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Centre of Cardiovascular Research and Education in Therapeutics Annual Report 2009 www.ccretherapeutics.org.au Contents Director's report . . . . . . . . . . . . . . 1 Mission statement . . . . . . . . . . . . . . 2 Scientific Advisory Board . . . . . . . . . . . 3 Operational review . . . . . . . . . . . . . . 8 Caulfield Clinical Trial Centre . . . . . . . . . 16 Research training and education . . . . . . . . 24 Meetings and symposia 26 Grants . . . . . . . . . . . . . . . . 28 Publications . . . . . . . . . . . . . . . 30 Contact . . . . . . . . . . . . . . . . 38 | Annual Report 2009 Director's report It gives me great pleasure to present this year's CCRE Therapeutics Annual Report 2009 was the first year of CCRET being a stand-alone Monash-approved research centre This evolved from CCRET's previous incarnation as an NHMRC Centre of Clinical Research Excellence Based on all metrics, CCRE Therapeutics is now a well-established, growing and self-sufficient stand-alone centre Indeed, 2009 was CCRET's most productive year ever, academically This is reflected by the large body of research work published, presentations given at local, national and international meetings as well as teaching load and student supervision Highlights of 2009 include: • SCREEN-HF: This study has been presented at both the 2009 CSANZ and European Society of Cardiology meetings following successful recruitment of more than 4000 patients in the cross-sectional cohort study Leveraging off this initial cohort we have been successful in obtaining further funding for this study Our close collaborator on SCREEN-HF, Associate Professor Jock Campbell of the St Vincent's Research Institute, received an NHMRC Project Grant for longitudinal follow up of the 4000 patients in the initial cohort This will allow us to observe the potential for development of LV dysfunction over time as well as which patients are at greatest risk of this We were also successful in obtaining National Heart Foundation funding support for a drug intervention study in the highest of these high risk subjects to prevent the development of these cardiac abnormalities Furthermore, we have received additional funding from MBF for sequential NT-proBNP testing Therefore, SCREEN-HF has become a large and internationally important flagship project for CCRE Therapeutics • INTEGRATE: The Integrate study of physician inertia has been successfully completed involving participation by both general practitioners and their patients Almost 8000 patients were recruited by Australian GPs into this study The final phase of data collection was completed in late 2009 utilising CCRE Therapeutics web-enabled data capture technology • CHAT: The CHAT study has been completed and analysed Results were presented for the first time in a late-breaking session of the European Heart Failure Association meeting in Nice, France in June 2009 • ASPREE: Following a joint submission by the ASPREE researchers (led by Professor John McNeil) and colleagues from the USA (led by Professor Richard Grim) this large-scale double-blind randomised placebo-controlled trial of low dose aspirin for primary prevention of disease has received a USD$50 million grant from the National Institute of Health This funding will enable recruitment to commence early next year of the 19,500 participants involved • ATMOSPHERE: This global study of the effects of aliskiren in patients with systolic chronic heart failure aims to recruit more than 7000 participants I have been appointed Chairman of the Steering Committee of the study, which is also being conducted locally at The Alfred hospital Centre of Cardiovascular Research and Education in Therapeutics | 1 Highlights of 2009 continued • RENAL DENERVATION: CCRE Therapeutics led this pivotal and highly successful first-in-man study to evaluate this novel strategy in the treatment of refractory hypertension I presented these results at a late-breaking clinical trial session of the American College of Cardiology in March 2009 and the study results were simultaneously published in the Lancet Following the success of this proof-of-concept study, work continues with further clinical trials • STABILITY: This international trial of an investigational drug, darapladip, in patients with chronic coronary heart