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Coronary Artery Disease: HELP
Articles by Marcus D. Flather
Based on 31 articles published since 2008
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Between 2008 and 2019, M. Flather wrote the following 31 articles about Coronary Artery Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data. 2018

Head, Stuart J / Milojevic, Milan / Daemen, Joost / Ahn, Jung-Min / Boersma, Eric / Christiansen, Evald H / Domanski, Michael J / Farkouh, Michael E / Flather, Marcus / Fuster, Valentin / Hlatky, Mark A / Holm, Niels R / Hueb, Whady A / Kamalesh, Masoor / Kim, Young-Hak / Mäkikallio, Timo / Mohr, Friedrich W / Papageorgiou, Grigorios / Park, Seung-Jung / Rodriguez, Alfredo E / Sabik, Joseph F / Stables, Rodney H / Stone, Gregg W / Serruys, Patrick W / Kappetein, Arie Pieter. ·Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, Netherlands. Electronic address: s.head@erasmusmc.nl. · Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, Netherlands. · Department of Cardiology, Erasmus University Medical Center, Rotterdam, Netherlands. · Department of Cardiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea. · Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, Denmark. · Icahn School of Medicine at Mount Sinai, New York, NY, USA; Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, ON, Canada. · Norwich Medical School University of East Anglia and Norfolk and Norwich University Hospital, Norwich, UK. · Icahn School of Medicine at Mount Sinai, New York, NY, USA. · Stanford University School of Medicine, Stanford, CA, USA. · Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil. · Richard L Roudebush VA Medical Center, Indianapolis, IN, USA. · Department of Cardiology, Oulu University Hospital, Oulu, Finland. · Department of Cardiac Surgery, Herzzentrum Universität Leipzig, Leipzig, Germany. · Department of Cardiothoracic Surgery, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Biostatistics, Erasmus University Medical Center, Rotterdam, Netherlands. · Cardiac Unit, Otamendi Hospital, Buenos Aires, Argentina. · Department Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. · Institute of Cardiovascular Medicine and Science, Liverpool Heart and Chest Hospital, Liverpool, UK. · Columbia University Medical Center and the Center for Clinical Trials, Cardiovascular Research Foundation, New York, NY, USA. · Imperial College London, London, UK. ·Lancet · Pubmed #29478841.

ABSTRACT: BACKGROUND: Numerous randomised trials have compared coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) for patients with coronary artery disease. However, no studies have been powered to detect a difference in mortality between the revascularisation strategies. METHODS: We did a systematic review up to July 19, 2017, to identify randomised clinical trials comparing CABG with PCI using stents. Eligible studies included patients with multivessel or left main coronary artery disease who did not present with acute myocardial infarction, did PCI with stents (bare-metal or drug-eluting), and had more than 1 year of follow-up for all-cause mortality. In a collaborative, pooled analysis of individual patient data from the identified trials, we estimated all-cause mortality up to 5 years using Kaplan-Meier analyses and compared PCI with CABG using a random-effects Cox proportional-hazards model stratified by trial. Consistency of treatment effect was explored in subgroup analyses, with subgroups defined according to baseline clinical and anatomical characteristics. FINDINGS: We included 11 randomised trials involving 11 518 patients selected by heart teams who were assigned to PCI (n=5753) or to CABG (n=5765). 976 patients died over a mean follow-up of 3·8 years (SD 1·4). Mean Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score was 26·0 (SD 9·5), with 1798 (22·1%) of 8138 patients having a SYNTAX score of 33 or higher. 5 year all-cause mortality was 11·2% after PCI and 9·2% after CABG (hazard ratio [HR] 1·20, 95% CI 1·06-1·37; p=0·0038). 5 year all-cause mortality was significantly different between the interventions in patients with multivessel disease (11·5% after PCI vs 8·9% after CABG; HR 1·28, 95% CI 1·09-1·49; p=0·0019), including in those with diabetes (15·5% vs 10·0%; 1·48, 1·19-1·84; p=0·0004), but not in those without diabetes (8·7% vs 8·0%; 1·08, 0·86-1·36; p=0·49). SYNTAX score had a significant effect on the difference between the interventions in multivessel disease. 5 year all-cause mortality was similar between the interventions in patients with left main disease (10·7% after PCI vs 10·5% after CABG; 1·07, 0·87-1·33; p=0·52), regardless of diabetes status and SYNTAX score. INTERPRETATION: CABG had a mortality benefit over PCI in patients with multivessel disease, particularly those with diabetes and higher coronary complexity. No benefit for CABG over PCI was seen in patients with left main disease. Longer follow-up is needed to better define mortality differences between the revascularisation strategies. FUNDING: None.

2 Clinical Trial Randomized trial of atopaxar in the treatment of patients with coronary artery disease: the lessons from antagonizing the cellular effect of Thrombin–Coronary Artery Disease Trial. 2011

Wiviott, Stephen D / Flather, Marcus D / O'Donoghue, Michelle L / Goto, Shinya / Fitzgerald, Desmond J / Cura, Fernando / Aylward, Philip / Guetta, Victor / Dudek, Dariusz / Contant, Charles F / Angiolillo, Dominick J / Bhatt, Deepak L / Anonymous3160692. ·Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA. swiviott@partners.org ·Circulation · Pubmed #21502571.

ABSTRACT: BACKGROUND: Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease (LANCELOT-CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD. METHODS AND RESULTS: Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6%; atopaxar, 3.9%; relative risk, 6.82, P=0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%; P for trend=0.01) and TIMI criteria (placebo, 6.8%; atopaxar, 10.3%; relative risk, 1.52, P=0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%; P for trend=0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups. CONCLUSIONS: In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00312052.

3 Clinical Trial Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. 2010

Goto, Shinya / Ogawa, Hisao / Takeuchi, Masaru / Flather, Marcus D / Bhatt, Deepak L / Anonymous6090671. ·Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Kanagawa 259-1143, Japan. shinichi@is.icc.u-tokai.ac.jp ·Eur Heart J · Pubmed #20805115.

ABSTRACT: AIMS: Two multicentre, randomized, double-blind, placebo-controlled Phase II studies assessed the safety and efficacy of the oral protease-activated receptor 1 (PAR-1) antagonist E5555 in addition to standard therapy in Japanese patients with acute coronary syndrome (ACS) or high-risk coronary artery disease (CAD). METHODS AND RESULTS: Patients with ACS (n = 241) or high-risk CAD (n = 263) received E5555 (50, 100, or 200 mg) or placebo once daily for 12 (ACS patients) or 24 weeks (CAD patients). The incidence of TIMI major, minor, and minimal bleeds requiring medical attention was similar in the placebo and combined E5555 (atopaxar) groups (ACS: 6.6% placebo vs. 5.0% E5555; CAD: 1.5% placebo vs. 1.5% E5555). There were no TIMI major bleeds and three CURE major bleeds (two with placebo; one with 100 mg E5555). There was a numerical increase in 'any' TIMI bleeding with the E5555 200 mg dose (ACS: 16.4% placebo vs. 23.0% E5555, P = 0.398; CAD: 4.5% placebo vs. 13.2% E5555, P = 0.081). The rate of major cardiovascular adverse events in the combined E5555 group was not different from placebo (ACS: 6.6% placebo vs. 5.0% E5555, P = 0.73; CAD: 4.5% placebo vs. 1.0% E5555, P = 0.066). There was a statistically significant dose-dependent increase in liver function abnormalities and QTcF with E5555. At trough dosing levels in both populations, mean inhibition of platelet aggregation was > 90% with 100 and 200 mg E5555, and 20-60% with 50 mg E5555. CONCLUSION: E5555 (50, 100, and 200 mg) did not increase clinically significant bleeding, although there was a higher rate of any TIMI bleeding with the highest two doses. All doses tested achieved a significant level of platelet inhibition. There was a significant dose-dependent increase in liver function abnormalities and QTcF. Although further study is needed, PAR-1 antagonism may have the potential to be a novel pathway for platelet inhibition to add on to the current standard of care therapy.

