Direct oral anticoagulants in patients with nonvalvular atrial fibrillation and extreme body weight.

BACKGROUND: Limited clinical data exist describing the use of direct oral anticoagulants (DOACs) in patient with extreme body weight. Thus, the International Society of Thrombosis and Haemostasis (ISTH) recommends avoiding DOACs in patients with weight >120 Kg, and on the contrary, no restrictions exist for underweight patients. OBJECTIVE: To evaluate the effects of extreme body weight on DOAC activity and to compare the clinical outcomes of patients with an extreme body weight versus patients with a normal weight (61-119 Kg) treated with DOACs. METHODS: Single tertiary care Italian centre multidisciplinary registry including nonvalvular atrial fibrillation (NVAF) patients treated with DOACs. Based on weight, three subcohorts were defined: (i) underweight patients (≤60 Kg); (ii) patients with a normal weight (61-119 Kg, as control group); and (iii) overweight patients (≥120 Kg). Primary efficacy endpoint was 2-year rate of thromboembolic events. Primary safety endpoint was 2-year rate of major bleeding. Event-free survival curves among groups were compared using Cox-Mantel test. RESULTS: 812 NVAF patients were included, 108 patients weighed ≤60 Kg (13%, underweight), 688 weighed between 61 and 119 Kg (85%, normal weight), and 16 weighed ≥120 Kg (2%, overweight). In particular, among underweight patients, dabigatran was prescribed in 26% patients, apixaban in 27%, rivaroxaban in 28% and edoxaban in 22% ones. Instead, among overweight patients, 44% were treated with dabigatran, 25% with apixaban, 25% with rivaroxaban and 4% with edoxaban. Underweight patients were older, more frequently women, with lower creatinine clearance and a history of previous strokes, resulting in higher CHA2DS2-VASc score than in both remaining groups. Up to 2 years, no statistically significant difference was observed between the three groups of weight for thromboembolic events (P = .765) and for overall bleeding (P = .125), but a trend towards decreased overall bleeding rates was noticed as weight increased (24.1% vs 16.7% vs 12.5%, respectively). CONCLUSION: In this tertiary care centre registry, 15% of patients treated with DOACs presented an extreme weight. Compared to patients with a normal weight, no significant rates of thromboembolic events were observed for underweight or overweight patients. A trend towards decreased overall bleeding frequency as weight increased was highlighted up to 2 years. The present results should be considered as preliminary and hypothesis generating.

MMP13 and TIMP1 are functional markers for two different potential modes of action by mesenchymal stem/stromal cells when treating osteoarthritis.

Mesenchymal stem cells (MSCs) have been investigated as a potential injectable therapy for the treatment of knee osteoarthritis, with some evidence of success in preliminary human trials. However, optimization and scale-up of this therapeutic approach depends on the identification of functional markers that are linked to their mechanism of action. One possible mechanism is through their chondrogenic differentiation and direct role in neo-cartilage synthesis. Alternatively, they could remain undifferentiated and act through the release of trophic factors that stimulate endogenous repair processes within the joint. Here, we show that extensive in vitro aging of bone marrow-derived human MSCs leads to loss of chondrogenesis but no reduction in trophic repair, thereby separating out the two modes of action. By integrating transcriptomic and proteomic data using Ingenuity Pathway Analysis, we found that reduced chondrogenesis with passage is linked to downregulation of the FOXM1 signaling pathway while maintenance of trophic repair is linked to CXCL12. In an attempt at developing functional markers of MSC potency, we identified loss of mRNA expression for MMP13 as correlating with loss of chondrogenic potential of MSCs and continued secretion of high levels of TIMP1 protein as correlating with the maintenance of trophic repair capacity. Since an allogeneic injectable osteoar therapy would require extensive cell expansion in vitro, we conclude that early passage MMP13+ , TIMP1-secretinghigh MSCs should be used for autologous OA therapies designed to act through engraftment and chondrogenesis, while later passage MMP13- , TIMP1-secretinghigh MSCs could be exploited for allogeneic OA therapies designed to act through trophic repair.

Long-term clinical effects of recanalization of chronic coronary total occlusions in patients with left ventricular systolic dysfunction.

