Morphine Analgesia Pre-PPCI Is Associated with Prothrombotic State, Reduced Spontaneous Reperfusion and Greater Infarct Size

Schattauer GmbH Stuttgart.The emergency management of ST-elevation myocardial infarction (STEMI) involves treatment with dual-antiplatelet therapy (DAPT) and primary percutaneous coronary intervention (PPCI). Pain is generally treated with opiates, which may delay gastric transit and reduce DAPT absorption. We sought to assess the effect of morphine on reperfusion, infarct size and thrombotic status in 300 patients presenting for PPCI. Morphine was given in a non-randomized fashion as required by emergency teams en route to the heart attack centre. All patients received DAPT and PPCI according to standard care, with optional glycoprotein IIb/IIIa inhibitor (GPI) use. Patients were assessed for ST-segment resolution, coronary flow, thrombotic status and peak troponin. Patients receiving morphine (n = 218; 72.7%) experienced less spontaneous ST-segment resolution pre-PPCI, lower rate of TIMI 2/3 flow in the infarct-related artery pre-PPCI and higher peak troponin level post-PPCI (median [interquartile range]; 1,906 [1,002-4,398] vs. 1,268 [249-2,920] ng/L; p = 0.016) than those who did not. Patients receiving morphine exhibited significantly enhanced platelet reactivity and impaired endogenous fibrinolysis on arrival, compared with no-morphine patients. Morphine administration was an independent predictor of failure of spontaneous ST-segment resolution after adjustment for other variables (odds ratio: 0.26; confidence interval: 0.08-0.84; p = 0.025). Among patients receiving GPI, there was no difference in pre-PPCI flow or peak troponin according to morphine use, suggesting that the adverse effects of morphine relate to delayed DAPT absorption, which may be overcome by GPI. Our hypothesis-generating data suggest that morphine use in STEMI is associated with enhanced platelet reactivity, reduced spontaneous myocardial reperfusion (pre-PPCI) and larger infarct size, and these adverse effects may be influenced by GPI use. CLINICAL TRIAL REGISTRATION:  URL: http://www.clinicaltrials.gov. Unique identifier: NCT02562690.Peer reviewedFinal Accepted Versio

Rationale and design of "Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)" study : A randomised trial modulating endogenous fibrinolysis in patients with acute coronary syndrome

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time > 2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.Peer reviewedFinal Published versio

Use of bioresorbable vascular scaffold : a meta-analysis of patients with coronary artery disease

BACKGROUND: Differences in outcomes between bioresorbable vascular scaffold (BVS) systems and drug-eluting metal stents (DES) have not been fully evaluated. We aimed to compare clinical and angiographic outcomes in randomised studies of patients with coronary artery disease (CAD), with a secondary analysis performed among registry studies. METHODS: A meta-analysis comparing outcomes between BVS and DES in patients with CAD. Overall estimates of treatment effect were calculated with random-effects model and fixed-effects model. RESULTS: In 6 randomised trials (3818 patients), BVS increased the risk of subacute stent thrombosis (ST) over and above DES (OR 2.14; CI 1.01 to 4.53; p=0.05), with a trend towards an increase in the risk of myocardial infarction (MI) (125 events in those assigned to BVS and 50 to DES; OR 1.36; CI 0.97 to 1.91; p=0.07). The risk of in-device late lumen loss (LLL) was higher with BVS than DES (mean difference 0.08 mm; CI 0.03 to 0.13; p=0.004). There was no difference in the risk of death or target vessel revascularisation (TVR) between the two devices. In 6 registry studies (1845 patients), there was no difference in the risk of death, MI, TVR or subacute ST between the two stents. Final BVS dilation pressures were higher in registry than in randomised studies (18.7±4.6 vs 15.2±3.3 atm; p<0.001). CONCLUSIONS: Patients treated with BVS had an increased risk of subacute ST and slightly higher LLL compared with those with DES, but this might be related to inadequate implantation techniques, in particular device underexpansion.Peer reviewedFinal Published versio

Methyl 3-(4-isopropyl­phen­yl)-1-phenyl-3,3a,4,9b-tetra­hydro-1H-chromeno[4,3-c]isoxazole-3a-carboxyl­ate

In the title compound, C27H27NO4, the five-membered isoxazole ring adopts an envelope conformation and the six-membered pyran ring adopts a half-chair conformation. The dihedral angle between the mean planes of the isoxazole ring and the chromene ring system is 54.95 (4)°

