Apixaban Versus Vitamin K Antagonists in Patients With Antiphospholipid Syndrome: A Cohort Study.

ABSTRACT: Current guidelines recommend that direct anticoagulants should not be used in prevention of recurrent thrombosis in patients with antiphospholipid syndrome (APS). However, except for triple-positive APS and rivaroxaban use, little evidence supports such recommendation. In a real-life cohort study, we evaluated the risk of thromboembolism and bleeding in patients with APS on apixaban versus vitamin K antagonists (VKA). We enrolled 152 patients with APS (aged 44 years [interquartile range 36-56], 83% women), including 66 patients treated with apixaban 5 mg bid and 86 with warfarin (target international normalized ratio [INR] 2-3). During a median follow-up of 53 months, we recorded venous thromboembolism, ischemic stroke, or myocardial infarction, along with major bleeding. We observed 4 thrombotic events (6.1%, 3 venous thromboembolism and 1 ischemic stroke) in patients on apixaban and 12 events (14%, 9 venous thromboembolism, 2 ischemic strokes and 1 myocardial infarction) in VKA patients. Patients with APS on apixaban had similar risk of recurrent thromboembolism compared with those on warfarin (hazard ratio [HR] = 0.327, 95% confidence interval [CI]: 0.104-1.035). Thromboembolic events occurred less commonly in statin users (8% vs. 50%, P = 0.01) and more frequently in triple-positive APS (50% vs. 22.1%, P = 0.028) and in patients with higher D-dimer at baseline ( P = 0.023); the latter difference was present in the apixaban group ( P = 0.02). Patients on apixaban had similar risk of major bleeding compared with warfarin (HR = 0.54, 95% CI: 0.201-1.448). In real-life patients with APS, apixaban appears to be similar to VKA for the prevention of thromboembolism and risk of bleeding, which might suggest that some patients with APS could be treated with apixaban.

Elevated 8-isoprostane concentration is associated with thromboembolic events in patients with atrial fibrillation.

BACKGROUND: Enhanced oxidative stress occurs in atrial fibrillation (AF), however its impact on the efficacy and safety of anticoagulation is unknown. We sought to evaluate whether 8-isoprostaglandin F2 (8-isoprostane) levels are associated with clinical outcomes in anticoagulated AF patients. METHODS: In a study involving 243 AF patients (median age 69 years), we measured serum 8-isoprostane, along with prothrombotic markers, including plasma fibrin clot permeability, clot lysis time (CLT), endogenous thrombin potential (ETP), von Willebrand factor (VWF), and fibrinolytic proteins. Ischemic cerebrovascular events, major bleeding, and death were recorded during a median follow-up of 53 months while on anticoagulation, largely on non-vitamin K antagonist oral anticoagulants (NOACs). RESULTS: Increased 8-isoprostane levels were observed in women, in patients with arterial hypertension, and those with paroxysmal or persistent AF. Patients with 8-isoprostane levels ≥559 pg/mL (the top quartile) compared with those with 8-isoprostane <250 pg/mL (the bottom quartile) had higher fibrinogen, lower VWF, higher plasminogen activator inhibitor 1, along with lower fibrin clot permeability with no difference in CHA2DS2-VASc score, CLT or ETP. Patients who experienced thromboembolic events (n = 20, 1.9%/year) had 48.6% higher 8-isoprostane concentrations compared to the remainder (P <0.01). Levels of 8-isoprostane >459 pg/mL based on the optimal cut-off value were associated with thromboembolic events during follow-up (hazard ratio 2.87, 95% confidence interval 1.17-7.03, P = 0.02). There were no associations between 8-isoprostane and major bleeding (2.0%/year) or all-cause mortality (1.9%/year). CONCLUSIONS: Increased 8-isoprostane levels partly through altered fibrin clot structure are associated with thromboembolic events despite anticoagulant therapy in AF patients.

Application of holography and augmented reality based technology to visualize the internal structure of the dental root - a proof of concept.