disease receiving standard practice care is being undertaken at our Clinical Trial Centre at Caulfield CCRET achieved second highest recruitment Australia-wide Patients will be followed every six months for approximately three-and-a-half years • MEDICAL EDUCATION, eg CSANZ symposia: CCRE Therapeutics continues its commitment to medical education programs and once again held two highly successful symposia at this year's CSANZ meeting, with further events scheduled for 2010 In summary, 2009 was another successful year at CCRE Therapeutics Based on local and international feedback the CCRE Therapeutics 'brand' is increasingly well recognised 2010 promises to be an even more exciting year for the Centre Henry Krum, MBBS, PhD, FRACP, FCSANZ Professor of Medicine Mission statement To improve clinical outcomes at the individual and community level through the use of evidence, based on high-quality clinical research 2 | Annual Report 2009 Scientific Advisory Board Director Professor Henry Krum MBBS, PhD, FRACP, FCSANZ Professor Henry Krum completed his MBBS at the University of Melbourne in 1981, became a Fellow of the Royal Australasian College of Physicians in 1989 and completed a PhD at the University of Melbourne in 1991. Professor Krum is a Consultant Physician based at the Heart Centre, The Alfred hospital, and a specialist in heart failure management. Professor Krum's grant achievements include awarding of a five-year NHMRC Program Grant for 2005 to 2009 in heart failure research which has recently been reviewed for 2010 to 2014. He is the author of over 280 peer-reviewed manuscripts, 16 book chapters and is co-author of a text book of heart failure therapeutics. He has been Principal Investigator, Executive Committee member and Data Safety Monitoring Board Chairman for numerous international trials in cardiovascular therapeutics. Associate Director Associate Professor Christopher Reid BA, DipEd, MSc, CertHealthEcon, PhD Chris graduated from the University of Queensland in 1980 before undertaking graduate studies in Exercise Physiology at West Virginia University and a PhD in this department. Previously, Chris was Head of the Cardiovascular Disease Prevention Unit at the then Baker Heart Research Institute (now Baker-IDI) and has held roles as the Director of the 2nd Australian National Blood Pressure Study and Program Director of the Australian Society of Cardiothoracic Surgeons Victorian database. Over the past ten years, his work has led to the development of a series of clinical tools for general practitioners to assist in the uptake of evidence-based management of both primary and secondary prevention of cardiovascular disease. He has been invited to give eight international and 26 national lectures and has participated as a WHO consultant for prevention of cardiovascular disease in both Mongolia and Vietnam. Centre of Cardiovascular Research and Education in Therapeutics | 3 Professor John McNeil MBBS, MSc, PhD, FRACP, FAFPHM Professor John McNeil has been Chair, Monash University Department of Epidemiology and Preventive Medicine at The Alfred hospital, Melbourne, since 1986. He graduated in medicine from the University of Adelaide, subsequently completing a PhD in Clinical Pharmacology at the University of Melbourne and a Master of Science degree in epidemiology at the University of London. He completed specialty training as a physician and subsequently held senior medical staff positions at the Austin, Repatriation, The Alfred and Monash Medical Centres in Victoria. His research interests focus on drug safety. He is Scientific Secretary of the International Society of Cardiovascular Pharmacotherapy and a member of the Editorial Board of 'Cardiovascular Drugs and Therapeutics'. He is a Fellow of Food Standards Australia and New Zealand and chairs the Ethics Committee at The Alfred hospital. He is also currently a member of the Colonial Foundation Board. During his career he has been a member of a wide range of national scientific advisory committees established by the National Health and Medical Research Council, the Commonwealth Departments of Health, Aging and Veteran's Affairs, the Royal Australasian College of Physicians, the National Heart Foundation, the National Stroke Foundation and Food Standards Australia. He has published over 300 scientific papers and in 2008, was