4 Article Bilateral versus Single Internal-Thoracic-Artery Grafts at 10 Years. 2019

Taggart, David P / Benedetto, Umberto / Gerry, Stephen / Altman, Douglas G / Gray, Alastair M / Lees, Belinda / Gaudino, Mario / Zamvar, Vipin / Bochenek, Andrzej / Buxton, Brian / Choong, Cliff / Clark, Stephen / Deja, Marek / Desai, Jatin / Hasan, Ragheb / Jasinski, Marek / O'Keefe, Peter / Moraes, Fernando / Pepper, John / Seevanayagam, Siven / Sudarshan, Catherine / Trivedi, Uday / Wos, Stanislaw / Puskas, John / Flather, Marcus / Anonymous4131080. ·From the Nuffield Department of Surgical Sciences, John Radcliffe Hospital (D.P.T., B.L.), the Centre for Statistics in Medicine, Botnar Research Centre (S.G., D.G.A.), and the Health Economics Research Centre, Nuffield Department of Population Health (A.M.G.), University of Oxford, Oxford, the School of Clinical Sciences, University of Bristol, and Bristol Royal Infirmary, Bristol (U.B.), the Department of Cardiac Surgery, Royal Infirmary of Edinburgh, Edinburgh (V.Z.), Royal Papworth Hospital, Cambridge (C.C., C.S.), the Department of Cardiac Surgery, Freeman Hospital, Newcastle (S.C.), the Department of Cardiac Surgery, King's College Hospital (J.D.), and Royal Brompton Hospital and Imperial College London (J. Pepper), London, the Department of Cardiac Surgery, Royal Infirmary, Manchester (R.H.), the Department of Cardiac Surgery, University Hospital of Wales, Cardiff (P.O.), the Department of Cardiac Surgery, Royal Sussex County, Brighton (U.T.), and Norwich Medical School, University of East Anglia, and Norfolk and Norwich University Hospital, Norwich (M.F.) - all in the United Kingdom · the Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York Presbyterian Hospital (M.G.), and Mount Sinai St. Luke's (J. Puskas) - both in New York · the Center for Cardiovascular Research and Development, American Heart of Poland (A.B.), and the Department of Cardiac Surgery, Medical University of Silesia (M.D., S.W.), Katowice, and the Department of Cardiac and Thoracic Surgery, Wroclaw Medical University, Wroclaw (M.J.) - all in Poland · the Department of Cardiac Surgery, Austin Health, Melbourne, VIC, Australia (B.B., S.S.) · and the Heart Institute of Pernambuco, Recife, Brazil (F.M.). ·N Engl J Med · Pubmed #30699314.

ABSTRACT: BACKGROUND: Multiple arterial grafts may result in longer survival than single arterial grafts after coronary-artery bypass grafting (CABG) surgery. We evaluated the use of bilateral internal-thoracic-artery grafts for CABG. METHODS: We randomly assigned patients scheduled for CABG to undergo bilateral or single internal-thoracic-artery grafting. Additional arterial or vein grafts were used as indicated. The primary outcome was death from any cause at 10 years. The composite of death from any cause, myocardial infarction, or stroke was a secondary outcome. RESULTS: A total of 1548 patients were randomly assigned to undergo bilateral internal-thoracic-artery grafting (the bilateral-graft group) and 1554 to undergo single internal-thoracic-artery grafting (the single-graft group). In the bilateral-graft group, 13.9% of the patients received only a single internal-thoracic-artery graft, and in the single-graft group, 21.8% of the patients also received a radial-artery graft. Vital status was not known for 2.3% of the patients at 10 years. In the intention-to-treat analysis at 10 years, there were 315 deaths (20.3% of the patients) in the bilateral-graft group and 329 deaths (21.2%) in the single-graft group (hazard ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.12; P=0.62). Regarding the composite outcome of death, myocardial infarction, or stroke, there were 385 patients (24.9%) with an event in the bilateral-graft group and 425 patients (27.3%) with an event in the single-graft group (hazard ratio, 0.90; 95% CI, 0.79 to 1.03). CONCLUSIONS: Among patients who were scheduled for CABG and had been randomly assigned to undergo bilateral or single internal-thoracic-artery grafting, there was no significant between-group difference in the rate of death from any cause at 10 years in the intention-to-treat analysis. Further studies are needed to determine whether multiple arterial grafts provide better outcomes than a single internal-thoracic-artery graft. (Funded by the British Heath Foundation and others; Current Controlled Trials number, ISRCTN46552265 .).

5 Article Economic Evaluation of Complete Revascularization for Patients with Multivessel Disease Undergoing Primary Percutaneous Coronary Intervention. 2017

Barton, Garry R / Irvine, Lisa / Flather, Marcus / McCann, Gerry P / Curzen, Nick / Gershlick, Anthony H / Anonymous7010908. ·Norwich Medical School, University of East Anglia, Norwich, UK. Electronic address: g.barton@uea.ac.uk. · Norwich Medical School, University of East Anglia, Norwich, UK. · Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; NIHR Leicester Cardiovascular Biomedical Research Unit, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, UK. · University Hospital Southampton NHS Foundation Trust, Southampton, UK; Faculty of Medicine, University of Southampton, Southampton, UK. ·Value Health · Pubmed #28577691.

ABSTRACT: OBJECTIVES: To determine the cost-effectiveness of complete revascularization at index admission compared with infarct-related artery (IRA) treatment only, in patients with multivessel disease undergoing primary percutaneous coronary intervention (P-PCI) for ST-segment elevation myocardial infarction. METHODS: An economic evaluation of a multicenter randomized trial was conducted, comparing complete revascularization at index admission to IRA-only P-PCI in patients with multivessel disease (12-month follow-up). Overall hospital costs (costs for P-PCI procedure(s), hospital length of stay, and any subsequent re-admissions) were estimated. Outcomes were major adverse cardiac events (MACEs, a composite of all-cause death, recurrent myocardial infarction, heart failure, and ischemia-driven revascularization) and quality-adjusted life-years (QALYs) derived from the three-level EuroQol five-dimensional questionnaire. Multiple imputation was undertaken. The mean incremental cost and effect, with associated 95% confidence intervals, the incremental cost-effectiveness ratio, and the cost-effectiveness acceptability curve were estimated. RESULTS: On the basis of 296 patients, the mean incremental overall hospital cost for complete revascularization was estimated to be -£215.96 (-£1390.20 to £958.29), compared with IRA-only, with a per-patient mean reduction in MACEs of 0.170 (0.044 to 0.296) and a QALY gain of 0.011 (-0.019 to 0.041). According to the cost-effectiveness acceptability curve, the probability of complete revascularization being cost-effective was estimated to be 72.0% at a willingness-to-pay threshold value of £20,000 per QALY. CONCLUSIONS: Complete revascularization at index admission was estimated to be more effective (in terms of MACEs and QALYs) and cost-effective (overall costs were estimated to be lower and complete revascularization thereby dominated IRA-only). There was, however, some uncertainty associated with this decision.

6 Article Associations Between Adding a Radial Artery Graft to Single and Bilateral Internal Thoracic Artery Grafts and Outcomes: Insights From the Arterial Revascularization Trial. 2017

Taggart, David P / Altman, Douglas G / Flather, Marcus / Gerry, Stephen / Gray, Alastair / Lees, Belinda / Benedetto, Umberto / Anonymous481121. ·From Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, United Kingdom (D.P.T., B.L.) · Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (D.G.A., S.G.), and Department of Public Health, Health Economics Research Centre (A.G.), University of Oxford, United Kingdom · Norwich Medical School, University of East Anglia, and Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, United Kingdom (M.F.) · and Bristol Heart Institute, School of Clinical Sciences, University of Bristol, United Kingdom (U.B.). ·Circulation · Pubmed #28566338.

