Cangrelor versus Ticagrelor in Patients Treated with Primary Percutaneous Coronary Intervention: Impact on Platelet Activity, Myocardial Microvascular Function and Infarct Size: A Randomized Controlled Trial.

BACKGROUND: Oral P2Y12 inhibitors take more than 2 hours to achieve full effect in healthy subjects and this action is further delayed in patients with acute myocardial infarction. Intravenous P2Y12 inhibition might lead to more timely and potent anti-platelet effect in the context of emergency primary angioplasty, improving myocardial recovery. OBJECTIVES: This article compares the efficacy of intravenous cangrelor versus ticagrelor in a ST-elevation myocardial infarction (STEMI) population treated with primary percutaneous coronary intervention (PPCI). MATERIALS AND METHODS: In an open-label, prospective, randomized controlled trial, 100 subjects with STEMI were assigned 1:1 to intravenous cangrelor or oral ticagrelor. The co-primary endpoints were platelet P2Y12 inhibition at infarct vessel balloon inflation time, 4 and 24 hours. Secondary endpoints included indices of coronary microcirculatory function: index of microvascular resistance (IMR), initial infarct size (troponin at 24 hours) and final infarct size at 12 weeks (cardiac magnetic resonance). Secondary endpoints included indices of coronary microcirculatory function (index of microvascular resistance [IMR]), initial infarct size (troponin at 24 hours), final infarct size at 12 weeks (cardiac magnetic resonance), corrected thrombolysis in myocardial infarction (TIMI) frame count, TIMI flow grade, myocardial perfusion grade, and ST-segment resolution (ClinicalTrials.gov NCT02733341). RESULTS: P2Y12 inhibition at first balloon inflation time was significantly greater in cangrelor-treated patients (cangrelor P2Y12 reaction unit [PRU] 145.2 ± 50.6 vs. ticagrelor 248.3 ± 55.1). There was no difference in mean PRU at 4 and 24 to 36 hours post-dosing. IMR, final infarct size, angiographic and electrocardiographic measures of reperfusion were all similar between groups. CONCLUSION: Cangrelor produces more potent P2Y12 inhibition at the time of first coronary balloon inflation time compared with ticagrelor. Despite this enhanced P2Y12 inhibition, coronary microvascular function and final infarct size did not differ between groups.

Co-Administration of an Excipient Oligonucleotide Helps Delineate Pathways of Productive and Nonproductive Uptake of Phosphorothioate Antisense Oligonucleotides in the Liver.

Phosphorothioate (PS) modified antisense oligonucleotides (ASOs) have progressed rapidly in the clinic for treating a variety of disease indications. We previously demonstrated that the activity of PS ASOs in the liver can be enhanced by co-infusion of an excipient oligonucleotide (EON). It was posited that the EON saturates a nonproductive uptake pathway(s) thereby permitting accumulation of the PS ASO in a productive tissue compartment. In this report, we measured PS ASO activity following administration by bolus, infusion or co-fusion with EON within hepatocytes and nonparenchymal cells (NPCs), of the liver. This revealed that while ASOs accumulate preferentially in NPCs, they are intrinsically more active in hepatocytes. Furthermore, we show that the EON enhances ASO potency when infused up to 72 h before or after administration of the active ASO suggesting that the EON can saturate and displace the ASO from nonproductive to productive compartments. Physical presence of the EON in tissues was required for optimal potentiation suggesting that there is a dynamic distribution of the ASO and EON between the compartments. Lastly, using a candidate approach, we confirmed Stabilin-2 as a molecular pathway for ASO uptake in sinusoidal endothelial cells and the ASGR as a pathway for ASO uptake into hepatocytes in the liver.

Synergistic effect of phosphorothioate, 5'-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA.

Chemical modifications are essential to improve metabolic stability and pharmacokinetic properties of siRNA to enable their systemic delivery. We investigated the effect of combing the phosphorothioate (PS) modification with metabolically stable phosphate analog (E)-5'-vinylphosphonate and GalNAc cluster conjugation on the activity of fully 2'-modified siRNA in cell culture and mice. Our data suggest that integrating multiple chemical approaches in one siRNA molecule improved potency 5-10 fold and provide a roadmap for developing more efficient siRNA drugs.

