One-year efficacy and safety of prasugrel and ticagrelor in patients with acute coronary syndromes: Results from a prospective and multicentre ACHILLES registry.

BACKGROUND: Prasugrel and ticagrelor have demonstrated higher efficacy than clopidogrel in their main clinical trials for patients with acute coronary syndrome (ACS). However, the long-term prognosis and different clinical characteristics related to the type of antiplatelet prescription in current clinical practice ACS patients have not been analysed in depth. The objective of this study was to analyse the clinical profile of ACS and the efficacy and safety of novel oral P2Y12 inhibitors in current clinical practice patients discharged afterACS. METHODS: We collected data from the ACHILLES registry, and an observational, prospective and multicentre registry of patients discharged after ACS. We analysed baseline characteristics, clinical profile and therapy during ACS admission and compared with the different treatments at discharge. After 1 year of follow-up, ischaemic and major bleeding events were analysed. Multivariate Cox regression analysis and Kaplan Meier curves were also plotted. RESULTS: Of 1717 consecutive patients, 1294 (75.4%) were discharged with a P2Y12 inhibitor without oral anticoagulation. Novel oral P2Y12 inhibitors were indicated in 47%. Patients treated with clopidogrel were elderly (69.1 ± 13.4 vs 60.4 ± 11.5 years; P < .001) and had a higher prevalence of cardiovascular risk factors. GRACE and CRUSADE scores were higher in the clopidogrel than in novel oral P2Y12 inhibitors group (P < .001). After 1 year of follow-up, 64(5.0%/year) patients had a new myocardial infarction, 127(10.0%/year) had a major adverse cardiovascular event (MACE) and 78(6.1%/year) died. Patients treated with clopidogrel had a significantly higher annual rate of cardiovascular mortality, MACE and all-cause mortality (allP < .001) without differences in major bleeding (P = .587) compared with novel oral P2Y12 inhibitors. After multivariate adjustment for the main clinical variables related to adverse prognosis in ACS patients, the discharge with novel oral P2Y12 inhibitors therapy was independently associated with lower risk of all-cause mortality (HR0.49, 95% CI [0.24-0.98], P = .044) and lower risk of MACE (HR0.64, 95% CI [0.41-0.98], P = .044). CONCLUSIONS: In this prospective, observational and current clinical practice ACS registry, the use of novel oral P2Y12 inhibitors was associated with a reduction in adverse events compared with clopidogrel in patients with ACS. Novel oral P2Y12 inhibitors prescription at discharge was independently associated with lower all-cause mortality and MACE without differences in bleeding events. However, clopidogrel remained the most common P2Y12 inhibitor employed for ACS, especially in older and high-risk patients.

Epidermal growth factor receptor (EGFR) signaling regulates epiphyseal cartilage development through ß-catenin-dependent and -independent pathways.

The epidermal growth factor receptor (EGFR) is an essential player in the development of multiple organs during embryonic and postnatal stages. To understand its role in epiphyseal cartilage development, we generated transgenic mice with conditionally inactivated EGFR in chondrocytes. Postnatally, these mice exhibited a normal initiation of cartilage canals at the perichondrium, but the excavation of these canals into the cartilage was strongly suppressed, resulting in a delay in the formation of the secondary ossification center (SOC). This delay was accompanied by normal chondrocyte hypertrophy but decreased mineralization and apoptosis of hypertrophic chondrocytes and reduced osteoclast number at the border of marrow space. Immunohistochemical analyses demonstrated that inactivation of chondrocyte-specific EGFR signaling reduced the amounts of matrix metalloproteinases (MMP9, -13, and -14) and RANKL (receptor activator of NF-κB ligand) in the hypertrophic chondrocytes close to the marrow space and decreased the cartilage matrix degradation in the SOC. Analyses of EGFR downstream signaling pathways in primary epiphyseal chondrocytes revealed that up-regulation of MMP9 and RANKL by EGFR signaling was partially mediated by the canonical Wnt/ß-catenin pathway, whereas EGFR-enhanced MMP13 expression was not. Further biochemical studies suggested that EGFR signaling stimulates the phosphorylation of LRP6, increases active ß-catenin level, and induces its nuclear translocation. In line with these in vitro studies, deficiency in chondrocyte-specific EGFR activity reduced ß-catenin amount in hypertrophic chondrocytes in vivo. In conclusion, our work demonstrates that chondrocyte-specific EGFR signaling is an important regulator of cartilage matrix degradation during SOC formation and epiphyseal cartilage development and that its actions are partially mediated by activating the ß-catenin pathway.

Clinical implications of diabetes mellitus in patients with acute coronary syndrome: Prognostic role and use of new P2Y12 receptor inhibitors.

