Impact of very low dose rivaroxaban in addition to dual antiplatelet therapy on endogenous fibrinolysis in acute coronary syndrome: The VaLiDate-R study.

BACKGROUND: Impaired endogenous fibrinolysis is adverse cardiovascular risk factor in acute coronary syndrome (ACS) patients. Addition of very low dose rivaroxaban (VLDR) to dual antiplatelet therapy (DAPT) reduces cardiovascular events but increases bleeding. OBJECTIVE: We aimed to assess whether addition of VLDR to DAPT can enhance endogenous fibrinolysis. METHODS: In a prospective, open-label trial, we assessed endogenous fibrinolysis in whole blood, in 549 patients with ACS using the Global Thrombosis Test (GTT) and Thromboelastography (TEG). Patients (n = 180) who demonstrated impaired endogenous fibrinolysis (lysis time [LT] >2000s with the GTT) were randomised 1:1:1 to (i) clopidogrel 75 mg daily; (ii) clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily; or (iii) ticagrelor 90 mg twice daily, for 30 days, in addition to aspirin. Fibrinolytic status was assessed at 0, 2, 4 and 8 weeks. The primary outcome was the change in LT from admission to week 4. We also measured thrombotic occlusion time (OT) at high shear, and rivaroxaban level. RESULTS: There was no difference between the groups with respect to LT or clot lysis with TEG, and no change in these parameters compared to baseline during study drug allocation. In the rivaroxaban plus clopidogrel group, OT was prolonged compared to the other groups, although rivaroxaban levels were low, suggesting non-compliance. CONCLUSION: Addition of rivaroxaban 2.5 mg twice daily to DAPT does not affect endogenous fibrinolysis of thrombus formed at either high or low shear. Further studies are needed to determine whether higher doses of rivaroxaban can favourably modulate fibrinolysis. CONDENSED ABSTRACT: Impaired endogenous fibrinolysis is a strong risk factor in ACS. We aimed to assess whether adding very low dose rivaroxaban (VLDR) to DAPT can enhance fibrinolysis. Fibrin and clot lysis were assessed in whole blood. ACS patients with impaired fibrinolysis were randomised 1:1:1 to clopidogrel 75 mg daily; clopidogrel 75 mg plus VLDR; or ticagrelor 90 mg twice daily, in addition to aspirin. At 30-days, there was no difference in lysis time between the groups, nor change from baseline. VLDR does not improve fibrinolysis at high or low shear. Further studies are needed to determine whether alternative antithrombotic regimens can enhance endogenous fibrinolysis.

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.

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.

Effect of P2Y12 inhibitors on thrombus stability and endogenous fibrinolysis.

Although used routinely to reduce thrombotic events in patients with coronary disease, the effects of P2Y12 inhibitors on thrombus stability and endogenous fibrinolysis are largely unknown. Blood taken from patients pre- and post-aspirin (n = 20) and on aspirin alone and on dual antiplatelet therapy comprising aspirin plus clopidogrel (n = 20), ticagrelor (n = 20) or cangrelor (n = 20), was tested using the Global Thrombosis Test. The number of "rebleeds" or drops (D) after early platelet-rich thrombus formation (occlusion time, OT), and before final lasting occlusion, was used as an inverse measure of thrombus stability. Whilst clopidogrel had no effect, ticagrelor and cangrelor both increased D significantly, reflecting increased thrombus instability [D pre- and post-clopidogrel 4.3 ±â€¯1.6 vs. 4.5 ±â€¯1.4, p = 0.833; pre- and post-ticagrelor 4.1 ±â€¯2.4 vs. 6.8 ±â€¯5.1, p = 0.048; pre- and post-cangrelor 3.6 ±â€¯2.0 vs. 7.9 ±â€¯8.9, p = 0.046]. Platelet reactivity was reduced by all P2Y12 inhibitors, demonstrated by OT prolongation (clopidogrel 378 ±â€¯87 s vs. 491 ±â€¯93 s, p < 0.001; ticagrelor 416 ±â€¯122 s vs. 549 ±â€¯121 s, p < 0.001; cangrelor 381 ±â€¯146 s vs. 613 ±â€¯210 s, p < 0.001). The magnitude of OT prolongation compared to baseline (ΔOT) was significantly greater for cangrelor compared to clopidogrel and ticagrelor. Cangrelor was the only agent to enhance fibrinolysis (lysis time pre- and post-cangrelor 1622[1240-2048]s vs. 1388[960-1634]s, p = 0.005). We demonstrate the ability to assess the effect of pharmacotherapy on thrombus stability in vitro and show that P2Y12 inhibitors potentiate thrombus instability at high shear. Cangrelor, and to a lesser extent ticagrelor, de-stabilised thrombus formation and cangrelor also enhanced fibrinolysis. Potentiation of thrombus instability could become a new pharmacological target, that may be particularly important in acute coronary syndromes.