OBJECTIVES: The aim of the present analysis is to evaluate the clinical impact of chronic total occlusions (CTOs) recanalization in patients with left ventricular (LV) systolic dysfunction. BACKGROUND: According to contemporary knowledge, patient selection for percutaneous CTO revascularization is not yet standardized. In particular, data on outcomes in patients with LV systolic dysfunction undergoing percutaneous coronary intervention (PCI) for CTO are scarce. METHODS: From a total of 2,421 consecutive patients with at least one CTO, 436 patients with ejection fraction (EF) ≤45%, who were referred for coronary angiography between January 1998 and September 2014, were selected. Patients with successful recanalization of the target CTO were assigned to CTO-revascularized group and those with failed or not attempted recanalization to the CTO-not revascularized (CTO-NR) group. Study endpoints were all-cause death, cardiac death, and occurrence of myocardial infarction on follow-up. RESULTS: Out of 436 CTO patients with reduced EF, 228 (52.3%) were successfully recanalized and 208 patients (47.7%) were not, either due to CTO-PCI failure (n = 106, 24.3%) or because CTO-PCI was not attempted (n = 102, 23.4%). At long-term follow-up, CTO-NR patients had significantly higher rate of overall (p = .021) and cardiac mortality (p = .035) compared to those successfully revascularized. CONCLUSION: In patients with systolic LV dysfunction (EF ≤ 45%), CTO revascularization was associated with significant lower rate of total and cardiac mortality compared to those with nonrevascularized CTO.

The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation.

Multipotent mesenchymal stem cells (MSCs) have enormous potential in tissue engineering and regenerative medicine. However, until now, their development for clinical use has been severely limited as they are a mixed population of cells with varying capacities for lineage differentiation and tissue formation. Here, we identify receptor tyrosine kinase-like orphan receptor 2 (ROR2) as a cell surface marker expressed by those MSCs with an enhanced capacity for cartilage formation. We generated clonal human MSC populations with varying capacities for chondrogenesis. ROR2 was identified through screening for upregulated genes in the most chondrogenic clones. When isolated from uncloned populations, ROR2+ve MSCs were significantly more chondrogenic than either ROR2-ve or unfractionated MSCs. In a sheep cartilage-repair model, they produced significantly more defect filling with no loss of cartilage quality compared with controls. ROR2+ve MSCs/perivascular cells were present in developing human cartilage, adult bone marrow, and adipose tissue. Their frequency in bone marrow was significantly lower in patients with osteoarthritis (OA) than in controls. However, after isolation of these cells and their initial expansion in vitro, there was greater ROR2 expression in the population derived from OA patients compared with controls. Furthermore, osteoarthritis-derived MSCs were better able to form cartilage than MSCs from control patients in a tissue engineering assay. We conclude that MSCs expressing high levels of ROR2 provide a defined population capable of predictably enhanced cartilage production. Stem Cells 2017;35:2280-2291.

Safety and efficacy of direct oral anticoagulants (DOACs) in very elderly patients (≥85 years old) with non-valvular atrial fibrillation.

BACKGROUND: Limited real-world data are available regarding the comparison about safety and efficacy of DOACs prescription in very elderly patients (≥85 years) with non-valvular atrial fibrillation (NVAF). Concern about the risk of bleeding with anticoagulation in very older patients still represents an important challenge for clinicians. The aim of this study was to evaluate the different prevalence of major bleeding and thromboembolic events between very elderly NVAF patients (≥85 years) compared to those non very elderly (<85 years). METHODS: Single center multidisciplinary registry including NVAF patients treated with DOACs. Primary safety endpoint was 2-year rate of major bleeding. Primary efficacy endpoint was 2-year rate of thromboembolic events. Event-free survival curves among groups were compared using Cox-Mantel Test. RESULTS: 908 NVAF consecutive patients were included, of these, 805 patients were <85 years (89%) and 103 patients were very elderly patients with ≥85 years (11%). Compared to patients <85 years, those very elderly have higher CHA2DS2-VASc Score (P=0.001), higher rate of hypertension (P=0.001), diabetes mellitus (P=0.030), previous bleeding events (P<0.001), previous stroke/TIA/SE (P≤0.001), heart failure (P≤0.001), and lower creatinine clearance (P<0.001). In terms of safety endpoints (overall ISTH-major bleeding) no significative difference between two groups (P=0.952) were observed up to 2-year follow-up. Systemic thromboembolic event (primary efficacy endpoint) was significantly higher in patients with ≥85 years (P=0.027). The incidence of all-cause death was significantly higher in very elderly patients (P<0.001). CONCLUSIONS: This single center registry, showed that the use of DOACs in very elderly NVAF was safe and is a therapeutic option to be pursued for stroke prevention especially for those who are at high risk of ischemic events.

Direct oral anticoagulants versus percutaneous left atrial appendage occlusion in atrial fibrillation: 5-year outcomes.