AIMS: We investigated the impact of diabetes mellitus (DM) in acute coronary syndrome (ACS) patients, and the 2-year prognosis based on antiplatelet therapy. METHODS: This is a prospective and multicenter registry including hospitalized ACS patients. Clinical management and antiplatelet therapy at discharge were recorded. Bleeding events, all-cause mortality and major adverse cardiovascular events (MACEs) were recorded during 2-years and compared according to DM and the P2Y12 receptor inhibitor. RESULTS: From 1717 ACS patients, 653 (38%) had DM. Diabetic patients were older, more commonly females, with higher prevalence of comorbidities and more conservative management. After excluding antiplatelet monotherapy or oral anticoagulation, clopidogrel was prescribed in 59.6% of DM patients. Cox regression analysis showed that DM was an independent risk factor for MACE (aHR 1.39, 95% CI 1.05-1.83). The use of clopidogrel instead of ticagrelor/prasugrel was also independently associated with MACE (aHR 1.71, 95% CI 1.11-2.63), and all-cause mortality (aHR 2.47, 95% CI 1.23-4.96) in diabetic patients (log-rank p-values < 0.001). CONCLUSIONS: In ACS patients, DM was associated with higher risk of MACE. In such patients, the use of ticagrelor/prasugrel reduced MACE and mortality compared to clopidogrel. Novel P2Y12 receptor inhibitors might be used as the first therapeutic choice in these high-risk patients.

Conservatively managed patients with non-ST-segment elevation acute coronary syndrome are undertreated with indicated medicines.

INTRODUCTION AND AIMS: Patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) are often managed conservatively. Clinical practice guidelines recommend treating these patients with the same pharmacological drugs as those who receive invasive treatment. We analyze the use of new antiplatelet drugs (NADs) and other recommended treatments in people discharged following an NSTE-ACS according to the treatment strategy used, comparing the medium-term prognosis between groups. METHODS: Prospective observational multicenter registry study in 1717 patients discharged from hospital following an ACS; 1143 patients had experienced an NSTE-ACS. We analyzed groups receiving the following treatment: No cardiac catheterization (NO CATH): n = 134; 11.7%; Cardiac catheterization without revascularization (CATH-NO REVASC): n = 256; 22.4%; percutaneous coronary intervention (PCI): n = 629; 55.0%; and coronary artery bypass graft (CABG): n = 124; 10.8%. We assessed major adverse cardiovascular events (MACE), all-cause mortality, and hemorrhagic complications at one year. RESULTS: NO CATH was the oldest, had the most comorbidities, and was at the highest risk for ischemic and hemorrhagic events. Few patients who were not revascularized with PCI received NADs (NO CATH: 3.7%; CATH-NO REVASC: 10.6%; PCI: 43.2%; CABG: 3.2%; p<0.001). Non-revascularized patients also received fewer beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and statins (p<0.001). At one year, MACE incidence in NO CATH group was three times that of the other groups (30.1%, p<0.001), and all-cause mortality was also much higher (26.3%, p<0.001). There were no significant differences in hemorrhagic events. Belonging to NO CATH group was an independent predictor for MACE at one year in the multivariate analysis (HR 2.72, 95% CI 1.29-5.73; p = 0.008). CONCLUSIONS: Despite current invasive management of NSTE-ACS, patients not receiving catheterization are at very high risk for under treatment with recommended drugs, including NADs. Their medium-term prognosis is poor, with high mortality. Patients treated with PCI receive better pharmacological management, with high use of NADs.

Therapeutic management and one-year outcomes in elderly patients with acute coronary syndrome.

BACKGROUND: Elderly represents a subgroup of high-risk ACS patients due to their advanced age and other comorbidities. Unfortunately, they are also often under-represented in many studies and clinical trials. Furthermore, cardiologists commonly find difficulties in the choice of the antiplatelet treatment and even on whether invasive revascularization should be used. In this study, the management of elderly ACS patients regarding antiplatelet therapy and revascularization procedures will be analyzed. METHODS: 1717 ACS patients were consecutively included in this study from 3 tertiary Hospitals in the Southeast of Spain. Of them, 529 (30.8%) were ≥ 75 years. They were mainly male (60.7%) with a mean age of 81.4±4.7 years. Clinical characteristics, treatment received (antiaplatelet therapy, revascularization) and outcome were analyzed. RESULTS: Regression analysis showed that being ≥ 75 years is independently associated with neither performing catheterization (79.6% vs 97.1%), nor revascularization (51.8% vs 72.5%), being the medical conservative treatment the election in these elderly patients (40.6% vs 18.9%) (p < 0.001 for all). Furthermore, ticagrelor prescription were significantly decreased in older patients (11.5% vs 19.6%; p < 0.001). Regarding patients outcome after one-year of follow-up, being ≥ 75 years was associated with death, major adverse cardiac events (MACE) and major bleeding (all of them p < 0.001). Importantly, nor performing catheterization was independently associated with MACE and death in Cox multivariate analysis in elderly patients. CONCLUSIONS: Elderly patients with ACS are undertreated both invasively and pharmacologically, and this fact might be associated with the observed worse outcomes.