made a member of the Order of Australia in recognition of his contribution to Public Health. Professor Andrew Tonkin MBBS, FRACP Professor Andrew Tonkin is Head of the Cardiovascular Research Unit in the Department of Epidemiology and Preventive Medicine, Monash University. He is also a Consultant Cardiologist at Austin Health. He has also been Chief Medical Officer with the National Heart Foundation of Australia. Professor Tonkin is past Chairman of the Australian Expert Advisory Group on Heart, Stroke and Vascular Diseases, which advised Government, and is a member of the Executive Board of the Council on Clinical Cardiology of the World Heart Federation. 4 | Annual Report 2009 Professor Paul Myles MBBS, DipRACOG, MD, FRCA Professor Paul Myles is the Director of Anaesthesia and Perioperative Medicine at the Alfred Hospital, and Professor of Anaesthesia at Monash University. Professor Myles is involved in a number of large multi-centre trials aiming to improve outcomes after surgery and anaesthesia. These include an investigation of nitrous oxide in anaesthesia (the ENIGMA Trial), and aspirin with or without tranexamic acid in coronary artery surgery (the ATACAS Trial). Professor Jamie Cooper MBBS, FRACP, MD, JFICM Professor Cooper has been Head of Trauma Intensive Care and a senior Intensivist at the Alfred Hospital since 1991. For most of this time he has been Associate Director, or more recently Deputy Director of ICU, and has acted as the Director of this large Department on many occasions. Through published research and involvement with Department of Human Service (DHS) committees concerning trauma and intensive care, he supported and highlighted the need for and the introduction of the current Victorian Trauma System. He Chairs the DHS Trauma Quality Committee which monitors and provides expert interpretation for the impact of the Trauma System on trauma outcomes in Victoria. In 2004, he was appointed Associate Director (Clinical Research) of the National Trauma Research Institute, having responsibility for coordinating all clinical research relating to Trauma at the Alfred (all specialities including Intensive Care). Professor Andrew Forbes BSc(Hons), MSc, PhD Professor Forbes provides biostatistical expertise and professional leadership to CCRE Therapeutics. He worked in the pharmaceutical industry in the US, before joining Monash University to head one of the largest biostatistical units in Victoria, in the Department of Epidemiology and Preventive Medicine. Centre of Cardiovascular Research and Education in Therapeutics | 5 Director Research assistants Professor Henry Krum Venu Ariyaratne Molly Bond Daniella Brasacchio Associate Director Harriet Carruthers Vibhasha Chand Associate Professor Christopher Reid Fiona Collier Lisa Curran Kristina Di Giambattista Research Fellows Kate Evans Amy Finlay Dr Nick Adrianopolous Alison Foster Ms Angela Brennan Molla Huq Mr Carl Costolloe Philippa Loane Dr Linda De Melis Jessica Lockery Dr Diem Dinh Fanny Sampurno Dr Andrea Driscoll Caroline Steer Dr Ruth Hannan Francesca Stewart Dr Alice Owen Trieu-Anh Thi Truong Dr Emily Parker Lavanya Vijayasingham Dr Kathlyn Ronaldson Ms Louise Shiel Mr John Varigos PhD students Dr Bing Wang Dr Katrina Watson Ms Zanfina Ademi Dr Robyn Woods Ms Jessica Chellappah Dr Maros Elsik Mr Steven Haas Software developers Dr Pupalan Iyngkaran Dr William Kemp Waranon Buranasiri Dr Dipak Kotecha Miteshkumar Chaudhari Dr Suree Lekawanjivit Andrew Hannaford Dr Michele McGrady Mahfuzal Haque Ms Lavinia Tran Nino Hay Dr Hendrik Zimmet Ramya Jaganathan Ms Ella Zomer Kunnapoj Pruksawongsin Phillip Scotney Douglas Wong General administration Igor Yeykelis Callum Brennan Laura Ellis Nursing Jo Harwood Anne Jenes Anne Bruce Sarah Mann Michelle Hooy Thomas Mann Kimberly Irwin Simon Montgomery Elizabeth Jenkins Ajitha Paldano Susan Loftis Jessica Maggs Sue Montgomery Christine Mulvany Christine Poole Louise Turnour Kathleen White 6 | Annual Report 2009 International collaborating academics Professor Barry Massie, MD, FACC Professor Salim Yusuf, MD (Bangalore), DPhil (Oxford), MRCP Professor of Medicine and Chief, Cardiology Division McMaster University San Francisco VAMC at University of California Faculty of Health Sciences San Francisco, USA Hamilton Health Sciences Corporation General Site, McMaster Clinic Professor