BACKGROUND: LAAO is an emerging option for thromboembolic event prevention in patients with NVAF. We previously reported data on comparison between LAAO and DOAC at two-year follow-up in NVAF patients at HBR (HAS-BLED ≥3). AIMS: Limited data are available on long term follow-up. We aimed to evaluate the efficacy and safety of DOACs versus LAAO indication after 5 years. METHODS: We enrolled 193 HBR treated with LAAO and 189 HBR patients with DOACs. At baseline, LAAO group had higher HAS-BLED (4.2 vs 3.3, p < 0.001) and lower CHADS-VASc (4.3 vs. 4.7, p = 0.005). After 1:1 PSM, 192 patients were included (LAAO n = 96; DOACs n = 96). RESULTS: At 5-year follow-up the rate of the combined safety and effectiveness endpoint (ISTH major bleeding and thromboembolic events) was significantly higher in LAAO group (p = 0.042), driven by a higher number of thromboembolic events (p = 0.047). The rate of ISTH-major bleeding events was similar (p = 0.221). After PSM no significant difference in the primary effectiveness (LAAO 13.3% vs DOACs 9.5%, p = 0.357) and safety endpoint (LAAO 7.5% vs DOACs 7.5%; p = 0.918) were evident. Overall bleeding rate was significantly higher in DOACs group (25.0% vs 13.7%, p = 0.048), while a non-significant higher number of TIA was reported in LAAO group (5.4% vs 1.1%, p = 0.098). All-cause and cardiovascular mortality were higher in LAAO group at both unmatched and matched analysis. CONCLUSION: We confirmed safety and effectiveness of both DOAC and LAAO in NVAF patients at HBR, with no significant differences in thromboembolic events or major bleeding were at 5-year follow-up. The observed increased mortality after LAAO warrants further investigations in RCTs.

Baseline Characteristics and 3-Year Outcome of Nonvalvular Atrial Fibrillation Patients Treated with the Four Direct Oral Anticoagulants (DOACs).

Direct oral anticoagulants (DOACs) represent the cornerstone therapy for cardioembolic events prevention in patients with nonvalvular atrial fibrillation (NVAF). In practice, the choice of one DOAC over another is guided by the decision-making process of the physician, which considers specific patient and drug characteristics. This study aimed to evaluate the clinical features and long-term outcomes of a real-world population treated with DOACs, where the use of the 4 different DOACs is quite equal. We conducted a retrospective observational, single-center, multidisciplinary study enrolling consecutive NVAF patients treated with one of the 4 DOACs. From an initial number of 753 patients, we excluded 72 patients because of loss to follow-up, at the end we enrolled 681:174 (23%) treated with dabigatran, 175 (23%) with apixaban, 190 (25%) with rivaroxaban, and 214 (29%) with edoxaban. Patients treated with apixaban were significantly older, more women represented (p <0.001), and with a higher cardioembolic and bleeding risk (p <0.001). Dabigatran was preferred in patients with liver failure (p = 0.008), whereas Apixaban and Edoxaban were chosen in chronic kidney disease (p = 0.002). At 3-year follow-up, 20 patients (2.7%) experienced a systemic thromboembolic event without significant differences in the 4 DOACs. In the same period, an International Society of Thrombosis and Hemostasis classification major bleeding event occurred in 26 patients (3.6%), more statistically correlated to edoxaban (6.1%) (p = 0.038). Thromboembolic events or major bleeding were higher in the edoxaban group (10%) compared with the others (p = 0.014). In our single-center real-world experience, the choice of the DOAC for a patient with NVAF was tailored to specific clinical features and drug pharmacokinetics of the patient. As a result, a small number of adverse events were observed.

Development of chimeric forms of the matrix metalloproteinase 2 collagen binding domain as artificial membrane binding proteins for targeting stem cells to cartilage lesions in osteoarthritic joints.