Evidence of improved fluid management in patients receiving haemodialysis following a self-affirmation theory-based intervention: A randomised controlled trial.

OBJECTIVE: Haemodialysis patients are at risk of serious health complications; yet, treatment non-adherence remains high. Warnings about health risks associated with non-adherence may trigger defensive reactions. We studied whether an intervention based on self-affirmation theory reduced resistance to health-risk information and improved fluid treatment adherence. DESIGN: In a cluster randomised controlled trial, 91 patients either self-affirmed or completed a matched control task before reading about the health-risks associated with inadequate fluid control. OUTCOME MEASURES: Patients' perceptions of the health-risk information, intention and self-efficacy to control fluid were assessed immediately after presentation of health-risk information. Interdialytic weight gain (IDWG), excess fluid removed during haemodialysis, is a clinical measure of fluid treatment adherence. IDWG data were collected up to 12 months post-intervention. RESULTS: Self-affirmed patients had significantly reduced IDWG levels over 12 months. However, contrary to predictions derived from self-affirmation theory, self-affirmed participants and controls did not differ in their evaluation of the health-risk information, intention to control fluid or self-efficacy. CONCLUSION: A low-cost, high-reach health intervention based on self-affirmation theory was shown to reduce IDWG over a 12-month period, but the mechanism by which this apparent behaviour change occurred is uncertain. Further work is still required to identify mediators of the observed effects.

Simvastatin improves the sexual health-related quality of life in men aged 40 years and over with erectile dysfunction: additional data from the erectile dysfunction and statin trial.

BACKGROUND: Erectile dysfunction is prevalent in men over 40 years, affecting their quality of life and that of their partners. The aims of this study were:a) To evaluate the internal reliability of the male erectile dysfunction specific quality of life (MED-QoL) scale and explore its factor structure.b) To evaluate the effect of simvastatin on subscales of the MED-QoL in men over forty years with erectile dysfunction. METHODS: This is a double blind randomised controlled trial of 40 mg simvastatin or placebo given once daily for six months to men over forty years with untreated erectile dysfunction, who were not at high cardiovascular risk and were not on anti-hypertensive or lipid-lowering medication. 173 eligible men were recruited from 10 general practices in East of England. Data were collected at two points over 30 weeks.We report on the factor structure of MED-QoL, the internal reliability of the scale and the derived subscales, and the effect of simvastatin on MED-QoL subscales. RESULTS: An initial analysis of the MED-QoL items suggested that a number of items should be removed (MED-QoL-R). Exploratory factor analysis identified three subscales within the MED-QoL-R which accounted for 96% of the variance, related to feelings of Control, initiating Intimacy, and Emotional response to erectile dysfunction. The alpha value for the revised scale (MED-Qol-R) was >0.95 and exceeded .82 for each subscale. Regression analysis showed that patients in the placebo group experienced a significantly reduced feeling of Control over erectile dysfunction than those in the statin group. Those in the placebo group had significantly lower Emotional response than those in the statin group at the close of trial, but there was no significant treatment effect on Intimacy. CONCLUSIONS: Our revised MED-QoL-R identified three subscales. Secondary analysis showed a significant improvement in sexual health related quality of life, specifically in relation to perception of control and emotional health in men with untreated erectile dysfunction given 40 mg simvastatin for six months. TRIAL REGISTRATION: Current Controlled Trials ISRCTN66772971.

Evidence that self-affirmation improves phosphate control in hemodialysis patients: a pilot cluster randomized controlled trial.

BACKGROUND: Hemodialysis patients are at risk of serious health complications, yet treatment non-adherence remains high. PURPOSE: Warnings about health risks associated with non-adherence may trigger defensive reactions. We studied whether an intervention based on self-affirmation theory (Steele 1988) reduced patients' resistance to health-risk information and improved adherence. METHODS: One hundred twelve patients either self-affirmed or completed a matched control task before reading about the risks associated with a lack of phosphate control. Serum phosphate was collected from baseline up to 12 months. RESULTS: Self-affirmed patients had significantly reduced serum phosphate levels at 1 and 12 months. However, contrary to the predictions derived from self-affirmation theory, self-affirmed participants and controls did not differ in their evaluation of the health-risk information, behavioural intention or self-efficacy. CONCLUSIONS: A low-cost, high-reach health intervention based on self-affirmation theory was shown to reduce serum phosphate over a 12 month period. Further work is required to identify mediators of the observed effects.