ABSTRACT: BACKGROUND: Whether the use of the radial artery (RA) can improve clinical outcomes in coronary artery bypass graft surgery remains unclear. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral internal thoracic artery (BITA) over single left internal thoracic artery (SITA). In the ART, a large proportion of patients (≈20%) also received an RA graft instead of a saphenous vein graft (SVG). We aimed to investigate the associations between using the RA instead of an SVG to supplement SITA or BITA grafts and outcomes by performing a post hoc analysis of the ART. METHODS: Patients enrolled in the ART (n=3102) were classified on the basis of conduits actually received (as treated). The analysis included 2737 patients who received an RA graft (RA group; n=632) or SVG only (SVG group; n=2105) in addition to SITA or BITA grafts. The primary end point was the composite of myocardial infarction, cardiovascular death, and repeat revascularization at 5 years. Propensity score matching and stratified Cox regression were used to compare the 2 strategies. RESULTS: Myocardial infarction, cardiovascular death, and repeat revascularization cumulative incidence was 2.3% (95% confidence interval [CI], 1.1-3.4), 3.5% (95% CI, 2.1-5.0), and 4.4% (95% CI, 2.8-6.0) in the RA group and 3.4% (95% CI, 2.0-4.8), 4.0% (95% CI, 2.5-5.6), and 7.6% (95% CI, 5.5-9.7) in the SVG group, respectively. The composite end point was significantly lower in the RA group (8.8%; 95% CI, 6.5-11.0) compared with the SVG group (13.6%; 95% CI, 10.8-16.3; CONCLUSIONS: This post hoc ART analysis showed that an additional RA was associated with lower risk for midterm major adverse cardiac events when used to supplement SITA or BITA grafts. CLINICAL TRIAL REGISTRATION: URL: https://www.situ.ox.ac.uk/surgical-trials/art. Unique identifier: ISRCTN46552265.

7 Article Inflammatory Differences in Plaque Erosion and Rupture in Patients With ST-Segment Elevation Myocardial Infarction. 2017

Chandran, Sujay / Watkins, Johnathan / Abdul-Aziz, Amina / Shafat, Manar / Calvert, Patrick A / Bowles, Kristian M / Flather, Marcus D / Rushworth, Stuart A / Ryding, Alisdair D. ·Norfolk and Norwich University Hospital, Norwich, United Kingdom. · Norwich Medical School, University of East Anglia, Norwich, United Kingdom. · PILAR Research and Education, Cambridge, United Kingdom. · Papworth Hospital NHS Foundation Trust, Papworth Everard Cambridge, United Kingdom. · Norfolk and Norwich University Hospital, Norwich, United Kingdom alisdair.ryding@nnuh.nhs.uk. ·J Am Heart Assoc · Pubmed #28468787.

ABSTRACT: BACKGROUND: Plaque erosion causes 30% of ST-segment elevation myocardial infarctions, but the underlying cause is unknown. Inflammatory infiltrates are less abundant in erosion compared with rupture in autopsy studies. We hypothesized that erosion and rupture are associated with significant differences in intracoronary cytokines in vivo. METHODS AND RESULTS: Forty ST-segment elevation myocardial infarction patients with <6 hours of chest pain were classified as ruptured fibrous cap (RFC) or intact fibrous cap (IFC) using optical coherence tomography. Plasma samples from the infarct-related artery and a peripheral artery were analyzed for expression of 102 cytokines using arrays; results were confirmed with ELISA. Thrombectomy samples were analyzed for differential mRNA expression using quantitative real-time polymerase chain reaction. Twenty-three lesions were classified as RFC (58%), 15 as IFC (38%), and 2 were undefined (4%). In addition, 12% (12 of 102) of cytokines were differentially expressed in both coronary and peripheral plasma. I-TAC was preferentially expressed in RFC (significance analysis of microarrays adjusted CONCLUSIONS: These results demonstrate differential intracoronary cytokine expression in RFC and IFC. Elevated thrombospondin 1 and epidermal growth factor may play an etiological role in erosion.

8 Article One-year costs of bilateral or single internal mammary grafts in the Arterial Revascularisation Trial. 2017

Gray, Alastair M / Murphy, Jacqueline / Altman, Douglas G / Benedetto, Umberto / Campbell, Helen / Flather, Marcus / Gerry, Stephen / Lees, Belinda / Taggart, David P. ·Nuffield Department of Population Health, Health Economics Research Centre, University of Oxford, Headington, UK. · Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, Centre for Statistics in Medicine, Botnar Research Centre, University of Oxford, Oxford, UK. · School of Clinical Sciences, University of Bristol and Bristol Royal Infirmary, Bristol, UK. · Norwich Medical School, University of East Anglia and Norfolk and Norwich University Hospital, Norwich, UK. · Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. ·Heart · Pubmed #28450552.

ABSTRACT: OBJECTIVE: Coronary artery bypass grafting (CABG) using bilateral internal mammary arteries (BIMA) may improve survival over CABG using single internal mammary arteries (SIMA), but may be surgically more complex (and therefore costly) and associated with impaired sternal wound healing. We report, for the first time, a detailed comparison of healthcare resource use and costs over 12 months, as part of the Arterial Revascularisation (ART) Trial. METHODS: 3102 patients in 28 hospitals in seven countries were randomised to CABG surgery using BIMA (n=1548) or SIMA (n=1554). Detailed resource use data were collected covering surgery, the initial hospital episode, and for 12 months post randomisation. Using UK unit costs, total costs were calculated and compared between trial arms and for subgroups. RESULTS: Patients randomised to BIMA spent 20 min longer in theatre (95% CI 15 to 25, p<0.001) and also required more treatment for sternal wound problems. Mean (SD) total costs per patient at 12 months were £13 839 (£10 534) for BIMA and £12 717 (£9719) for SIMA (mean cost difference £1122, 95% CI £407 to £1838, p=0.002). No tests for interaction between subgroups and treatment allocation were significant. CONCLUSIONS: At 12 months from randomisation, mean costs were approximately 9% higher in BIMA than SIMA patients, primarily due to longer time in theatre and in-hospital stay, and slightly higher costs related to sternal wound problems during follow-up. Follow-up to the primary trial endpoint of 10 years will reveal whether longer-term differences emerge in graft patency or in overall survival. TRIAL REGISTRATION NUMBER: Controlled-trials.com (ISRCTN46552265).

9 Article Impact of dual antiplatelet therapy after coronary artery bypass surgery on 1-year outcomes in the Arterial Revascularization Trial. 2017

Benedetto, Umberto / Altman, Douglas G / Gerry, Stephen / Gray, Alastair / Lees, Belinda / Flather, Marcus / Taggart, David P / Anonymous6140902. ·Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Bristol, UK. · Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK. · Department of Public Health, Health Economics Research Centre, University of Oxford, Headington, Oxford, UK. · Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. · Research and Development Unit, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK. ·Eur J Cardiothorac Surg · Pubmed #28387790.