BACKGROUND: The Augmented Reality (AR) blends digital information with the real world. Thanks to cameras, sensors, and displays it can supplement the physical world with holographic images. Nowadays, the applications of AR range from navigated surgery to vehicle navigation. DEVELOPMENT: The purpose of this feasibility study was to develop an AR holographic system implementing Vertucci's classification of dental root morphology to facilitate the study of tooth anatomy. It was tailored to run on the AR HoloLens 2 (Microsoft) glasses. The 3D tooth models were created in Autodesk Maya and exported to Unity software. The holograms of dental roots can be projected in a natural setting of the dental office. The application allowed to display 3D objects in such a way that they could be rotated, zoomed in/out, and penetrated. The advantage of the proposed approach was that students could learn a 3D internal anatomy of the teeth without environmental visual restrictions. CONCLUSIONS: It is feasible to visualize internal dental root anatomy with AR holographic system. AR holograms seem to be attractive adjunct for learning of root anatomy.

Eligible-and-enrolled vs. eligible-but-not-enrolled patients with chronic ischaemic heart failure in randomized clinical trials of myocardial regeneration.

Introduction: Clinical trial applicability to routine clinical practice is a fundamental consideration. Little is known about factors that determine enrolment (vs. non-enrolment) in chronic ischaemic heart failure (CIHF) interventional randomized controlled trials (iRCT). Aim: To compare clinical characteristics and medical therapy in eligible-and-enrolled (E-E) vs. eligible-but-not-enrolled (E-NE) patients in CIHF myocardial regeneration iRCTs. Material and methods: Clinical characteristics and medical treatment were compared for E-E and E-NE in 4 periods (32 months): P1 (iRCT#1 recruitment), P2 (between iRCT#1 and iRCT#2), P3 (iRCT#2 recruitment), P4 (post iRCT#2). iRCT#1 and iRCT#2 shared inclusion/exclusion criteria. Results: Evaluation involved 5,436 hospitalized patients (P1-P4; CIHF-526). 283 were iRCT eligible (53.8%). The eligibility rate was similar throughout P1-P4 (43.1-58.5%, p = 0.08). Eligible patient characteristics and pharmacotherapy did not differ in recruitment vs. non-recruitment periods. Principal reasons for ineligibility were recent/planned cardiac intervention outside iRCT (22.8%), age above threshold (14.6%) and coexisting disease as the exclusion criterion (12.2%). Primary reasons for eligible patient non-enrolment (n = 89) were other trial participation (52.8%) and no consent (28.1%). E-E patients did not differ from E-NE in characteristics including CIHF medical management and clinical stage; the exception was more severe left ventricular impairment in E-E (LVEF 31.2 vs. 33.9%, p = 0.039; end-diastolic volume 197.8 vs. 160.4 ml, p < 0.0001). Conclusions: CIHF medical management was similar in E-E and E-NE. Ineligibility resulted mainly from recent/planned intervention outside iRCT and age > 80 years. LV impairment was more severe in E-E patients, consistent with higher-risk patient enrolment in CIHF-iRCTs. This contrasts with typical lower-risk patient enrolment in other cardiovascular RCT types and populations.

Trans-endocardial delivery of progenitor cells to compromised myocardium using the "needle technique"and risk of myocardial injury.

Introduction: Recent analysis from CHART-1 study indicated that the therapeutic effects of trans-endocardial cardiopoetic cell transplantation in chronic ischemic heart failure (iCHF) may be lost with an increasing number of injections perfomed to deliver therapeutic cells. Aim: To evaluate global and regional contractility and diastolic function of the left ventricle of patients with iCHF who received trans-endomyocardial cardiopoietic stem cells (CSCs) delivery or sham procedures. Material and methods: The study included patients (mean age: 60.8 ±7.1 years) with iCHF (left ventricular ejection fraction (LVEF) < 35%) and a history of hospitalization for worsening heart failure within 12 months despite optimal medical therapy. The patients underwent transmyocardial CSCs transplantation using perforated needle technique or a sham procedure. The wall motion score index (WMSI), LVEF, transmitral E-velocity, E-wave deceleration time, E/A-ratio, and E/e'-mean value were measured with two-dimensional echocardiography on days 1 and 30. Results: A total of 170 segments were analyzed, including 48 targeted segments where 92 injections of 0.5 ml of CSCs were performed. In the transendocardial injections cohort, a decrease in regional contractility was observed in 30.6% (26/85) and 18.9% (16/85) of the segments on days 1 and 30, respectively. This was accompanied by an increase in WMSI by 0.32 ±0.06 and 0.19 ±0.18 (day 1, p = 0.02, day 30, p = 0.03) and a reduction in LVEF (-3.15 ±1.23%, p = 0.065). Conclusions: Transendocardial injections performed to deliver therapeutic cells were associated with myocardial injury. This adverse effect remained, albeit at a lesser degree, at 30-days. Mechanical injury with trans-endocardial delivery of progenitor cells using the "needle technique" may counterbalance, at least in part, any cell-related benefit(s).