Can simvastatin improve erectile function and health-related quality of life in men aged ≥40 years with erectile dysfunction? Results of the Erectile Dysfunction and Statins Trial [ISRCTN66772971].

OBJECTIVE: To evaluate the effectiveness and cost-effectiveness of simvastatin on erectile function and health-related quality of life in men aged ≥40 years with erectile dysfunction (ED). PATIENTS AND METHODS: ED is common in men aged ≥40 years and impacts upon their overall health-related quality of life and that of their partners. Men aged ≥40 years who were not receiving lipid lowering or anti-hypertensive medication and not at high cardiovascular risk were recruited from 10 general practices in the East of England. In total, 173 eligible men with untreated ED were randomized to double-blind treatment with 40 mg of simvastatin or placebo once daily for 6 months. Data were collected at three points over 30 weeks. The main outcome was erectile function (International Index of Erectile Function-5 score). Secondary outcomes included male ED-specific quality of life (MED-QoL), quality-adjusted life years (QALYs) using the generic Euroqol measure (EQ-5D), endothelial function, cardiovascular risk, cholesterol and health service costs. RESULTS: There was no significant difference in erectile function between the simvastatin and placebo groups (mean change, 1.28 vs 0.07, z = 1.1, p = 0.27), although a significant improvement in MED-QoL was observed (5% vs 2%, z = 2.09, p = 0.04). Both 10-year cardiovascular risk and low-density lipoprotein were reduced (cardiovascular risk, z = -3.67, p < 0.001; low-density lipoprotein, z = -5.46, p < 0.001), with no consistent change in endothelial function. The frequency of sexual encounters is correlated with improved erectile function. The joint distribution of costs and QALY benefits indicates that the probability of simvastatin being cost-effective for willingness-to-pay thresholds of £20,000 and £30,000 is 86% and 83%, respectively. CONCLUSIONS: Identifying men with ED provides an opportunity to modify future cardiovascular risk and to improve MED-QoL by treating them with 40 mg of simvastatin. The joint analysis of costs and QALY benefits suggests that there is high probability that simvastatin is a cost-effective strategy in men with ED. The findings could influence urological and primary care practice by including questions on ED during routine consultations and relevant clinical protocols. This provides an opportunity to impart lifestyle advice.

Can simvastatin improve erectile function and health-related quality of life in men aged >40 years with erectile dysfunction? Rationale and design of the Erectile Dysfunction and Statins (EDS) Trial [ISRCTN66772971](1).

UNLABELLED: What's known on the subject? and What will the study add? Erectile dysfunction is often associated with endothelial dysfunction. It is also recognized as a marker for underlying vascular disease. This study tests the hypothesis that statin therapy may improve erectile function and also reduce the risk of future cardiovascular events via a reduction in serum cholesterol and by improving endothelial function. The study will also determine whether the treatment improves quality of life related to sexual function. OBJECTIVE: • To describe the rationale and design of the Erectile Dysfunction and Statins (EDS) Trial which aims to evaluate the effectiveness of simvastatin on erectile function and health-related quality of life in men aged ≥40 years with erectile dysfunction. PATIENTS AND METHODS: • The study is a randomized, double-blind, placebo-controlled trial to test the hypotheses that statins improve endothelial function and reduce cholesterol and may improve erectile function in men with untreated erectile dysfunction (ED). • Study subjects are men ≥40 years who are not receiving lipid-lowering or anti-hypertensive medication and have no other cardiovascular disease (CVD) risk factors. • Eligible men with untreated ED are randomized to double-blind treatment with 40 mg simvastatin or placebo once daily for 6 months. • Data are collected at baseline, mid-trial and at the final follow-up visit at 30 weeks. • The main outcome is erectile function measured by the five-item version of the International Index of Erectile Function. Secondary outcomes include sexual-health-related quality of life and endothelial function. RESULTS: • Ten general practices have been recruited in the east of England. • We have randomized 173 men for a power of 90% to assess the main outcome. • To date there have been no serious unexpected adverse events. • Study findings will be available in September 2011. CONCLUSION: • If simvastatin improves erectile function it would provide an inexpensive treatment for ED suitable for most men, and reduce the risk of future CVD.