ABSTRACT: OBJECTIVES: There is still little evidence to boldport routine dual antiplatelet therapy (DAPT) with P2Y12 antagonists following coronary artery bypass grafting (CABG). The Arterial Revascularization Trial (ART) was designed to compare 10-year survival after bilateral versus single internal thoracic artery grafting. We aimed to get insights into the effect of DAPT (with clopidogrel) following CABG on 1-year outcomes by performing a post hoc ART analysis. METHODS: Among patients enrolled in the ART (n = 3102), 609 (21%) and 2308 (79%) were discharged on DAPT or aspirin alone, respectively. The primary end-point was the incidence of major adverse cerebrovascular and cardiac events (MACCE) at 1 year including cardiac death, myocardial infarction, cerebrovascular accident and reintervention; safety end-point was bleeding requiring hospitalization. Propensity score (PS) matching was used to create comparable groups. RESULTS: Among 609 PS-matched pairs, MACCE occurred in 34 (5.6%) and 34 (5.6%) in the DAPT and aspirin alone groups, respectively, with no significant difference between the 2 groups [hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.59-1.59; P = 0.90]. Only 188 (31%) subjects completed 1 year of DAPT, and in this subgroup, MACCE rate was 5.8% (HR 1.11, 95% CI 0.53-2.30; P = 0.78). In the overall sample, bleeding rate was higher in DAPT group (2.3% vs 1.1%; P = 0.02), although this difference was no longer significant after matching (2.3% vs 1.8%; P = 0.54). CONCLUSIONS: Based on these findings, when compared with aspirin alone, DAPT with clopidogrel prescribed at discharge was not associated with a significant reduction of adverse cardiac and cerebrovascular events at 1 year following CABG.

10 Article Randomized Trial of Bilateral versus Single Internal-Thoracic-Artery Grafts. 2016

Taggart, David P / Altman, Douglas G / Gray, Alastair M / Lees, Belinda / Gerry, Stephen / Benedetto, Umberto / Flather, Marcus / Anonymous901283. ·From Nuffield Department of Surgical Sciences (D.P.T., B.L.), Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre (D.G.A., S.G.), and the Health Economics Research Centre, Nuffield Department of Population Health (A.M.G.), University of Oxford, Oxford, the School of Clinical Sciences, University of Bristol and Bristol Royal Infirmary, Bristol (U.B.), and Norwich Medical School, University of East Anglia and Norfolk and Norwich University Hospital, Norwich (M.F.) - all in the United Kingdom. ·N Engl J Med · Pubmed #27959712.

ABSTRACT: BACKGROUND: The use of bilateral internal thoracic (mammary) arteries for coronary-artery bypass grafting (CABG) may improve long-term outcomes as compared with the use of a single internal-thoracic-artery plus vein grafts. METHODS: We randomly assigned patients scheduled for CABG to undergo single or bilateral internal-thoracic-artery grafting in 28 cardiac surgical centers in seven countries. The primary outcome was death from any cause at 10 years. The composite of death from any cause, myocardial infarction, or stroke was a secondary outcome. Interim analyses were prespecified at 5 years of follow-up. RESULTS: A total of 3102 patients were enrolled; 1554 were randomly assigned to undergo single internal-thoracic-artery grafting (the single-graft group) and 1548 to undergo bilateral internal-thoracic-artery grafting (the bilateral-graft group). At 5 years of follow-up, the rate of death was 8.7% in the bilateral-graft group and 8.4% in the single-graft group (hazard ratio, 1.04; 95% confidence interval [CI], 0.81 to 1.32; P=0.77), and the rate of the composite of death from any cause, myocardial infarction, or stroke was 12.2% and 12.7%, respectively (hazard ratio, 0.96; 95% CI, 0.79 to 1.17; P=0.69). The rate of sternal wound complication was 3.5% in the bilateral-graft group versus 1.9% in the single-graft group (P=0.005), and the rate of sternal reconstruction was 1.9% versus 0.6% (P=0.002). CONCLUSIONS: Among patients undergoing CABG, there was no significant difference between those receiving single internal-thoracic-artery grafts and those receiving bilateral internal-thoracic-artery grafts with regard to mortality or the rates of cardiovascular events at 5 years of follow-up. There were more sternal wound complications with bilateral internal-thoracic-artery grafting than with single internal-thoracic-artery grafting. Ten-year follow-up is ongoing. (Funded by the British Heart Foundation and others; ART Current Controlled Trials number, ISRCTN46552265 .).

11 Article Infarct size following complete revascularization in patients presenting with STEMI: a comparison of immediate and staged in-hospital non-infarct related artery PCI subgroups in the CvLPRIT study. 2016

Khan, Jamal N / Nazir, Sheraz A / Greenwood, John P / Dalby, Miles / Curzen, Nick / Hetherington, Simon / Kelly, Damian J / Blackman, Daniel / Ring, Arne / Peebles, Charles / Wong, Joyce / Sasikaran, Thiagarajah / Flather, Marcus / Swanton, Howard / Gershlick, Anthony H / McCann, Gerry P. ·Department of Cardiovascular Sciences, University of Leicester and the NIHR Leicester Cardiovascular Biomedical Research Unit, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, UK. · Multidisciplinary Cardiovascular Research Centre and The Division of Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK. · Harefield Hospital, Royal Brompton and Harefield Foundation Trust, NIHR Cardiovascular Biomedical Research Unit, Middlesex, UK. · University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK. · Kettering General Hospital, Kettering, NN16 8UZ, UK. · Royal Derby Hospital, Derby, UK. · Leicester Clinical Trials Unit, University of Leicester, UK and Department of Mathematical Statistics and Actuarial Science, University of Leicester, University of the Free State, Bloemfontein, South Africa. · Norfolk and Norwich University Hospitals NHS Foundation Trust and Norwich Medical School, University of East Anglia, Norwich, UK. · The Heart Hospital, University College London Hospitals, London, UK. · Department of Cardiovascular Sciences, University of Leicester and the NIHR Leicester Cardiovascular Biomedical Research Unit, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, UK. gpm12@le.ac.uk. ·J Cardiovasc Magn Reson · Pubmed #27842548.

ABSTRACT: BACKGROUND: The CvLPRIT study showed a trend for improved clinical outcomes in the complete revascularisation (CR) group in those treated with an immediate, as opposed to staged in-hospital approach in patients with multivessel coronary disease undergoing primary percutaneous intervention (PPCI). We aimed to assess infarct size and left ventricular function in patients undergoing immediate compared with staged CR for multivessel disease at PPCI. METHODS: The Cardiovascular Magnetic Resonance (CMR) substudy of CvLPRIT was a multicentre, prospective, randomized, open label, blinded endpoint trial in PPCI patients with multivessel disease. These data refer to a post-hoc analysis in 93 patients randomized to the CR arm (63 immediate, 30 staged) who completed a pre-discharge CMR scan (median 2 and 4 days respectively) after PPCI. The decision to stage non-IRA revascularization was at the discretion of the treating interventional cardiologist. RESULTS: Patients treated with a staged approach had more visible thrombus (26/30 vs. 31/62, p = 0.001), higher SYNTAX score in the IRA (9.5, 8-16 vs. 8.0, 5.5-11, p = 0.04) and a greater incidence of no-reflow (23.3 % vs. 1.6 % p < 0.001) than those treated with immediate CR. After adjustment for confounders, staged patients had larger infarct size (19.7 % [11.7-37.6] vs. 11.6 % [6.8-18.2] of LV Mass, p = 0.012) and lower ejection fraction (42.2 ± 10 % vs. 47.4 ± 9 %, p = 0.019) compared with immediate CR. CONCLUSIONS: Of patients randomized to CR in the CMR substudy of CvLPRIT, those in whom the operator chose to stage revascularization had larger infarct size and lower ejection fraction, which persisted after adjusting for important covariates than those who underwent immediate CR. Prospective randomized trials are needed to assess whether immediate CR results in better clinical outcomes than staged CR. TRIAL REGISTRATION: ISRCTN70913605 , Registered 24th February 2011.

12 Article Pedicled and skeletonized single and bilateral internal thoracic artery grafts and the incidence of sternal wound complications: Insights from the Arterial Revascularization Trial. 2016

Benedetto, Umberto / Altman, Douglas G / Gerry, Stephen / Gray, Alastair / Lees, Belinda / Pawlaczyk, Rafal / Flather, Marcus / Taggart, David P / Anonymous8680865. ·Bristol Heart Institute, University of Bristol, School of Clinical Sciences, Bristol, United Kingdom. Electronic address: Umberto.benedetto@bristol.ac.uk. · Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. · Department of Public Health, Health Economics Research Centre, University of Oxford, Headington, Oxford, United Kingdom. · Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. · Department of Cardiovascular Surgery, Medical University of Gdansk, Poland. · Research and Development Unit, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, United Kingdom. ·J Thorac Cardiovasc Surg · Pubmed #27112712.