Targeting stem cells to cartilage lesions has the potential to enhance engraftment and chondrogenesis. Denatured type II collagen fibrils (gelatin) are exposed in lesions at the surface of osteoarthritic articular cartilage and are therefore ideal target sites. We have designed and investigated chimeric mutants of the three modules of the MMP-2 collagen binding domain (CBD) as potential ligands for stem cell targeting. We expressed full-length CBD for the first time and used it to identify the most important amino acid residues for binding to gelatin. Module 2 of CBD had the highest affinity binding to both Type I and Type II gelatin, whereas module 1 showed specificity for type II gelatin and module 3 for type I gelatin. We went on to generate chimeric forms of CBD consisting of three repeats of module 1 (111), module 2 (222) or module 3 (333). 111 lacked solubility and could not be further characterised. However 222 was found to bind to type II gelatin 14 times better than CBD, suggesting it would be optimal for attachment to cartilage lesions, whilst 333 was found to bind to type I gelatin 12 times better than CBD, suggesting it would be optimal for attachment to lesions in type I collagen-rich tissues. We coated 222 onto the external membrane of Mesenchymal Stem Cells and demonstrated higher attachment of the coated cells to type II gelatin than uncoated cells. We conclude that the three modules of CBD each have specific biological properties that can be exploited for targeting stem cells to cartilage lesions and other pathological sites.

Effectiveness and cost-efficacy of diuretics home administration via peripherally inserted central venous catheter in patients with end-stage heart failure.

BACKGROUND: End-stage heart failure (ESHF) is characterized by severe cardiac dysfunction with persistent disabling symptoms and recurrent acute decompensated heart failure (ADHF), despite guideline-directed medical therapy. The aim of this study was to evaluate the efficacy and safety of intravenous diuretics administration at home through a peripherally inserted central venous catheter (PICC) in ESHF patients. METHODS AND RESULTS: Forty-one ESHF patients received PICC implantation for intravenous diuretic administration at home. The primary efficacy endpoint was the patient-level number of HF hospitalizations in the short (1-3 months), medium (six months), and long term (1 year), before and after PICC implantation. Pre- and post-PICC ADHF-free days were also evaluated as co-primary endpoint. Secondary endpoints comprised changes in clinical, laboratory and echocardiographic parameters, and device safety. A cost-effectiveness analysis was performed to estimate the economic impact of using PICC. For each time frame analyzed, a significant reduction in the number of hospitalizations due to ADHF was observed, resulting in a significant increase in ADHF-free days (71 ± 44 vs. 163 ± 136, p = 0.003). In matched patients' analysis, significant decrease in body weight (68 ± 16 kg vs. 63 ± 10 kg, p = 0.041) and mitral regurgitation grade 3/4 (55% vs. 18%, p < 0.001) were also observed. Freedom from PICC-related complications was observed in 61% of patients. A significant reduction in overall ADHF-hospitalizations cost was observed. CONCLUSIONS: This proof-of-concept study demonstrates the effectiveness and safety of home administration of intravenous diuretic therapy via PICC in ESHF patients. This palliative cost-effective strategy can be taken in consideration for selected end-stage patients no longer responsive to conventional therapies.

Resting cardiac energy metabolism is inversely associated with heart rate in healthy young adult men.

BACKGROUND: 31-Phosphorus-magnetic resonance spectroscopy may provide pathophysiological insights into the high-energy phosphate metabolism of the myocardium as measured by phosphocreatine to adenosine triphosphate (PCr/ATP) ratio. Aim of the present study was to determine in vivo the relation between cardiac PCr/ATP ratio and heart rate in normal male subjects. METHODS: One hundred twelve apparently healthy, young male individuals (age 34 ± 10 years) were prospectively evaluated. They underwent cardiac cine magnetic resonance imaging to assess left ventricular (LV) function and morphology and 3D-ISIS (31)P-magnetic resonance spectroscopy of the LV to assess the PCr/ATP ratio (a recognized in vivo marker of myocardial energy metabolism). Data were analyzed after segregation by tertiles of the resting PCr/ATP ratio. RESULTS: A significant inverse association between PCr/ATP ratios and resting heart rate was observed (Spearman ρ: r=-0.37; P < .0001). PCr/ATP ratios were also inversely associated with body mass index, diastolic blood pressure, wall mass and with insulin resistance, but in multiple regression analysis heart rate was found to be independently related to PCr/ATP. CONCLUSIONS: The present study shows that resting heart rate is proportionally lower across tertiles of increasing PCr/ATP ratio of the LV in apparently healthy young male individuals, supporting the hypothesis that heart rate is a major determinant of cardiac energy stores. These findings may explain the prognostic role of heart rate in the general population as evidenced by previous large epidemiological studies.

Inappropriate dose of nonvitamin-K antagonist oral anticoagulants: prevalence and impact on clinical outcome in patients with nonvalvular atrial fibrillation.