Commercial software upgrades may significantly alter Perfusion CT parameter values in colorectal cancer.

OBJECTIVE: To determine how commercial software platform upgrades impact on derived parameters for colorectal cancer. MATERIALS AND METHODS: Following ethical approval, 30 patients with suspected colorectal cancer underwent Perfusion CT using integrated 64 detector PET/CT before surgery. Analysis was performed using software based on modified distributed parameter analysis (Perfusion software version 4; Perfusion 4.0), then repeated using the previous version (Perfusion software version 3; Perfusion 3.0). Tumour blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were determined for identical regions-of-interest. Slice-by-slice and 'whole tumour' variance was assessed by Bland-Altman analysis. RESULTS: Mean BF, BV and PS was 20.4%, 59.5%, and 106% higher, and MTT 14.3% shorter for Perfusion 4.0 than Perfusion 3.0. The mean difference (95% limits of agreement) were +13.5 (-44.9 to 72.0), +2.61 (-0.06 to 5.28), -1.23 (-6.83 to 4.36), and +14.2 (-4.43 to 32.8) for BF, BV, MTT and PS respectively. Within subject coefficient of variation was 36.6%, 38.0%, 27.4% and 60.6% for BF, BV, MTT and PS respectively indicating moderate to poor agreement. CONCLUSION: Software version upgrades of the same software platform may result in significantly different parameter values, requiring adjustments for cross-version comparison.

First direct comparison of platelet reactivity and thrombolytic status between Japanese and Western volunteers: possible relationship to the "Japanese paradox".

OBJECTIVE: To determine and compare thrombotic and endogenous thrombolytic status in Japanese and Western populations. BACKGROUND: Incidence of coronary heart disease (CHD) and AMI in Japan remains lower than in Western countries. Primary genetic effects are unlikely, given the increased CHD in Japanese migrants. For men, cholesterol and blood pressure have been similar in Japan and the U.S. Dietary factors are implicated, but how these effect CHD is unclear. We postulated that differences in thrombotic and/or thrombolytic status may contribute. METHODS: We measured thrombotic and thrombolytic status in 100 healthy Japanese (J) from Japan and 100 healthy Westerners (W) from the U.K. using the Global Thrombosis Test (GTT). The GTT employs non-anticoagulated blood to create platelet-rich thrombi under high shear (occlusion time OT; seconds), and then measures the restart of blood flow, due to spontaneous thrombolysis (lysis time LT; seconds). RESULTS: OT was longer in (J) compared to (W) (545 vs. 364, p<0.0001). LT was longer in (J) than in (W) (1753 vs. 1052, p<0.0001). Distribution of LT in (J) did not conform to a normal population, with markedly impaired thrombolytic status (LT>3,000 s) in 18%, compared to none of the Westerners (p<0.0001). CONCLUSIONS: There are marked differences in thrombotic and thrombolytic status, with (J) having less prothrombotic (longer OT) but less favourable endogenous thrombolytic profile (longer LT). This may be important in the aetiology of thrombotic events. Since platelets and thrombolysis were both inhibited in (J) and yet incidence of AMI is lower, OT would seem more important than LT as a determinant of overall thrombotic risk in this population.

A pilot study of the epilepsy risk awareness checklist (ERAC) in people with epilepsy and learning disabilities.

PURPOSE: People with epilepsy are at risk of injury, and protection from potential dangers must be balanced against the need for autonomy. We developed an epilepsy risk awareness checklist (ERAC) as a tool to assess potential risks of epilepsy and related injuries, aiming to improve management strategies. It was designed for use by specialist nurses (in learning disability and epilepsy), as there was no existing tool for this. This study refined and tested this checklist in patients with epilepsy and learning disability in a range of community settings. METHOD: We used quantitative and qualitative measures to devise and revise the tool. Eleven qualified learning disability nurses completed the ERAC in three patients each (33 patients) using a purposive sampling method. They provided quantitative and qualitative feedback through questionnaires and interviews, and an expert panel reviewed and commented on the checklist. RESULTS: The checklist was revised through the evaluation process. All eleven nurses concluded that they would use the tool again. CONCLUSION: The epilepsy risk awareness checklist (ERAC) provides a measure of risk, and this study suggests that it is a useful tool in the care of people with learning disability and epilepsy. A larger scale study is planned.

Assessment of the spatial pattern of colorectal tumour perfusion estimated at perfusion CT using two-dimensional fractal analysis.