ABSTRACT: OBJECTIVES: The question of whether skeletonized internal thoracic artery harvesting reduces the incidence of sternal wound complications in comparison with the pedicled technique, in the context of single or bilateral internal thoracic arteries, remains controversial. We studied the impact of the internal thoracic artery harvesting strategy on sternal wound complication in the Arterial Revascularization Trial. METHODS: Patients enrolled in the Arterial Revascularization Trial (n = 3102) were randomized to coronary artery bypass grafting with single or bilateral internal thoracic arteries. Sternal wound complication rates were examined according to the harvesting technique that was documented in 2056 patients. The internal thoracic artery harvesting technique, based on the surgeon's preference, resulted in 4 groups: pedicled single internal thoracic artery (n = 607), pedicled bilateral internal thoracic artery (n = 459), skeletonized single internal thoracic artery (n = 512), and skeletonized bilateral internal thoracic artery (n = 478). Propensity scores weighting was used to estimate the impact of the harvesting technique on sternal wound complications. RESULTS: A total of 219 of 2056 patients (10.6%) experienced a sternal wound complication within 1 year from the index operation. Of those, only 25 patients (1.2%) required sternal wound reconstruction. Pedicled bilateral internal thoracic artery (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.23-2.63) but not skeletonized bilateral internal thoracic artery (OR, 1.00; 95% CI, 0.65-1.53) or skeletonized single internal thoracic artery (OR, 0.89; 95% CI, 0.57-1.38) was associated with a significantly increased risk of any sternal wound complications compared with pedicled single internal thoracic artery. CONCLUSIONS: The present Arterial Revascularization Trial substudy suggests that, with a skeletonization technique, the risk of sternal wound complication with bilateral internal thoracic artery grafting is similar to that after standard pedicled single internal thoracic artery harvesting, whereas skeletonized single internal thoracic artery harvesting did not add any further benefit when compared with pedicled single internal thoracic artery harvesting.

13 Article Use of Coronary Computed Tomographic Angiography to Guide Management of Patients With Coronary Disease. 2016

Williams, Michelle C / Hunter, Amanda / Shah, Anoop S V / Assi, Valentina / Lewis, Stephanie / Smith, Joel / Berry, Colin / Boon, Nicholas A / Clark, Elizabeth / Flather, Marcus / Forbes, John / McLean, Scott / Roditi, Giles / van Beek, Edwin J R / Timmis, Adam D / Newby, David E / Anonymous6810864. ·British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. · Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom. · Health Economics Research Centre, University of Oxford, Oxford, United Kingdom. · Institute for Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom. · Norwich Medical School, University of East Anglia, Norwich, United Kingdom. · Health Research Institute, University of Limerick, Limerick, Ireland. · National Health Service, Fife, United Kingdom. · William Harvey Research Institute, Queen Mary University of London, London, United Kingdom. · British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: d.e.newby@ed.ac.uk. ·J Am Coll Cardiol · Pubmed #27081014.

ABSTRACT: BACKGROUND: In a prospective, multicenter, randomized controlled trial, 4,146 patients were randomized to receive standard care or standard care plus coronary computed tomography angiography (CCTA). OBJECTIVES: The purpose of this study was to explore the consequences of CCTA-assisted diagnosis on invasive coronary angiography, preventive treatments, and clinical outcomes. METHODS: In post hoc analyses, we assessed changes in invasive coronary angiography, preventive treatments, and clinical outcomes using national electronic health records. RESULTS: Despite similar overall rates (409 vs. 401; p = 0.451), invasive angiography was less likely to demonstrate normal coronary arteries (20 vs. 56; hazard ratios [HRs]: 0.39 [95% confidence interval (CI): 0.23 to 0.68]; p < 0.001) but more likely to show obstructive coronary artery disease (283 vs. 230; HR: 1.29 [95% CI: 1.08 to 1.55]; p = 0.005) in those allocated to CCTA. More preventive therapies (283 vs. 74; HR: 4.03 [95% CI: 3.12 to 5.20]; p < 0.001) were initiated after CCTA, with each drug commencing at a median of 48 to 52 days after clinic attendance. From the median time for preventive therapy initiation (50 days), fatal and nonfatal myocardial infarction was halved in patients allocated to CCTA compared with those assigned to standard care (17 vs. 34; HR: 0.50 [95% CI: 0.28 to 0.88]; p = 0.020). Cumulative 6-month costs were slightly higher with CCTA: difference $462 (95% CI: $303 to $621). CONCLUSIONS: In patients with suspected angina due to coronary heart disease, CCTA leads to more appropriate use of invasive angiography and alterations in preventive therapies that were associated with a halving of fatal and non-fatal myocardial infarction. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).

14 Article Effects of on-pump and off-pump surgery in the Arterial Revascularization Trial. 2015

Taggart, David P / Altman, Douglas G / Gray, Alastair M / Lees, Belinda / Nugara, Fiona / Yu, Ly-Mee / Flather, Marcus / Anonymous2370806. ·Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK david.taggart@orh.nhs.uk. · Centre for Statistics in Medicine, University of Oxford, Oxford, UK Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, Oxford, UK. · Department of Public Health, Health Economics Research Centre, University of Oxford, Headington, Oxford, UK. · Clinical Trials and Evaluation Unit, Royal Brompton and Harefield NHS Trust, London, UK National Heart and Lung Institute, Imperial College London, London, UK. · Clinical Trials and Evaluation Unit, Royal Brompton and Harefield NHS Trust, London, UK. ·Eur J Cardiothorac Surg · Pubmed #25217501.

ABSTRACT: OBJECTIVES: The Arterial Revascularization Trial (ART) is a randomized comparison of bilateral internal mammary artery (BIMA) versus single internal mammary artery (SIMA) grafting in coronary artery bypass graft (CABG) surgery and is one of the largest randomized trials of surgery ever conducted. ART is also one of the largest studies of contemporary CABG with a high proportion of off-pump surgeries (41%). The objective of this post hoc analysis was to evaluate the surgical process and 1-year outcomes for surgery performed on-pump compared with off-pump. METHODS: ART randomized 3102 patients with multivessel coronary artery disease (CAD) to SIMA or BIMA grafts to determine if BIMA grafts have an additional survival advantage at 10 years. The 1-year interim analysis showed an overall very low mortality and major morbidity rate irrespective of whether the procedure was with an SIMA or BIMA. The surgical process and 1-year outcomes were analysed according to whether surgery was performed on-pump or off-pump. RESULTS: Baseline variables were not statistically significantly different between on- and off-pump surgery within each treatment group after taking account of the effects of clustering by individual surgeons. At both 30 days and 1 year, there was a low incidence of death (1.2%, 2.3%), stroke (1.1%, 1.7%), myocardial infarction (MI) (1.4%, 1.9%), repeat revascularization (0.5%, 1.5%) and wound reconstruction (1.2%). A similar average number of grafts were performed with on- and off-pump surgery (median = 3), but the duration of surgery was 20-30 min and ventilation time ∼ 2 h shorter with off-pump surgery. Blood loss and platelet transfusions were lower in the off-pump group, with no difference in the need for balloon pump or renal support. Sternal wound reconstruction was similar with off-pump surgery in the SIMA group (0.5 vs 0.6%) and lower with off-pump surgery in the BIMA group (1.4 vs 2.2%). Repeat revascularization was marginally higher in off-pump patients at 30 days (0.8 vs 0.3%) and at 1 year (1.7 vs 1.3%). CONCLUSIONS: The outcomes of contemporary CABG are excellent with low mortality, stroke, myocardial infarction and need for wound reconstruction and repeat revascularization whether performed on-pump or off-pump. CLINICAL TRIAL REGISTRATION: Controlled-trials.com (ISRCTN46552265).