Effectiveness of a walking programme to support adults with intellectual disabilities to increase physical activity: walk well cluster-randomised controlled trial.

BACKGROUND: Programs to change health behaviours have been identified as one way to reduce health inequalities experienced by disadvantaged groups. The objective of this study was to examine the effectiveness of a behaviour change programme to increase walking and reduce sedentary behaviour of adults with intellectual disabilities. METHODS: We used a cluster randomised controlled design and recruited participants over 18 years old and not regularly involved in physical activity from intellectual disabilities community-based organisations. Assessments were carried out blind to allocation. Clusters of participants were randomly allocated to the Walk Well program or a 12-week waiting list control. Walk Well consisted of three face-to-face physical activity consultations incorporating behaviour change techniques, written resources for participants and carers, and an individualised, structured walking programme. The primary outcome measured with accelerometers was change in mean step count per day between baseline and 12 weeks. Secondary outcomes included percentage time per day sedentary and in moderate-vigorous physical activity (MVPA), body mass index (BMI), and subjective well being. RESULTS: One hundred two participants in 50 clusters were randomised. 82 (80.4%) participants completed the primary outcome. 66.7% of participants lived in the most deprived quintile on the Scottish Index of Multiple Deprivation. At baseline, participants walked 4780 (standard deviation 2432) steps per day, spent 65.5% (standard deviation 10.9) of time sedentary and 59% percent had a body mass in the obesity range. After the walking programme, the difference between mean counts of the Walk Well and control group was 69.5 steps per day [95% confidence interval (CI) -1054 to 1193.3]. There were no significant between group differences in percentage time sedentary 1.6% (95% CI -2.984 to 6.102), percentage time in MVPA 0.3% (95% CI -0.7 to 1.3), BMI -0.2 kg/m(2) (95% CI -0.8 to 0.4) or subjective well-being 0.3 (95% CI -0.9 to 1.5). CONCLUSIONS: This is the first published trial of a walking program for adults with intellectual disabilities. Positively changing physical activity and sedentary behaviours may require more intensive programmes or upstream approaches to address the multiple social disadvantages experienced by adults with intellectual disabilities. Since participants spent the majority of their time sedentary, home-based programmes to reduce sitting time may be a viable health improvement approach. TRIAL REGISTRATION: Current Controlled Trials ISRCTN50494254.

Lipid nanoparticles improve activity of single-stranded siRNA and gapmer antisense oligonucleotides in animals.

We evaluated the abilities of an antisense oligonucleotide (ASO), a small interfering RNA (siRNA), and a single-stranded siRNA (ss-siRNA) to inhibit expression from the PTEN gene in mice when formulated identically with lipid nanoparticles (LNPs). Significantly greater reductions in levels of PTEN mRNA were observed for LNP-formulated agents compared to unformulated drugs when gene silencing was evaluated after a single dose in the livers of mice. An unformulated ss-siRNA modified with a metabolically stable phosphate mimic 5'-(E)-vinylphosphonate showed dose-dependent reduction of PTEN mRNA in mice, albeit at doses significantly higher than those observed for formulated ss-siRNA. These results demonstrate that LNPs can be used to deliver functional antisense and ss-siRNA therapeutics to the liver, indicating that progress in the field of siRNA delivery is transferable to other classes of nucleic acid-based drugs.

Changes in body weight and food choice in those attempting smoking cessation: a cluster randomised controlled trial.