Apixaban Enhances Endogenous Fibrinolysis in Patients with Atrial Fibrillation

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.AIMS: Approximately 20% of ischaemic stroke patients exhibit spontaneous arterial recanalization, attributable to endogenous fibrinolysis, which strongly relates to improved functional outcome. The impact of oral anticoagulants on endogenous fibrinolysis is unknown. Our aim was to test the hypothesis that apixaban enhances endogenous fibrinolysis in non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: In a prospective cross-sectional analysis, we compared endogenous fibrinolysis in NVAF patients (n = 180) taking aspirin, warfarin, or apixaban. In a prospective longitudinal study, patients were tested before and after apixaban (n = 80). Endogenous fibrinolysis was assessed using the Global Thrombosis Test (GTT) and thromboelastography (TEG). Endogenous fibrinolysis [measured by GTT lysis time (LT)] was shorter on apixaban compared with warfarin or aspirin [median 1850 (IQR 1591-2300) vs. 2758 (2014-3502) vs. 2135 (1752-2463) s, P < 0.0001]. Among TEG indices, a small but significant difference in clot lysis time (CLT) was observed [apixaban 60.0 (45.0-61.0) vs. warfarin 61.0 (57.0-62.0) vs. aspirin 61.0 (59.0-61.0) min, P = 0.036]. Apixaban improved endogenous fibrinolysis measured using the GTT [LT pre-treatment 2204 (1779-2738) vs. on-treatment 1882 (1607-2374) s, P = 0.0003], but not by using TEG. Change in LT (ΔLT) with apixaban correlated with baseline LT (r = 0.77, P < 0.0001). There was weak correlation between ΔLT and ΔCLT in response to apixaban (r = 0.28, P = 0.02) and between on-apixaban LT and CLT (r = 0.25, P = 0.022). CONCLUSION: Apixaban enhances endogenous fibrinolysis, with maximal effect in those with impaired fibrinolysis pre-treatment. Apixaban-treated patients exhibit more favourable fibrinolysis profiles than those taking warfarin or aspirin. Whether apixaban may confer additional thrombotic risk reduction in NVAF patients with impaired fibrinolysis, compared to warfarin, merits further study.Peer reviewedFinal Accepted Versio

Relative effects of different non-vitamin K antagonist oral anticoagulants on global thrombotic status in atrial fibrillation

This is an Accepted Manuscript of an article published by Taylor & Francis GroupNon-vitamin K antagonist oral anticoagulants (NOACs) reduce the risk of thromboembolism in patients with atrial fibrillation (AF). There has been no head-to-head comparison of the effect of these agents on ex vivo thrombotic and thrombolytic status. Enhanced platelet reactivity and impaired endogenous thrombolysis are risk factors for recurrent thrombotic events. We aimed to assess the comparative effect of NOACs and warfarin using an ex vivo test of thrombosis and thrombolysis. Eighty patients with newly diagnosed non-valvular AF were tested before, and after being established on apixaban (n = 20), dabigatran (n = 20), rivaroxaban (n = 20), or warfarin (n = 20). Thrombotic status was assessed with the automated, point-of-care Global Thrombosis Test (GTT) that assesses both platelet reactivity and endogenous thrombolysis from native blood. The time taken to form an occlusive thrombus (occlusion time, OT) and the time required to restore flow through endogenous thrombolysis (lysis time, LT) were measured. All anticoagulants caused OT prolongation compared to baseline (apixaban 403 ± 102s vs. 496 ± 125s, p = 0.006; dabigatran 471 ± 106s vs. 656 ± 165s, p < 0.00001; rivaroxaban 381 ± 119s vs. 579 ± 158, p < 0.00001; warfarin 420 ± 145s vs. 604 ± 124s, p < 0.00001). Apixaban reduced LT from baseline (1895[1702-2167]s vs. 1435[347-1990]s; p = 0.006). A trend for LT reduction was seen with other NOACs (dabigatran 1594[1226-2069]s vs. 1539[561-2316]s, p = 0.499; rivaroxaban 2085[1366-2428]s vs. 1885[724-2420]s, p = 0.295) but not with warfarin (1490[1206-1960]s vs. 1776[1545-2334], p = 0.601). Our results suggest that NOACs and warfarin have a similar favorable effect on reducing platelet reactivity. All NOACs exhibited a trend toward enhancing endogenous thrombolytic status, although this was significant only for apixaban. This raises the possibility of using NOACs to enhance impaired endogenous fibrinolysis in patients at high-thrombotic risk.Peer reviewedFinal Accepted Versio

Impaired endogenous fibrinolysis at high shear using a point-of-care test in STEMI is associated with alterations in clot architecture