Marcus Flather, BSc, MBBS, FRCP 237 Barton St. E. Director Hamilton, Ontario, Canada Clinical Trials and Evaluation Unit Royal Brompton Hospital Professor Stefan Blankenberg, MD London, UK Department of Medicine II Johannes Gutenberg-University Professor Frank Ruschitzka, MD Mainz, Germany Assistant Professor of Medicine Department of Cardiology Professor Richard Grimm, MD, PhD University of Zurich Director Zurich, Switzerland Berman Center for Outcomes and Clinical Research Minneapolis Medical Research Foundation Professor William T Abraham, MD, FACP, FACC, FAHA Minneapolis, MN, USA Director Division of Cardiovascular Medicine Dr Anne Murray, MD Deputy Director HFA Senior Care Clinic Davis Heart and Lung Research Institute 1425 10th Avenue South The Ohio State University, USA Minneapolis, MN 55404 Professor P Gabriel Steg Dr Paul Sobotka, MD Professor of Cardiology Department of Cardiology Université Paris-VII Hennepin County Medical Center Director of Coronary Care Unit Minneapolis, MN, USA Hôpital Bichat Paris, France Dr Deepak Bhatt, MD, FACC, FAHA Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program at Brigham and Women's Hospital and the VA Boston Healthcare System The CCRE Therapeutics group Centre of Cardiovascular Research and Education in Therapeutics | 7 Operational review CCRE Therapeutics can divide its core strengths into three main areas: clinical trials, clinical informatics and pharmacoepidemiology/translational research. Clinical Trials systolic and diastolic blood pressure following the procedure. In addition, there was evidence of reduced renal sympathetic activity. Collaborators were Baker Our clinical trials activities are conducted at the Heart Institute and St Vincent's Hospital, Melbourne. Clinical Pharmacology department at the Alfred This exciting work now proceeds to the randomised Hospital and also at the Clinical Trial Centre at clinical trial stage. Caulfield Hospital. Our clinical trials focus on mechanistic and hospital-based studies, Publications a number of which are outlined in the next section. Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Renal Denervation as a Therapeutic Renal denervation Approach for Hypertension: Novel Implications for an CCRE led the pivotal first-in-man study to evaluate this Old Concept. Hypertension, 2009 Dec;54(6):1195–1201. novel strategy in the treatment of refractory hypertension. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal denervation involves a catheter-based approach Renal sympathetic-nerve ablation for uncontrolled via femoral access to knock out the sympathetic nerves hypertension. N Engl J Med. 2009 Aug 27; that run adjacent to the renal artery. This percutaneous 361(9):932–4. (letter) approach is minimally invasive and the procedure takes about 40 minutes. First-in-man results were presented Krum H, Schlaich M, Whitbourn R, Sobotka PA, by Henry Krum at a late-breaking clinical trial session Sadowski J, Bartus K, Kapelak B,Walton A, Sievert H, of the American College of Cardiology meeting in Thambar S, Abraham WT, Esler M. Catheter-based March 2009 and simultaneously published in the Lancet. renal sympathetic denervation for resistant hypertension: The key findings were those of peri-procedural and a multicentre safety and proof-of-principle cohort study. long-term safety as well as marked reduction in both Lancet 2009; 373:1275–1281. 8 | Annual Report 2009 Aliskiren Trial to Minimize OutcomeS in particular effects on the ventricular remodelling process. Patients with HEart failuRE (ATMOSPHERE) The primary efficacy parameter of UNIVERSE was change Henry Krum has been appointed as Study Chair of the in left ventricular ejection fraction (LVEF) from baseline to ATMOSPHERE study which is being conducted at the 26 weeks post randomisation in response to placebo or Alfred Hospital and approximately 800 other sites high-dose rosuvastatin (40mg/day). throughout the world. The aim is to recruit more than 7000 patients with systolic chronic heart failure to test the Other parameters measured included echocardiogram, question of whether direct renin inhibition with the agent, high sensitive C-reactive protein and tumour necrosis aliskiren, is useful as add-on therapy to the gold standard factor alpha. However, despite previous data indicating agent (ACE-inhibitors) or may even be used as an