BACKGROUND: Limited real-world data are available regarding the outcome of patients treated with inappropriate dose of nonvitamin-K antagonist oral anticoagulants (NOACs). OBJECTIVE: To assess the prevalence and factors associated with inappropriate dose prescription of NOACs and to evaluate adverse events that come from this inappropriate prescription. METHODS: Single-center multidisciplinary registry including nonvalvular atrial fibrillation patients treated with NOACs. Based on guidelines criteria for dose reduction, two subcohorts were defined as treated with appropriate or inappropriate NOACs dose. Primary efficacy endpoint was 2-year rate of thromboembolic events. Primary safety endpoint was 2-year rate of major bleeding. Event-free survival curves among groups were compared using Cox-Mantel test. RESULTS: A total of 760 nonvalvular atrial fibrillation patients were included; 32% patients were treated with dabigatran, 34% with apixaban, 24% with rivaroxaban and 10% with edoxaban. An inappropriate dose was prescribed in 96 patients (12.6%), and in most cases (68%) it was too low. Rivaroxaban (15%) and apixaban (18.5%) were the most frequently prescribed with an inappropriate dose. Patients treated with an inappropriate dose were elderly people, with low-creatinine clearance value, who had experienced previous bleeding and with a high CHADS2 VASc score. In 2 years, a trend for higher numbers of thromboembolic events (5.2 vs. 3.3%, P = 0.348) and less major bleeding (2.1 vs. 4.2%, P = 0.316) has been observed in patients with inappropriate NOACs prescriptions. CONCLUSION: Nearly 13% of patients were treated with an inappropriate dose of NOACs, in this single-center study. A trend for higher numbers of thromboembolic events was observed in these patients. The results should be considered as hypothesis generating.

Heavy metal resistance of some thermophiles: potential use of alpha-amylase from Anoxybacillus amylolyticus as a microbial enzymatic bioassay.

Six thermophilic extremophiles, Anoxybacillus amylolyticus, Geobacillus thermoleovorans, Geobacillus thermoleovorans subspecies stromboliensis, Geobacillus toebii subspecies decanicus, Bacillus thermantarcticus and Thermus oshimai, isolated from different environmental sites, were studied for their heavy metal resistance. The effects of heavy metals on microorganism growth were studied here in a pilot fermenter tank spiked with various trace metals, (Ni(2+), Zn(2+), Co(2+), Hg(2+), Mn(2+), Cr(6+), Cu(2+), Fe(3+) and Cd(2+)) at concentrations spanning from 0.01 to 20 mM. Trace metal toxicity varied depending on the species and metal considered. Among the tested microorganisms, attention was focused on alpha-amylase producing-A. amylolyticus, an acidothermophilic bacterium recently isolated from geothermal soil samples from Mount Rittmann in Antarctica. The effect of heavy metals on the biosynthesis and activity of alpha-amylase of A. amylolyticus was investigated. When bacteria were grown in the presence of heavy metals, a decrease in alpha-amylase activity, correlated with a decrease in alpha-amylase production, was observed, suggesting an effect on the biosynthesis of the enzyme. A decrease in enzyme activity was also noted when the assay was performed in the presence of heavy metals. Thus, alpha-amylase could represent a potential sensitive bioassay for detecting trace heavy metals.

Safety and efficacy of doxazosin as an "add-on" antihypertensive therapy in mild to moderate heart failure patients.

OBJECTIVE: Doxazosin treatment has been discouraged in hypertensive patients in order to prevent heart failure (HF) development. However, this drug is still prescribed as an "add-on" medication to achieve a better blood pressure (BP) control. The aim of this study was to evaluate the safety and efficacy of doxazosin as an "add-on" medication in HF patients with uncontrolled hypertension. METHODS AND RESULTS: We reviewed our HF clinic files to collect patient variables recorded at baseline and during follow-up visits in patients receiving, or not, doxazosin. We compared HF-related hospitalization rates and all-cause and cardiovascular mortality rates between patients on doxazosin and those not on doxazosin. We constructed cumulative risk curves for time to first event (HF-related hospitalization and/or death) for both groups of patients. Fifty-two HF patients had been prescribed doxazosin. At baseline, several relevant variables were unevenly distributed between patients receiving doxazosin and those not receiving doxazosin (N=122), such as left ventricular ejection fraction (LVEF) and NYHA class. HF-related hospitalization and death rates were similar between patients on doxazosin and those not on doxazosin at the end of the follow-up. Even after adjustment for all potentially confounding variables, doxazosin was not associated with HF-related hospitalization and/or death. Doxazosin significantly reduced BP, but did not affect NYHA class. CONCLUSIONS: Doxazosin, "on top" of other antihypertensive treatments was safe and effective, and did not appear to be associated with HF-related hospitalization and mortality rates in our patients with mild/moderate HF.

