endothelial progenitor cells) through a mechanism involving the activation of cAMP/PKA (protein kinase A), PI3K (phosphoinositide 3-kinase)/Akt/eNOS (endothelial NO synthase) and ERK (extracellular-signal-regulated kinase)/p38 MAPK (mitogen-activated protein kinase) signalling pathways. Cilostazol also enhanced proliferation, chemotaxis, NO production and vascular tube formation in HUVECs (human umbilical vein endothelial cells) through activation of multiple signalling pathways downstream of PI3K/Akt/eNOS. Cilostazol up-regulated VEGF (vascular endothelial growth factor)-A165 expression and secretion of VEGF-A in HUVECs through activation of the PI3K/Akt/eNOS pathway. In a mouse hindlimb ischaemia model, recovery of blood flow ratio (ipsilateral/contralateral) 14 days after surgery was significantly improved in cilostazol-treated mice (10 mg/kg of body weight) compared with vehicle-treated controls (0.63±0.07 and 0.43±0.05 respectively, P<0.05). Circulating CD34+ cells were also increased in cilostazol-treated mice (3614±670 compared with 2151±608 cells/ml, P<0.05). Expression of VEGF and phosphorylation of PI3K/Akt/eNOS and ERK/p38 MAPK in ischaemic muscles were significantly enhanced by cilostazol. Our data suggest that cilostazol produces a vasculo-angiogenic effect by up-regulating a broad signalling network that includes the ERK/p38 MAPK, VEGF-A165, PI3K/Akt/eNOS and cAMP/PKA pathways.