15 Article Darapladib for preventing ischemic events in stable coronary heart disease. 2014

Anonymous4340789 / White, Harvey D / Held, Claes / Stewart, Ralph / Tarka, Elizabeth / Brown, Rebekkah / Davies, Richard Y / Budaj, Andrzej / Harrington, Robert A / Steg, P Gabriel / Ardissino, Diego / Armstrong, Paul W / Avezum, Alvaro / Aylward, Philip E / Bryce, Alfonso / Chen, Hong / Chen, Ming-Fong / Corbalan, Ramon / Dalby, Anthony J / Danchin, Nicolas / De Winter, Robbert J / Denchev, Stefan / Diaz, Rafael / Elisaf, Moses / Flather, Marcus D / Goudev, Assen R / Granger, Christopher B / Grinfeld, Liliana / Hochman, Judith S / Husted, Steen / Kim, Hyo-Soo / Koenig, Wolfgang / Linhart, Ales / Lonn, Eva / López-Sendón, José / Manolis, Athanasios J / Mohler, Emile R / Nicolau, José C / Pais, Prem / Parkhomenko, Alexander / Pedersen, Terje R / Pella, Daniel / Ramos-Corrales, Marco A / Ruda, Mikhail / Sereg, Mátyás / Siddique, Saulat / Sinnaeve, Peter / Smith, Peter / Sritara, Piyamitr / Swart, Henk P / Sy, Rody G / Teramoto, Tamio / Tse, Hung-Fat / Watson, David / Weaver, W Douglas / Weiss, Robert / Viigimaa, Margus / Vinereanu, Dragos / Zhu, Junren / Cannon, Christopher P / Wallentin, Lars. · ·N Engl J Med · Pubmed #24678955.

ABSTRACT: BACKGROUND: Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2. METHODS: In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization). RESULTS: During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02). CONCLUSIONS: In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

16 Article Complete Versus culprit-Lesion only PRimary PCI Trial (CVLPRIT): a multicentre trial testing management strategies when multivessel disease is detected at the time of primary PCI: rationale and design. 2013

Kelly, Damian J / McCann, Gerald P / Blackman, Daniel / Curzen, Nicholas P / Dalby, Miles / Greenwood, John P / Fairbrother, Kathryn / Shipley, Lorraine / Kelion, Andrew / Heatherington, Simon / Khan, Jamal N / Nazir, Sheraz / Alahmar, Albert / Flather, Marcus / Swanton, Howard / Schofield, Peter / Gunning, Mark / Hall, Roger / Gershlick, Anthony H. ·Department of Cardiology, University Hospitals of Leicester, Leicester, United Kingdom. ·EuroIntervention · Pubmed #23425543.

ABSTRACT: AIMS: Primary percutaneous coronary intervention (PPCI) is the preferred strategy for acute ST-segment elevation myocardial infarction (STEMI), with evidence of improved clinical outcomes compared to fibrinolytic therapy. However, there is no consensus on how best to manage multivessel coronary disease detected at the time of PPCI, with little robust data on best management of angiographically significant stenoses detected in non-infarct-related (N-IRA) coronary arteries. CVLPRIT will determine the optimal management of N-IRA lesions detected during PPCI. METHODS AND RESULTS: CVLPRIT (Complete Versus culprit-Lesion only PRimary PCI Trial) is an open-label, prospective, randomised, multicentre trial. STEMI patients undergo verbal "assent" on presentation. Patients are included when angiographic MVD has been detected, and randomised to culprit (IRA)-only PCI (n=150) or in-patient complete multivessel PCI (n=150). Cumulative major adverse cardiac events (MACE) - all-cause mortality, recurrent MI, heart failure, need for revascularisation (PCI or CABG) will be recorded at 12 months. Secondary endpoints include safety endpoints of confirmed ischaemic stroke, intracranial haemorrhage, major non-intracranial bleeding, and repair of vascular complications. A cardiac magnetic resonance (CMR) substudy will provide mechanistic data on infarct size, myocardial salvage index and microvascular obstruction. A cost efficacy analysis will be undertaken. CONCLUSIONS: The management of multivessel coronary artery disease in the setting of PPCI for STEMI, including the timing of when to perform non-culprit-artery revascularisation if undertaken, remains unresolved. CVLPRIT will yield mechanistic insights into the myocardial consequence of N-IRA intervention undertaken during the peri-infarct period.

17 Article Radial artery pulse wave analysis for non-invasive assessment of coronary artery disease. 2013

Kotecha, Dipak / New, Gishel / Collins, Peter / Eccleston, David / Krum, Henry / Pepper, John / Flather, Marcus D. ·Clinical Trials & Evaluation Unit, Royal Brompton Hospital & National Heart & Lung Institute, Imperial College London, United Kingdom. dipak.kotecha@monash.edu ·Int J Cardiol · Pubmed #22483418.

ABSTRACT: BACKGROUND: Angiographically-normal coronary arteries are reported in 10-20% of patients undergoing diagnostic coronary angiography despite screening with risk factors and functional tests. We sought to validate and determine the clinical value of radial artery pulse wave analysis (PWA), a simple, quick and non-invasive marker of central artery stiffness and define its ability to predict coronary artery disease in high-risk patients. MATERIALS AND METHODS: 531 consecutive patients referred for elective coronary angiography, irrespective of previous co-morbidity, were assessed in a prospective, multicenter observational study [the Alternative Risk Markers in Coronary Artery Disease (ARM-CAD) study]. RESULTS: Mean age was 65 ± 11 years, 33% were women, 18% had impaired left-ventricular function and 22% a prior myocardial infarction. Angiography demonstrated normal coronary arteries in 20% of participants. The only independent associations with this outcome were younger age, female gender, absence of diabetes and PWA-derived central augmentation pressure <24 mm Hg. The odds ratio for the latter after adjustment for medications and baseline risk factors (including blood pressure, high-sensitivity C-reactive protein and B-type natriuretic peptide) was 3.4 (95% CI 1.2 to 9.5; p=0.021). The specificity for the multivariate model that included PWA was 95.7% with a receiver operator curve area of 0.876. Validation studies suggested that systolic variables from PWA were robust regardless of waveform quality and similar to measured aortic pressures (mean difference 2.7 mm Hg). CONCLUSIONS: Assessment of radial artery waveforms is a useful non-invasive clinical test that can stratify the likelihood of coronary disease and assist in identifying patients who require diagnostic angiography.

18 Article The effect of age on outcomes of coronary artery bypass surgery compared with balloon angioplasty or bare-metal stent implantation among patients with multivessel coronary disease. A collaborative analysis of individual patient data from 10 randomized trials. 2012

Flather, Marcus / Rhee, June-Wha / Boothroyd, Derek B / Boersma, Eric / Brooks, Maria Mori / Carrié, Didier / Clayton, Tim C / Danchin, Nicholas / Hamm, Christian W / Hueb, Whady A / King, Spencer B / Pocock, Stuart J / Rodriguez, Alfredo E / Serruys, Patrick / Sigwart, Ulrich / Stables, Rodney H / Hlatky, Mark A. ·University of East Anglia, Norwich, United Kingdom. ·J Am Coll Cardiol · Pubmed #23153843.