The aim was to evaluate the feasibility of fractal analysis for assessing the spatial pattern of colorectal tumour perfusion at dynamic contrast-enhanced CT (perfusion CT). Twenty patients with colorectal adenocarcinoma underwent a 65-s perfusion CT study from which a perfusion parametric map was generated using validated commercial software. The tumour was identified by an experienced radiologist, segmented via thresholding and fractal analysis applied using in-house software: fractal dimension, abundance and lacunarity were assessed for the entire outlined tumour and for selected representative areas within the tumour of low and high perfusion. Comparison was made with ten patients with normal colons, processed in a similar manner, using two-way mixed analysis of variance with statistical significance at the 5% level. Fractal values were higher in cancer than normal colon (p < or = 0.001): mean (SD) 1.71 (0.07) versus 1.61 (0.07) for fractal dimension and 7.82 (0.62) and 6.89 (0.47) for fractal abundance. Fractal values were lower in 'high' than 'low' perfusion areas. Lacunarity curves were shifted to the right for cancer compared with normal colon. In conclusion, colorectal cancer mapped by perfusion CT demonstrates fractal properties. Fractal analysis is feasible, potentially providing a quantitative measure of the spatial pattern of tumour perfusion.

Can perfusion CT assessment of primary colorectal adenocarcinoma blood flow at staging predict for subsequent metastatic disease? A pilot study.

We aimed to determine whether perfusion CT measurements at colorectal cancer staging may predict for subsequent metastatic relapse. Fifty two prospective patients underwent perfusion CT at staging to estimate tumour blood flow, blood volume, mean transit time, and permeability surface area product. Patients considered metastasis free and suitable for surgery underwent curative resection subsequently. At final analysis, a median of 48.6 months post-surgery, patients were divided into those who remained disease free, and those with subsequent metastases. Vascular parameters for these two groups were compared using t-testing, and receiver operator curve analysis was performed to determine the sensitivity and specificity of these vascular parameters for predicting metastases. Thirty seven (71%) patients underwent curative surgery; data were available for 35: 26 (74%) remained disease free; 9 (26%) recurred (8 metastatic, 1 local). Tumour blood flow differed significantly between disease-free and metastatic patients (76.0 versus 45.7 ml/min/100 g tissue; p = 0.008). With blood flow <64 ml/min/100 g tissue, sensitivity and specificity (95% CI) for development of metastases were 100% (60-100%) and 73% (53-87%), respectively. Our preliminary findings suggest that primary tumour blood flow might potentially be a useful predictor warranting further study.

Colorectal tumor vascularity: quantitative assessment with multidetector CT--do tumor perfusion measurements reflect angiogenesis?

PURPOSE: To establish the relationships between quantitative perfusion computed tomography (CT) parameters-specifically, primary tumor blood flow, blood volume, transit time, and permeability surface-area product-and immunohistologic markers of angiogenesis in colorectal cancer. MATERIALS AND METHODS: After institutional review board approval and informed patient consent were obtained for this prospective study, 23 patients (11 men, 12 women; mean age, 68.4 years; age range, 34.8-87.1 years) with colorectal adenocarcinoma underwent a 65-second perfusion CT examination, and tumor blood flow, blood volume, mean transit time, and permeability surface-area product were determined. After surgery, resected specimens were sectioned and stained immunohistochemically to identify CD34 for quantification of microvessel density (MVD), to identify smooth muscle actin for assessment of pericyte coverage index, to identify vascular endothelial growth factor (VEGF), and to identify glucose transporter protein (GLUT-1). Perfusion CT measurements were correlated with MVD, pericyte coverage index, VEGF expression, and GLUT-1 expression by using Pearson or Spearman rank correlation analysis, with significance assigned at the 5% level. RESULTS: Mean blood flow, blood volume, transit time, and permeability surface-area product values were 72.1 mL/min/100 g of tissue +/- 28.4 (standard deviation), 6.2 mL/100 g of tissue +/- 1.4, 9.3 seconds +/- 3.9, and 13.9 mL/min/100 g of tissue +/- 3.2, respectively. Blood volume (r = 0.59, P = .002) and permeability surface-area product (r = 0.46, P = .03) correlated positively with MVD, but blood flow (r = 0.27, P = .22) and transit time (r = -0.18, P = .44) did not. There were no significant associations between any perfusion CT parameter and pericyte coverage index (r .05), VEGF score (rho or= .15), or GLUT-1 score (rho < 0.21, P >or= .33). CONCLUSION: Tumor permeability surface-area product and blood volume correlate positively with MVD and may reflect the microvascularity of colorectal tumors.