Validation of a new score for outcome prediction in patients with heart failure with reduced ejection fraction.

BACKGROUND: Most models for outcome prediction in heart failure are under-utilized because complex or including non-routine clinical use variables. We aimed to develop a prognostic score for patients with stable heart failure, including only easily obtainable parameters. METHODS: In 376 outpatients with heart failure (ejection fraction ≤40%), twelve variables were individually correlated with 5-year mortality. Those resulted significant predictors of cardiac and overall mortality were used to obtain a risk score. It was validated on a different sample of 325 patients previously enrolled in other clinical studies, according to tertiles of score. RESULTS: Previous acute decompensated heart failure, atrial fibrillation, ejection fraction <30%, not-taking beta-blockers, chronic renal failure were the variables included in the final model. There was a significant difference in 5-year cardiac (P=0.004) and all-cause (P=0.003) mortality risk. Compared to the first tertile of the score, the second tertile and the third tertile had an increasing risk for cardiac cause admission (respectively, HR: 2.7; 95% CI: 1.5-4.9 and HR: 3.2; 95% CI: 1.7-6.1) and for heart failure worsening hospitalization (HR:4.3; 95% CI: 1.3-14.5 and HR: 3.8; 95% CI: 1.03-14.1) as well as the third tertile (respectively, HR:3.2; 95% CI: 1.7-6.1 and HR:3.8; 95% CI: 1.03-14.1.). CONCLUSIONS: Our prognostic model, named OSR HF Risk Score, is a simple, quick, inexpensive tool for predicting patient outcome in 5 years. It might be used as an adjunctive tool in outpatients evaluation alongside more complex scores.

Real-world 2-year outcome of atrial fibrillation treatment with dabigatran, apixaban, and rivaroxaban in patients with and without chronic kidney disease.

Patients with non-valvular atrial fibrillation (NVAF) and chronic kidney disease (CKD) are at increased risk of stroke and bleeding. Although direct oral anticoagulant (DOAC) trials excluded patients with severe CKD, a growing portion of CKD patients have been starting DOACs and limited data from real-world outcome in this high-risk setting are available. The INSigHT registry included 632 consecutive NVAF patients that started apixaban (256 patients, 41%), dabigatran (245, 39%) and rivaroxaban (131, 20%) between 2012 and 2015. Based on creatinine clearance, two sub-cohorts were defined: (1) non-CKD group (CrCl 60-89 mL/min, 413 patients) and (2) CKD group (15-59 ml/min, 219). Compared to non-CKD patients, those with CKD, were at higher ischemic (CHA2DS2-VASc 4.5 vs 2.9, p < 0.001) and hemorrhagic risk (HAS-BLED 2.4 vs 1.8, p < 0.001). At 2-year follow-up, the overall ISTH-major bleeding and thromboembolic event rates were 5.2% and 2.3% and no significant difference between non-CKD and CKD patients for both efficacy and safety endpoints were observed. In non-CKD patients, the 2-year ISTH-major bleeding rates were higher in rivaroxaban group (HR 2.9, 95% CI 1.1-7.3; p = 0.047) while dabigatran showed non-significant excess in thromboembolic events (HR 4.3, 95% CI 0.9-20.8; p = 0.068). In CKD patients, a significantly higher rate of thromboembolic events was observed in rivaroxaban (HR 6.3, 95% CI 1.1-38.1; p = 0.044). This real-world, non-insurance database registry shows remarkable 2-year safety and efficacy profile of DOACs even in patients with moderate to severe CKD. Head to head differences between DOACs are exploratory, hypothesis generating and warrant further investigation in larger studies.

Real-life indications to ivabradine treatment for heart rate optimization in patients with chronic systolic heart failure.