ABSTRACT: OBJECTIVES: This study sought to assess whether patient age modifies the comparative effectiveness of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI). BACKGROUND: Increasingly, CABG and PCI are performed in older patients to treat multivessel disease, but their comparative effectiveness is uncertain. METHODS: Individual data from 7,812 patients randomized in 1 of 10 clinical trials of CABG or PCI were pooled. Age was analyzed as a continuous variable in the primary analysis and was divided into tertiles for descriptive purposes (≤56.2 years, 56.3 to 65.1 years, ≥65.2 years). The outcomes assessed were death, myocardial infarction and repeat revascularization over complete follow-up, and angina at 1 year. RESULTS: Older patients were more likely to have hypertension, diabetes, and 3-vessel disease compared with younger patients (p < 0.001 for trend). Over a median follow-up of 5.9 years, the effect of CABG versus PCI on mortality varied according to age (interaction p < 0.01), with adjusted CABG-to-PCI hazard ratios and 95% confidence intervals (CI) of 1.23 (95% CI: 0.95 to 1.59) in the youngest tertile; 0.89 (95% CI: 0.73 to 1.10) in the middle tertile; and 0.79 (95% CI: 0.67 to 0.94) in the oldest tertile. The CABG-to-PCI hazard ratio of less than 1 for patients 59 years of age and older. A similar interaction of age with treatment was present for the composite outcome of death or myocardial infarction. In contrast, patient age did not alter the comparative effectiveness of CABG and PCI on the outcomes of repeat revascularization or angina. CONCLUSIONS: Patient age modifies the comparative effectiveness of CABG and PCI on hard cardiac events, with CABG favored at older ages and PCI favored at younger ages.

19 Article Paraoxonase-1 is not associated with coronary artery calcification in type 2 diabetes: results from the PREDICT study. 2012

Mackness, Bharti / Marsillach, Judit / Elkeles, Robert S / Godsland, Ian F / Feher, Michael D / Rubens, Michael B / Flather, Marcus D / Humphries, Steve E / Cooper, Jackie / Mackness, Mike. ·Pontech Art, Calle De L'Argelagar, Tarragona, Spain. ·Dis Markers · Pubmed #22846213.

ABSTRACT: OBJECTIVES: To determine any association between serum paraoxonase-1 (PON1) activity, protein and coding region genetic polymorphisms and coronary artery calcification (CACS) and to determine factors which modulate serum PON1 in type 2 diabetes (T2DM). METHODS AND RESULTS: 589 patients (419 Caucasian, 120 South Asian, 50 other) from the PREDICT Study were investigated. All patients were asymptomatic for coronary disease and had established T2DM. CACS, lipids, lipoproteins, inflammatory markers, insulin resistance and PON1 activity, concentration and Q192R and L55M genotypes were measured. Independent associations were: 1) PON1 activity negatively with insulin resistance, triglycerides and PON1-55 genotype and positively with PON1-192 genotype; 2) PON1 concentration negatively with Caucasian ethnicity, duration of diabetes and statin use and positively with plasma creatinine and PON1-192 genotype. There was no association between CACS and any of the PON1 activity, concentration or genotype and this finding was not different in the various ethnic groups within the PREDICT study. CONCLUSION: PON1 is modulated by a number of factors, some of which are reported here for the first time, including ethnicity and insulin resistance in subjects with T2DM. No association between CACS and PON1 was found.

20 Article Atopaxar and its effects on markers of platelet activation and inflammation: results from the LANCELOT CAD program. 2012

O'Donoghue, Michelle L / Bhatt, Deepak L / Flather, Marcus D / Goto, Shinya / Angiolillo, Dominick J / Goodman, Shaun G / Zeymer, Uwe / Aylward, Philip E / Montalescot, Gilles / Ziecina, Rafal / Kobayashi, Hiroyuki / Ren, Fang / Wiviott, Stephen D. ·Cardiovascular Division and TIMI Study Group, Brigham and Women's Hospital, 350 Longwood Avenue, 1st floor, Boston, MA 02115, USA. modonoghue@partners.org ·J Thromb Thrombolysis · Pubmed #22653705.

ABSTRACT: Atopaxar is a reversible protease activated receptor (PAR)-1 thrombin receptor antagonist that interferes with platelet signaling. The effects of PAR-1 antagonists on biomarkers remain unknown. The primary objective was to assess the effects of atopaxar on biomarkers of inflammation and platelet activation. The LANCELOT-CAD trial randomized 720 subjects to atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks. Biomarkers were assessed at serial time points. A linear mixed model to account for repeated measures was used to evaluate the change in biomarker concentration from randomization across time to week 24. Least square means were determined from the linear mixed models. The concentration of sCD40L decreased on average over time by -553 (95 % CI -677, -429) ng/L in the combined atopaxar group versus -30.3 (-249 to 189) ng/L fall in the placebo arm (P < 0.001) and a dose-dependent trend was seen across treatment groups (P < 0.001 for trend). In contrast, Lp-PLA(2) mass rose on average over time by 12.6 (95 % CI 10.0, 15.3) ng/ml in the combined atopaxar group as compared with 2.6 (95 % CI -2.1, 7.3) ng/ml in the placebo arm (P < 0.001). Similarly, the concentration of IL-18 rose by 17.5 (95 % CI 12.4, 22.6) pg/ml in the atopaxar group versus a -1.2 (95 % CI -10.2, 7.8) pg/ml fall in the placebo group (P < 0.001). The effects of atopaxar on Lp-PLA(2) and IL-18 appeared to be dose-dependent (P < 0.001 for trend) and were observed in J-LANCELOT. Atopaxar did not have a significant effect on other inflammatory markers. In conclusion, atopaxar appeared to decrease sCD40L, but did not demonstrate an anti-inflammatory effect in patients with stable CAD. Although atopaxar increased the concentration of Lp-PLA(2) and IL-18, the clinical relevance of these findings remains unknown and warrants further investigation and validation.

21 Article Low responsiveness to clopidogrel increases risk among CKD patients undergoing coronary intervention. 2011

Htun, Patrik / Fateh-Moghadam, Suzanne / Bischofs, Christian / Banya, Winston / Müller, Karin / Bigalke, Boris / Stellos, Konstantinos / May, Andreas E / Flather, Marcus / Gawaz, Meinrad / Geisler, Tobias. ·Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Universitätsklinikum der Eberhard-Karls-Universität Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. ·J Am Soc Nephrol · Pubmed #21273381.

ABSTRACT: Patients with CKD are at higher risk for major events after percutaneous coronary intervention (PCI) compared with subjects with normal renal function. The aims of this study were to evaluate responsiveness to clopidogrel in patients with CKD and to examine the effect of antiplatelet drug response on post-PCI outcome. We retrospectively evaluated a consecutive cohort of 1567 patients with symptomatic coronary artery disease undergoing PCI, 648 (41%) of whom had stage 3 to 5 CKD. We assessed responsiveness to clopidogrel by ADP-induced platelet aggregation after oral administration of a 600-mg clopidogrel loading dose and 100 mg of aspirin. In a multivariate survival analysis that included 1335 (85%) of the cohort, stage 3 to 5 CKD and low response to clopidogrel were independent predictors of the primary end point (composite of myocardial infarction, ischemic stroke, and death within 1 year). In summary, a low response to clopidogrel might be an additional risk factor for the poorer outcomes in patients with stage 3 to 5 CKD compared with patients with better renal function.

22 Article Can protein biomarkers provide an index of coronary artery calcification in patients with Type 2 diabetes? 2010

Godsland, I F / Pavitt, D / Okoturo, O / Edwards, R J / Rubens, M B / Feher, M D / Flather, M D / Elkeles, R S / Anonymous4510673. ·Endocrinology and Metabolic Medicine, Imperial College London, London, UK. i.godsland@imperial.ac.uk ·Atherosclerosis · Pubmed #20880528.