BACKGROUND: Fear of weight gain is a barrier to smoking cessation and significant cause of relapse for many people. The provision of nutritional advice as part of a smoking cessation programme may assist some in smoking cessation and perhaps limit weight gain. The aim of this study was to determine the effect of a structured programme of dietary advice on weight change and food choice, in adults attempting smoking cessation. METHODS: Cluster randomised controlled design. Classes randomised to intervention commenced a 24-week intervention, focussed on improving food choice and minimising weight gain. Classes randomised to control received "usual care". RESULTS: Twenty-seven classes in Greater Glasgow were randomised between January and August 2008. Analysis, including those who continued to smoke, showed that actual weight gain and percentage weight gain was similar in both groups. Examination of data for those successful at giving up smoking showed greater mean weight gain in intervention subjects (3.9 (SD 3.1) vs. 2.7 (SD 3.7) kg). Between group differences were not significant (p = 0.23, 95% CI -0.9 to 3.5). In comparison to baseline improved consumption of fruit and vegetables and breakfast cereal were reported in the intervention group. A higher percentage of control participants continued smoking (74% vs. 66%). CONCLUSIONS: The intervention was not successful at minimising weight gain in comparison to control but was successful in facilitating some sustained improvements in the dietary habits of intervention participants. Improved quit rates in the intervention group suggest that continued contact with advisors may have reduced anxieties regarding weight gain and encouraged cessation despite weight gain. Research should continue in this area as evidence suggests that the negative effects of obesity could outweigh the health benefits achieved through reductions in smoking prevalence.

The inverse relationship between alanine aminotransferase in the normal range and adverse cardiovascular and non-cardiovascular outcomes.

BACKGROUND: High serum alanine aminotransferase (ALT) levels have been associated with increased risk of diabetes and with increased mortality, but associations of variations of ALT in the normal range with outcomes have been less well studied. METHODS: We studied the relationship between ALT, mortality and cardiovascular events in the West of Scotland Coronary Prevention Study (WOSCOPS) and the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trials that explicitly excluded subjects with clinically significant liver damage, plus the Leiden 85-plus, a study of survivors to age 85 years. The associations between ALT and morbidity and mortality outcomes were investigated using Cox proportional hazard models adjusting for a comprehensive panel of cardiovascular risk factors. RESULTS: In all three study cohorts, ALT displayed an independent inverse relationship with all-cause mortality so that hazard ratios for fourth versus first quarter of ALT were all below 1.0; HRs 0.64 [95% confidence interval (CI) 0.50-0.81], 0.86 (0.73-1.01), 0.66 (0.50-0.87); WOSCOPS, PROSPER, Leiden 85-plus, respectively. In WOSCOPS and PROSPER, ALT was also inversely associated with risk of fatal plus non-fatal cardiovascular events, including coronary heart disease (CHD) events and stroke. CONCLUSIONS: In three independent populations, ALT in the normal range displayed an inverse relationship with total mortality, cardiovascular events and non-cardiovascular events in middle-to-older aged subjects without evidence of clinically significant liver damage, independent of traditional cardiovascular and other risk factors. These findings indicate that the relationship between ALT and clinical outcomes is more complex than generally appreciated.

Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

BACKGROUND: Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke. METHODS AND FINDINGS: In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31), in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20). CONCLUSIONS: In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.

C-reactive protein and prediction of coronary heart disease and global vascular events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER).

BACKGROUND: The role of C-reactive protein (CRP) in predicting vascular events and response to statin therapy remains uncertain. Additional large prospective studies are required. METHODS AND RESULTS: Baseline CRP was related to risk over 3.2 years for primary a combined end point (definite or suspected death from coronary heart disease, nonfatal myocardial infarction, and fatal or nonfatal stroke; n=865 events) and secondary (coronary heart disease events or stroke alone) and tertiary (stroke plus transient ischemic attack) end points in the Prospective Study of Pravastatin in the Elderly at Risk (n=5804 men and women; age, 70 to 82 years). CRP levels were higher in subjects who had a subsequent primary end-point event compared with those who did not (geometric mean; 3.64 mg/L [SD, 3.08 mg/L] versus 3.01 mg/L [SD, 3.05 mg/L]; P<0.0001). CRP correlated positively with body mass index and smoking status and negatively with high-density lipoprotein cholesterol. The unadjusted hazard ratio for the primary end point was 1.48 (95% CI, 1.26 to 1.74) in a comparison of top and bottom thirds for CRP, falling to 1.36 (95% CI, 1.15 to 1.61) with adjustment for established predictors and body mass index. Similar results were obtained for other end points or when results were examined separately by history of vascular disease. However, baseline CRP added minimally to risk prediction beyond conventional predictors and did not relate to the magnitude of pravastatin benefit. CONCLUSIONS: Elevated CRP minimally enhances cardiovascular disease prediction beyond established vascular risk factors and does not predict response to statin therapy in elderly subjects at risk. These data suggest that CRP has limited clinical value in cardiovascular disease risk stratification or predicting response to statin therapy in elderly people.