: Ivabradine is a selective and specific inhibitor of If current. With its pure negative chronotropic action, it is recommended by European Society of Cardiology and American College of Cardiology/American Heart Association guidelines in symptomatic heart failure patients (NYHA ≥ 2) with ejection fraction 35% or less, sinus rhythm and heart rate (HR) at least 70 bpm, despite maximally titrated ß-blocker therapy. Data supporting this indication mainly derive from the SHIFT study, in which ivabradine reduced the combined endpoint of mortality and hospitalization, despite the fact that only 26% of patients enrolled were on optimal ß-blocker doses. The aim of the present analysis is to establish the real-life eligibility for ivabradine in a population of patients with systolic heart failure, regularly attending a single heart failure clinic and treated according to guideline-directed medical therapy (GDMT). The clinical cards of 308 patients with heart failure with reduced ejection fraction (HFrEF) through a 68-month period of observation were retrospectively analyzed. GDMT, including ß-blocker up-titration to maximal tolerated dose, was implemented during consecutive visits at variable intervals. Demographic, clinical and echocardiographic data were collected at each visit, together with 12-leads ECG and N-terminal pro-B-type natriuretic peptide levels. Out of 308 analyzed HFrEF patients, 220 (71%) were on effective ß-blocker therapy, up-titrated to effective/maximal tolerated dose (55 ±â€Š28% of maximal dose) (HR 67 ±â€Š10 bpm). Among the remaining 88 patients, 10 (3.2%) were on maximally tolerated ß blocker and ivabradine; 21 patients (6.8%), despite being on maximal tolerated ß-blocker dose, had still HR ≥70 bpm, ejection fraction 35% or less and were symptomatic NYHA ≥2, being therefore eligible for ivabradine treatment. The remaining 57 (18%) patients were not on ß blocker due to either intolerance or major contraindications. Among them, 13 (4%) were taking ivabradine alone. Of the final 44 (14%) patients, 27 (9%) showed an inadequate HR control (74 ±â€Š6 bpm). Of these, only eight (3%) patients resulted to be eligible for ivabradine introduction according to HR and ejection fraction parameters. Overall ivabradine was indicated in 52 patients (16.8%) out of 308 enrolled.In conclusion, in a carefully managed population of patients with moderate and stable HFrEF, in which optimal GDMT is properly attained, indication to ivabradine treatment is around 17%.

Two-year cardiac mortality after MitraClip treatment of functional mitral regurgitation in ischemic and non-ischemic dilated cardiomyopathy.

BACKGROUND: MitraClip implantation has evolved as a new tool for treatment of inoperable or high-risk patients with severe functional mitral regurgitation (FMR) due to dilated cardiomyopathy (DCM). Limited data are available regarding MitraClip outcomes comparing patients with ischemic and non-ischemic DCM. METHODS: From 2008 to 2016, 314 patients received MitraClip for FMR at four institutions: Brescia, Zurich and Milan. Patients were stratified according to MR aetiology in non-ischemic FMR (n = 99) and ischemic FMR (n = 215). Preoperative risk factors, operative variables and outcomes up to 2-year were evaluated. A multivariable Cox Proportional Hazards survival model with covariate adjustments was used to assess the relationship between FMR aetiology and 2-year cardiac mortality. RESULTS: As expected, patients with ischemic FMR had significantly more risk factors and comorbidities. Overall procedural success rate was 80% and in-hospital cardiac mortality was 3% without significant differences between aetiology. Two-year overall (25% vs. 19%, p = 0.574) and cardiac (18% vs. 16%, p = 0.990) mortality rates were comparable. No differences were detected in terms of re-hospitalization rates (32%), LVAD implantation (4.5%) and mitral valve surgery (1%). LVEF ≤ 25%, LVEDV > 216 ml, NT-proBNP ≥ 10.000 pg/ml and AF were the strongest baseline predictors of 2-year cardiac mortality. Greater improvements of 6MWT and NYHA functional class were observed in patients with non-ischemic FMR. CONCLUSIONS: The ischemic or non-ischemic aetiology of DCM did not affect in-hospital and 2-year cardiac mortality after MitraClip in patients with FMR. In case of unfavorable baseline clinical condition, the indication for MitraClip should be carefully weighed in favour of conservative medical therapy alone or left ventricular assist device.

Platelet reactivity in response to loading dose of atorvastatin or rosuvastatin in patients with stable coronary disease before percutaneous coronary intervention: The STATIPLAT randomized study.