© The Author(s) 2019Impaired endogenous fibrinolysis is an adverse prognostic biomarker in acute coronary syndrome (ACS). Abnormally dense in vitro fibrin thrombi have been demonstrated in ACS patients and related to hypofibrinolysis using cumbersome, laboratory-based methods. We aimed to assess endogenous fibrinolysis using a point-of-care technique and relate this to clot architecture. From patients with ST-segment elevation myocardial infarction (STEMI), venous blood was drawn immediately on arrival to assess thrombotic status. Blood was assessed using the point-of-care Global Thrombosis Test which measures occlusive thrombus formation under high shear and subsequently endogenous fibrinolysis (lysis time, LT). Two samples per patient were run in parallel. In one channel, the measurement was allowed to proceed as normal. In the other, after occlusion, thrombus was extracted, washed, fixed in glutaraldehyde, dried, sputter-coated, and assessed using scanning electron microscope. Endogenous fibrinolysis was strongly associated fibrin fibre thickness (p = 0.0001). As LT increased (less efficient fibrinolysis), the fibrin network of the thrombus was significantly more compact and dense, with thinner fibrin fibres and smaller gaps. Fibrin fibre thickness correlated inversely with LT (r = - 0.89, p = 0.001). Adverse clot architecture in vitro is directly related to impaired endogenous fibrinolysis using a relatively new point-of-care technique in patients with STEMI. This may transform the relevance of fibrin clot architecture from an off-line laboratory association to being directly relevant to endogenous fibrinolysis at the patient bedside, which could be used as a near-patient test to guide prognosis and assess the effect of treatment.Peer reviewedFinal Published versio

Return and Volatility Spillovers of Asian Pacific Stock Markets’ Energy Indices

The aim of the study was to investigate the presence of volatility among the Energy Indices of Asia Pacific Stock Markets. To test the volatility among the daily returns of Energy Indices of Asia Pacific Stock Markets, the study selected five sample Asian Pacific stock markets’ Energy Indices on the basis of availability of data. The findings of descriptive statistics and the ADF Test revealed, that the daily returns of the sample energy indices of Asian Pacific stock markets were not normally distributed and achieved stationarity at level difference, over the research period. Hence the data may be used for additional analysis. The data were then analysed, by using the GARCH (1,1) model to assess the considerable volatility of daily returns of sample energy indices and the study, which revealed that during the study period, all of the sample energy indices were volatile

Enhancing medical students` confidence and performance in integrated structured clinical examinations (ISCE) through a novel near-peer, mixed model approach during the COVID-19 pandemic

Background: Near-peer medical education serves as an important method of delivering education to junior students by senior students. Due to the reduced clinical exposure because of the COVID-19 pandemic, we developed a mentorship scheme to help medical students with their Integrated Structured Clinical Examinations (ISCEs) by providing a combination of near-peer mentorship together with lecture-based teaching on a weekly basis for a 12-week period. Students attended a specialty-focused lecture every Tuesday followed by a small group teaching session organised by their tutor. Methods: A longitudinal evaluative interventional study was undertaken by the international student led medical education organisation, OSCEazy. The teaching programme was organised and conducted by third year medical students to a recruited cohort of second year medical students. Students’ perceptions of ISCEs (confidence, anxiety, and overall performance) were evaluated using 5-point Likert scales while their knowledge of the specialty was assessed using 10 single best answer questions which were distributed via Google® forms at the start and end of each week. In addition, we assessed tutor perceptions of their teaching and learning experience. Results: Seventy-two tutees were enrolled in the programme (mean age: 24.4, female: 77.8%). 88.9% of the participants had not attended any online ISCE teaching prior to this. They preferred in-person ISCE teaching as compared to virtual sessions [median 4.5 (IQR 4–5) vs 3 (IQR 3–4), p < 0.0001), respectively]. There was a significant overall increase in knowledge when comparing pre-session and post-session performance [mean 53.7% vs 70.7%, p < 0.0001)]. There was a significant increase in student confidence [Confidence: median 3 (IQR:3–4) vs 4 (IQR 3–4), p < 0.0001] while no change was seen in the anxiety and perception of their overall performance in an ISCE. [Anxiety: median 3 (IQR 2–4) vs 3 (IQR 3–4), p = 0.37, Performance: median 3 (IQR 3–4) vs median 3 (IQR 3–4), p < 0.0001]. The tutors reported an increase in their confidence in teaching ISCEs online [median 3 (IQR 2–3.25) vs median 4 (IQR 4–5), p < 0.0001)]. Conclusion: Online near-peer teaching increases the confidence of both tutees and tutors involved while enhancing the tutees’ knowledge of the specialty. Thus, medical schools should incorporate near-peer teaching in their curriculum to enhance the student learning experience