Our inability to predict thromboembolic events after prosthetic valve surgery.

BACKGROUND AND AIM OF THE STUDY: Thromboembolic and bleeding complications detract from outcome for patients with prosthetic heart valves. The study aim was to investigate whether measurement of coagulation activation markers and transcranial Doppler ultrasound microembolic signals (MES) could identify patients at subsequent higher risk of thromboembolism or bleeding events. METHODS: A total of 526 patients (mean age 66 years; 266 males, 260 females) who underwent elective valve replacement surgery was enrolled between April 1999 and October 2002. Clinical assessment and blood sampling for coagulation activation markers was performed preoperatively and at three and 12 months postoperatively. Transcranial Doppler MES were recorded in the first 144 patients. Status was reviewed between 21st April and 9th June 2005, with 99.4% follow up. RESULTS: Among patients, 62% had an aortic valve replaced, and mechanical valves constituted 60% of all implants. The mean follow up was 3.61 years; total follow up was 1,899.2 patient-years (pt-yr). In total, 115 patients died, while 61 experienced a total of 80 thromboembolic events: linearized event rates were 3.94% (mechanical valves) and 4.4% (bioprostheses). There was no difference between mitral and aortic implants, or among bileaflet, tilting-disc mechanical and porcine valves. Atrial fibrillation was not influential. Coagulation activation markers were not associated with thromboembolic events, except for an elevated von Willebrand factor (vWF), which was associated with a five-fold increase in embolic event rate. Fifty-one patients experienced 59 bleeding events; eight patients experienced multiple events. Linearized event rates were 3.37% (mechanical valves) and 2.49% (bioprostheses). The INR was suboptimal in 44-58% of patients. Transcranial Doppler MES were not associated with blood coagulation markers or thromboembolic events. CONCLUSION: Coagulation activation markers (except vWF) and MES did not predict thromboembolic events in valve replacement patients. Thromboembolic and bleeding event rates for West of Scotland patients generally exceeded reported rates: suboptimal anticoagulation appeared common and most likely influenced thromboembolic and bleeding event rates more than any other factor.

Predictors of functional decline in elderly people with vascular risk factors or disease.

OBJECTIVE: to determine contributors to decline in functional capacity in elderly patients with known vascular risk factors or disease. DESIGN: secondary analysis of longitudinal data gathered over an average 3.2 years of follow-up. PARTICIPANTS: 5,804 community-dwelling subjects aged 70-82 years with a history of, or risk factors for, ischaemic vascular disease. MEASUREMENTS: basic activities of daily living were measured serially through the study using the 20-point Barthel index and extended activities using a 14-point Instrumental Activities of Daily Living (IADL). RESULTS: over the period of study 896/5,661 (16%) subjects had deterioration in Barthel (mean reduction 0.35, SD 1.76) and 1,270/5,662 (22%) had a reduction in IADL score (mean 0.63, SD 2.15). Independent risk factors at baseline for a reduction in Barthel and IADL were age, female gender and diabetes mellitus. A history of vascular disease and smoking were also significant predictors of reduction in IADL. The development of a new cerebrovascular event was associated with a greatly increased risk of reduction in the Barthel and IADL score (multivariate OR 3.71 (95% CI 2.94, 4.69) and 3.71 (95% CI 2.96, 4.66), respectively). A similar pattern was seen for non-fatal myocardial infarction. Incident cerebrovascular events and non-fatal myocardial infarction accounted for 31 and 11%, respectively, of the population decline in Barthel, and 24 and 10% of the decline in IADL. CONCLUSION: incident vascular events were important contributors to functional decline in this population, accounting for almost half of the observed deterioration in basic activities of daily living and approximately one-third of the reduction in IADL. Prevention of ischaemic vascular events over the short to medium term should reduce the burden of disability in high-risk older subjects.