BACKGROUND: The acute effects of statin loading dose (LD) on platelet reactivity in patients with chronic stable angina (CSA) are not completely clear. HYPOTHESIS: We hypothesized that LDs of atorvastatin and rosuvastatin have different pharmacodynamic acute effects on platelet aggregability in CSA patients with baseline normal platelet reactivity while on dual antiplatelet therapy (DAPT). METHODS: From September 2011 to February 2014, all consecutive CSA patients on chronic DAPT (aspirin and clopidogrel) were evaluated before elective percutaneous coronary intervention (PCI). An initial assessment of platelet reactivity in response to thrombin receptor agonist, ADP, and ASP (respectively, indicative of the response to clopidogrel and aspirin) was performed with impedance aggregometry. Patients with high platelet reactivity to ADP test (area under the curve >47) were excluded. The remaining patients were randomized into 3 treatment groups: Group A, atorvastatin LD 80 mg; Group B, rosuvastatin LD 40 mg; and Group C, no statin LD (control group). A second assessment of platelet reactivity was performed ≥12 hours after statin LD. RESULTS: 682 patients were screened and 145 were randomized into the 3 groups. At baseline and after statin LD, no significant difference was found in platelet reactivity in response to 3 different agonists between the 3 groups. Subgroup analysis showed that platelet reactivity to ADP test was significantly lower in patients chronically treated with low-dose statins (n = 94) compared with statin-naïve patients (n = 51; 15.32 ± 1.50 vs 18.59 ± 1.30; P = 0.007). CONCLUSIONS: Loading dose of atorvastatin (80 mg) or rosuvastatin (40 mg) did not induce significant variation in platelet reactivity in CSA patients with baseline reduced platelet reactivity as in chronic DAPT. Our data confirm that chronic concomitant treatment with low-dose statins and clopidogrel resulted in significantly lower platelet reactivity compared with clopidogrel alone.

Long-term clinical outcomes of patients with rheumatoid arthritis and concomitant coronary artery disease.

BACKGROUND: Rheumatoid arthritis (RA) is associated with high morbidity and mortality predominately due to increased cardiovascular risk. Few reports are available regarding the management of coronary artery disease (CAD) in RA patients and the long-term clinical outcomes after coronary revascularization. METHODS AND RESULTS: All consecutive patients with RA were identified by retrospective review at a rheumatology tertiary center in Milan, Italy between 2001 and 2013. RA patients affected by significant CAD (RA-CAD+) were prospectively followed for major adverse cardiovascular and cerebrovascular events (MACCE) after percutaneous coronary revascularization (RA-PCI), coronary artery bypass grafting (RA-CABG) or medical therapy (RA-MT). Among 936 patients with RA, the presence of clinically significant CAD was found in 5.6% (53 patients, RA-CAD+). Of these, 32 patients (60%) underwent PCI (RA-PCI), 10 patients (19%) underwent CABG (RA-CABG) and 11 patients (21%) treated with MT (RA-MT). After a mean follow-up of 9±7 years, the rate of MACCE was 56% in RA-PCI patients, 50% in RA-CABG and 27% in RA-MT patients (P=0.184). The high MACCE rate was mainly driven by repeat coronary revascularization (47%) in the RA-PCI group and high rate of strokes (30%) in RA-CABG patients. CONCLUSION: In patients with rheumatoid arthritis and concomitant coronary artery disease (RA-CAD+), we observed at long-term follow-up a high MACCE rate, predominantly in those who underwent coronary revascularization.

Impact and evolution of right ventricular dysfunction after successful MitraClip implantation in patients with functional mitral regurgitation.

BACKGROUND: Right ventricular dysfunction (RVdysf) is a predictor of poor outcome in patients with heart failure and valvular disease. The aim of this study was to evaluate the evolution and the impact of RVdysf in patients with moderate-severe functional mitral regurgitation (FMR) successfully treated with MitraClip. METHODS AND RESULTS: From October 2008 to July 2014, 60 consecutive high surgical risk FMR patients were evaluated and stratified into two groups: RVdysf group (TAPSE < 16 mm and/or S'TDI < 10 cm/s, 21 patients) and No-RVdysf group (38 patients). The overall mean age of patients was 73 ± 8 (83% male). Ischemic FMR etiology was present in 67%. Mean LVEF was 30 ± 10%. Overall mean time follow-up was 565 ± 310 days. The only significant difference between the two groups was a greater prevalence of stroke, ICD and use of aldosterone antagonist in RVdysf group. Acute procedural success was achieved in 90% of patients. At 6-month echo-matched analysis significant RV function improvement was observed in patients with baseline RVdysf (TAPSE 15 ± 3.0 vs. 19 ± 4.5, p = 0.007; S'TDI 7 ± 1.2 vs. 11 ± 2.8, p < 0.0001; baseline vs. 6-month, respectively). The mean improvement in the 6-min walking test was significant in both groups (120 and 143 m, RVdysf and No-RVdysf groups, respectively). At Kaplan-Meier analysis, the presence of RVdysf did not affect the outcome in terms of freedom from composite efficacy endpoint. CONCLUSIONS: This study shows that successful MitraClip implantation in patients with FMR and concomitant right ventricular dysfunction yields significant improvement of RV function at mid-term follow-up. Further data on larger population will be required to confirm our observations.