beneficial effect of statins on CHF, and a large reduction alternative to these agents. in plasma lipids achieved, this study did not observe a rosuvastatin-induced improvement in LVEF or indeed Chronic Heart failure Assisted most other imaging or blood parameters in comparison by Telephone study (CHAT) to placebo. We therefore conducted a substudy to explore The CHAT study was a randomised control trial of mechanistic reasons why beneficial remodelling effects telephone support for chronic heart failure patients at were not observed in this study. high risk of rehospitalisation. This project was funded by the NHMRC, Heart Foundation of Australia and the Blood samples were collected from UNIVERSE patients Medical Benefits Fund. at baseline and after 26 weeks of treatment, and stored for analysis of serum coenzyme Q10, PINP and PIIINP This project implemented the first Australia-wide trial of analysis. CoQ levels were significantly reduced after telephone support for CHF patients. The aims of the study 26 weeks of rosuvastatin statin therapy, compared to were to determine whether automated telephone support placebo in CHF patients in UNIVERSE trial. Patients with will improve quality of life and reduce death and hospital CHF matched for age, gender and severity of disease who admission for rural and remote CHF patients and to test had been taking statins for 12 months or longer had CoQ this system of care as an exemplar of a novel chronic levels significantly lower than UNIVERSE patients at disease management strategy in areas remote from baseline (p=0.0001). Serum type I and III N-terminal access to multi-disciplinary care. procollagen peptide (PINP and PIIINP), measures of collagen turnover which can contribute to cardiac fibrosis The automated telephone support comprised of an were significantly increased in the rosuvastatin group interactive telecommunication software tool (Telewatch) compared to baseline in UNIVERSE patients (PINP: with follow up by trained cardiac nurses. Patients with p=0.03, PIIINP: p=0.001). These data are now a General Practice (GP) diagnosis of heart failure were published in Int. J. Cardiol. randomised to telephone support (217 patients) or usual care (188 patients) using a cluster design involving Publications 136 GPs throughout Australia. Results showed that Ashton E, Windebank E, Skiba M, Reid C, Schneider H, automated telephone support to the rural and remote Rosenfeldt F, Tonkin A, Krum H. Why did high-dose heart failure patients resulted in a 30 per cent reduction rosuvastatin not improve cardiac remodelling in chronic in risk of all-cause death and hospitalisation. The CHAT heart failure? Mechanistic insights from the UNIVERSE study explored a novel system of healthcare delivery, study. Int J Cardiol, 2009 (in press). targeting rural and remote Australians with chronic disease. Automated telephone support may become ATACAS Trial a useful tool to address access issues for management Cardiac surgery activates platelets and coagulation programs in chronic disease patients. factors, and the fibrinolytic pathway. Excessive bleeding is common. This may require surgical re-exploration and Results were presented in a late breaking trials session increases morbidity and mortality. Recent aspirin exposure at the European Heart Failure Association meeting increases surgical bleeding, and so it is routine practice in in Nice, France. most cardiac surgical centres for aspirin to be ceased one week before elective cardiac surgery. But a recent study UNIVERSE: Coenzyme Q10 found that aspirin had a lower mortality, as well as less and Collagen Substudy stroke, renal failure and bowel infarction (all P<0.01). The rosUvastatiN Impact on VEntricular Remodelling Another drug, tranexamic acid (TxA), is sometimes used to cytokineS and neurohormonEs (UNIVERSE) Study was reduce bleeding after cardiac surgery. It works by blocking established to address the deficit in prospective clinical fibrinolysis ('clot breakdown') during and after surgery. trial data regarding the use of statins in CHF and in It can block the bleeding risk associate with aspirin, Centre of Cardiovascular Research and Education in Therapeutics | 9 and does not increase thrombotic risk. Meta-analyses The study design and rationale underwent peer review of trials have shown that antifibrinolytic therapy reduces and was published in the American Heart Journal blood loss, need for blood transfusion and re-operation (March 2009). This NHMRC-funded clinical trial involves for bleeding in cardiac surgery. 