Infarct size and long-term left ventricular remodelling in acute myocardial infarction patients subjected to transcoronary delivery of progenitor cells.

Introduction: Infarct size (IS) is a fundamental determinant of left-ventricular (LV) remodelling (end-systolic and end-diastolic volume change, ΔESV, ΔEDV) and adverse clinical outcomes after myocardial infarction (MI). Our prior work found that myocardial uptake of transcoronary-delivered progenitor cells is governed by IS. Aim: To evaluate the relationship between IS, stem cell uptake, and the magnitude of LV remodelling in patients receiving transcoronary administration of progenitor cells shortly after MI. Material and methods: Thirty-one subjects (age 36-69 years) with primary percutaneous coronary intervention (pPCI)-treated anterior ST-elevation MI (peak CK-MB 584 [181-962] U/l, median [range]) and sustained left ventricle ejection fraction (LVEF) ≤ 45% were studied. On day 10 (median) 4.3 × 106 (median) autologous CD34+ cells (50% labelled with 99mTc-extametazime) were administered via the infarct-related artery (left anterior descending). ΔESV, ΔEDV, and mid circumferential myocardial strain (mCS) were evaluated at 24 months. Results: Infarct mass (cMRI) was 57 [11-112] g. Cell label myocardial uptake (whole-body γ-scans) was proportional to IS (r = 0.62), with a median 2.9% uptake in IS 1st tercile (≤ 45 g), 5.2% in 2nd (46-76 g), and 6.7% in 3rd (> 76 g) (p = 0.0006). Cell uptake in proportion to IS attenuated the IS-ΔESV (p = 0.41) and IS-ΔEDV (p = 0.09) relationship. At 24 months, mCS improved in IS 2nd tercile (p = 0.028) while it showed no significant change in smaller (p = 0.87) or larger infarcts (p = 0.58). Conclusions: This largest human study with labelled CD34+ cell transplantation shortly after MI suggests that cell uptake (proportional to IS) may attenuate the effect of IS on LV adverse remodelling. To boost this effect, further strategies should involve cell types and delivery techniques to maximize myocardial uptake.

Fibrinogen ß chain and FXIII polymorphisms affect fibrin clot properties in acute pulmonary embolism.

BACKGROUND: Prothrombotic fibrin clot properties, including increased clot density, are in part genetically determined. We investigated whether fibrinogen alpha-chain gene (FGA) c.991A>G (rs6050), fibrinogen beta chain gene (FGB) -455G>A (rs1800790) and factor XIII gene (F13) c.103G>T (rs5985) polymorphisms affect plasma fibrin clot properties in patients with acute pulmonary embolism (PE). METHODS: As many as 126 normotensive patients with PE, free of cancer, were genotyped by TaqMan assay. Fibrin clot permeability (Ks ), clot lysis time (CLT) and endogenous thrombin potential (ETP) were assessed on admission. RESULTS: The minor allele frequencies were as follows: FGA rs6050 (n = 62, 0.31), FGB rs1800790 (n = 40, 0.17) and F13 rs5985 (n = 49, 0.23). There were no differences related to any of the polymorphisms with regard to demographic, clinical and laboratory data, except for fibrinogen concentration, which was higher in carriers of F13 rs5985 polymorphism (p = .024), and PE combined with deep-vein thrombosis, which was less prevalent in FGB rs1800790 polymorphism carriers (p = .004). Carriers of FGB rs1800790 A allele and F13 rs5985 T allele had lower Ks , prolonged CLT and higher ETP compared with major homozygotes (all p < .05). After adjustment for fibrinogen, all differences remained significant (all p < .01). There were no associations between the FGA rs6050 polymorphism and Ks , CLT or ETP. CONCLUSION: Our study showed that FGB rs1800790 and F13 rs5985 polymorphisms contribute to the prothrombotic fibrin clot phenotype and these effects are strong enough to be observed in the acute phase of PE.