ABSTRACT: OBJECTIVES: By exploring differences between patients with high and low coronary artery calcification score (CACS), a plasma protein biomarker might be identified as an alternative to CACS screening. METHODS: We selected stored samples (12 per group) from a cohort study of patients with Type 2 diabetes and CACS >1000 or <100 Agatston units, with matching for age, BMI, blood pressure, lipids and lipoproteins and fibrinogen. Multiplex, immunobead-based assay or ELISA measured 18 cardiovascular-related protein biomarkers. SELDI-TOF mass spectrometry (MS) screened for proteins differing significantly between high and low CACS. RESULTS: Only monocyte chemotactic protein-1 was higher in the high compared with the low CACS group but concentrations overlapped appreciably. On SELDI-TOF MS, several mass/charge ratio peak intensities significantly discriminated high and low CACS but these differences were not confirmed in larger samples from the cohort. CONCLUSIONS: Plasma protein biomarkers are unlikely to provide an effective alternative to measurement of CACS.

23 Article Impact of inflammatory markers on platelet inhibition and cardiovascular outcome including stent thrombosis in patients with symptomatic coronary artery disease. 2010

Müller, Karin / Aichele, Simon / Herkommer, Mario / Bigalke, Boris / Stellos, Konstantinos / Htun, Patrik / Fateh-Moghadam, Suzanne / May, Andreas E / Flather, Marcus / Gawaz, Meinrad / Geisler, Tobias. ·Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität, Tübingen, Germany. ·Atherosclerosis · Pubmed #20728084.

ABSTRACT: BACKGROUND: There is cumulative evidence that the degree of inflammation correlates with prognosis after percutaneous coronary interventions (PCI). Additionally, there is a cross-link between platelet activation and inflammatory pathways. The aim of the present analysis was to evaluate the association of inflammatory markers and effects of dual antiplatelet therapy on platelet function and outcome in patients undergoing PCI. METHODS AND RESULTS: In a pilot study, 157 patients with symptomatic coronary artery disease (CAD) undergoing PCI were consecutively evaluated. Platelet response to clopidogrel and acetylsalicylic acid was assessed using whole blood multiple electrode aggregometry (MEA). Baseline levels of IL-6, RANTES and MCP-1 were measured by Bio-Plex Cytokine assay. C-reactive protein (CRP) was determined by Immunoassay. Levels of IL-6, RANTES, and CRP correlated well with ADP and arachidonic acid (AA)-induced MEA. In a second step, a retrospective analysis of a cohort of 903 PCI-patients was performed to evaluate the association of on-treatment residual platelet aggregation (RPA) and baseline CRP levels on the incidence of myocardial infarction (MI), death and stent thrombosis (ST). Patients suffering a subsequent event had a significantly higher level of baseline CRP and higher RPA compared to patients without events. After multivariate adjustment high baseline CRP and high RPA were independent predictors for combined major events and ST after PCI. CONCLUSION: To our knowledge this is the first study linking inflammation, antiplatelet drug responsiveness and outcome in a large CAD-patient cohort. The results suggest a relevant interaction of these parameters and encourage multimodal therapeutic approaches to treat cardiovascular risk after PCI.

24 Article Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients. 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial. 2010

Kapur, Akhil / Hall, Roger J / Malik, Iqbal S / Qureshi, Ayesha C / Butts, Jeremy / de Belder, Mark / Baumbach, Andreas / Angelini, Gianni / de Belder, Adam / Oldroyd, Keith G / Flather, Marcus / Roughton, Michael / Nihoyannopoulos, Petros / Bagger, Jens Peder / Morgan, Kenneth / Beatt, Kevin J. ·London Chest Hospital, Barts and The London NHS Trust, Imperial College, London, England. ·J Am Coll Cardiol · Pubmed #20117456.

ABSTRACT: OBJECTIVES: The purpose of this study was to compare the safety and efficacy of percutaneous coronary intervention (PCI) with stenting against coronary artery bypass grafting (CABG) in patients with diabetes and symptomatic multivessel coronary artery disease. BACKGROUND: CABG is the established method of revascularization in patients with diabetes and multivessel coronary disease, but with advances in PCI, there is uncertainty whether CABG remains the preferred method of revascularization. METHODS: The primary outcome was a composite of all-cause mortality, myocardial infarction (MI), and stroke, and the main secondary outcome included the addition of repeat revascularization to the primary outcome events. A total of 510 diabetic patients with multivessel or complex single-vessel coronary disease from 24 centers were randomized to PCI plus stenting (and routine abciximab) or CABG. The primary comparison used a noninferiority method with the upper boundary of the 95% confidence interval (CI) not to exceed 1.3 to declare PCI noninferior. Bare-metal stents were used initially, but a switch to Cypher (sirolimus drug-eluting) stents (Cordis, Johnson & Johnson, Bridgewater, New Jersey) was made when these became available. RESULTS: At 1 year of follow-up, the composite rate of death, MI, and stroke was 10.5% in the CABG group and 13.0% in the PCI group (hazard ratio [HR]: 1.25, 95% CI: 0.75 to 2.09; p=0.39), all-cause mortality rates were 3.2% and 3.2%, and the rates of death, MI, stroke, or repeat revascularization were 11.3% and 19.3% (HR: 1.77, 95% CI: 1.11 to 2.82; p=0.02), respectively. When the patients who underwent CABG were compared with the subset of patients who received drug-eluting stents (69% of patients), the primary outcome rates were 12.4% and 11.6% (HR: 0.93, 95% CI: 0.51 to 1.71; p=0.82), respectively. CONCLUSIONS: The CARDia (Coronary Artery Revascularization in Diabetes) trial is the first randomized trial of coronary revascularization in diabetic patients, but the 1-year results did not show that PCI is noninferior to CABG. However, the CARDia trial did show that multivessel PCI is feasible in patients with diabetes, but longer-term follow-up and data from other trials will be needed to provide a more precise comparison of the efficacy of these 2 revascularization strategies. (The Coronary Artery Revascularisation in Diabetes trial; ISRCTN19872154).

25 Article Contemporary predictors of coronary artery disease in patients referred for angiography. 2010

Kotecha, Dipak / Flather, Marcus / McGrady, Michele / Pepper, John / New, Gishel / Krum, Henry / Eccleston, David. ·Clinical Trials and Evaluation Unit, Royal Brompton Hospital & National Heart and Lung Institute, Imperial College, London, UK. d.kotecha@rbht.nhs.uk ·Eur J Cardiovasc Prev Rehabil · Pubmed #19858725.

ABSTRACT: AIMS: Risk stratification is often used to determine the need and priority for coronary angiography. We investigated the contemporary value of Framingham and SCORE risk models, individual risk factors, B-type natriuretic peptide and high-sensitivity C-reactive protein (hs-CRP) in the current era of intensive risk management. METHODS AND RESULTS: Coronary artery disease (CAD) was obstructive (>or=50% stenosis) in 328 of 539 patients referred for elective diagnostic coronary angiography (61%). Lower rates of smoking, more exercise and lower cholesterol were noted in those with angiographic CAD, compatible with risk factor modification in these patients. Framingham and SCORE were associated with CAD both in patients with and without prior cardiovascular disease (CVD). In multivariate analysis only age, male sex, diabetes, chest pain and prior CVD were independent predictors of CAD; odds ratio 1.74 per 10 years (95% confidence interval: 1.34-2.27), 5.48 (3.36-8.92), 2.57 (1.44-4.60), 1.69 (1.02-2.81) and 2.61 (1.65-4.12), respectively. Classification of disease was not improved by B-type natriuretic peptide or hs-CRP when added to conventional risk factors, although the latter seems to have value in patients without earlier CVD and low-density lipoprotein-cholesterol of less than 3.4 mmol/l; the adjusted odds ratio for hs-CRP >or=2 mg/l in this sub-group was 2.49 (1.12-5.51, P=0.024). CONCLUSION: Framingham and SCORE risk models can be used in clinical practice to predict angiographic coronary disease although risk factor modification limits the predictive value of smoking, blood pressure, lipid profiles and cardiac biomarkers.

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