Coexistence and management of abdominal aortic aneurysm and coronary artery disease.

BACKGROUND: Abdominal aortic aneurysm (AAA) and coronary atherosclerosis share common risk factors. In this study, a single-center management experience of patients with a coexistence of AAA and coronary artery disease (CAD) is presented. METHODS: 271 consecutive patients who underwent elective AAA repair were reviewed. Coronary imaging in 118 patients was considered suitable for exploration of AAA coexistence with CAD. RESULTS: Significant coronary stenosis (> 70%) were found in 65.3% of patients. History of cardiac revascularization was present in 26.3% of patients, myocardial infarction (MI) in 31.4%, and 39.8% had both. In a subgroup analysis, prior history of percutaneous coronary intervention (PCI) (OR = 6.9, 95% CI 2.6-18.2, p < 0.001) and patients' age (OR = 1.1, 95% CI 1.0-1.2, p = 0.007) were independent predictors of significant coronary stenosis. Only 52.0% (40/77) of patients with significant coronary stenosis underwent immediate coronary revascularization prior to aneurysm repair: PCI in 32 cases (4 drug-eluting stents and 27 bare metal stents), coronary artery bypass graft in 8 cases. Patients undergoing revascularization prior to surgery had longer mean time from coronary imaging to AAA repair (123.6 vs. 58.1 days, p < 0.001). Patients undergoing coronary artery evaluation prior to AAA repair had shorter median hospitalization (7 [2-70] vs. 7 [3-181] days, p = 0.007) and intensive care unit stay (1 [0-9] vs. 1 [0-70] days, p = 0.014) and also had a lower rate of major adverse cardiovascular events or multiple organ failure (0% vs. 3.9%, p = 0.035). A total of 11.0% of patients had coronary artery aneurysms. CONCLUSIONS: Patients with AAA might benefit from an early coronary artery evaluation strategy.

Temporal changes in the pattern of invasive angiography use and its outcome in suspected coronary artery disease: implications for patient management and healthcare resources utilization.

INTRODUCTION: Invasive coronary angiography (CAG), the 'gold standard' in coronary artery disease (CAD) diagnosis, requires hospitalization, is not risk-free, and engages considerable healthcare resources. AIM: To assess recent (throught out 10 years) evolution of 'significant' (≥ 50% stenosis(es)) CAD prevalence in subjects undergoing CAG for CAD diagnosis in a high-volume tertiary referral center. MATERIAL AND METHODS: Anonymized medical records were compared for the last vs. the first 2-years of the decade (June 2007 to May 2018). Referrals for suspected CAD were 2067 of 4522 hospitalizations (45.7%) and 1755 of 5196 (33.8%) respectively (p < 0.001). RESULTS: The median patient age (64 vs. 68 years) and the prevalence of heart failure (24.1% vs. 42.2%) increased significantly (p < 0.001). The CAG atherosclerotic lesions, for all stenosis categories (< 50%; ≥ 50%; ≥ 70%; occlusion(s)), were significantly more prevalent in men. The proportion of subjects with any atherosclerosis on CAG increased (80.7% vs. 77.6%, p = 0.015). However, in the absence of any gross change in, for instance, the fraction of women (40.4% vs. 41.8%), the proportion of CAGs with significant CAD (lesion(s) ≥ 50%) decreased from 55.2% in 2007/2008 to below 1 in every 2 angiograms (48.9%) in 2017/2018 (p < 0.001). This unexpected finding occurred consistently across nearly all CAG referral categories. CONCLUSIONS: Despite more advanced age and a higher proportion of subjects with 'any' coronary atherosclerosis on CAG, the likelihood of a 'negative' angiogram (lesion(s) < 50%; no further evaluation/intervention) has increased significantly over the last decade. The exact nature of this phenomenon requires further investigation, particularly as a reverse trend would be expected with the growing role (and current high penetration) of contemporary non-invasive diagnostic tools to rule out significant CAD.