7000 patients to provide a definitive evaluation of the safety of nitrous oxide anaesthesia. The primary endpoint This large, multi-centre, randomised, double-blind, is a composite of death and serious cardiovascular events factorial trial in 4600 cardiac surgical patients is looking within 30 days of surgery. To date we have enrolled over for a reduction in major complications or death with aspirin 2600 patients in 30 centres throughout the world and/or TxA. We have established a trial network of at least (see: www.enigma2.org.au). 15 hospitals, with support from cardiac surgeons and anaesthetists from Australia, Canada and UK. Publications Patient enrolment has commenced, with more Myles PS, Leslie K, Peyton P, Paech M, Forbes A, than 780 patients to date (see: www.atacas.org.au). Chan MT, Sessler D, Devereaux PJ, Silbert BS, Jamrozik K, Beattie S, Badner N, Tomlinson J, Wallace S. The study design and rationale underwent peer review and Nitrous oxide and perioperative cardiac morbidity was published in the American Heart Journal (Feb 2008). (ENIGMA-II) Trial: rationale and design. ANZCA Trials We have also done a systematic review and meta-analysis Group. Am Heart J. 2009 Mar;157(3):488–494.e1. investigating the effects of antifibrinolytic therapy in cardiac surgical patients treated with aspirin Prevalence of ICD and/or CRT device therapy (Br J Anaesth, February 2009). in patients admitted to hospital with decompensated heart failure Publications Heart failure is associated with high hospitalisation and McIlroy DR, Myles PS, Phillips LE, Smith JA. mortality rates. Over the years there have been many Antifibrinolytics in cardiac surgical patients receiving randomised controlled trials that have shown the benefits aspirin: a systematic review and meta-analysis. of heart failure treatment strategies and have focussed Br J Anaesth. 2009 Feb;102(2):168–78. on the uptake and optimisation of pharmacotherapy. However there have been few studies that have ENIGMA-II Trial investigated the uptake of these devices. More than 2.5 million anaesthetics are given each year in Australia (1:10 Australians), with the majority receiving The aim of this study was to determine the proportion of nitrous oxide. Approximately 25 per cent of patients patients with heart failure that met the criteria for cardiac undergoing major surgery have known coronary artery resynchronisation therapy (CRT) device implantation disease (CAD) or risk factors for CAD. In 1990, approximately according to National Heart Foundation (NHF) guidelines, one million of the 25 million Americans who underwent and to evaluate the prevalence of device therapy use in non-cardiac surgery suffered a perioperative cardiac event, these patients. This study was funded by Medtronic. resulting in $20 billion in costs. This study was a retrospective review of 1274 medical Nitrous oxide interferes with vitamin B12 and folate records of patients discharged from hospital during 2007 metabolism. This impairs production of methionine with a primary discharge diagnosis of heart failure. (from homocysteine), used to form tetrahydrofolate The study involved six hospitals throughout Australia and thymidine during DNA synthesis. It has been which included four metropolitan, one rural and one repeatedly demonstrated that nitrous oxide anaesthesia private hospital. Of the medical records that were increases postoperative homocysteine levels. Chronic searched less than half (n=570) had a primary discharge hyperhomocysteinaemia is associated with cardiovascular diagnosis of heart failure. We found that 23 per cent disease, and acute hyperhomocysteinaemia is known (128/570) of patients had a device implanted. Only 1 per cent to cause endothelial dysfunction. One small trial has (4/29) of patients with no device met the NHF guideline demonstrated an increased incidence of postoperative criteria for CRT implantation. The mortality rate in patients myocardial ischaemia in patients receiving nitrous oxide with a CRT device was lower than patients with no device. anaesthesia. Reducing postoperative myocardial infarction and death are important aims for those with CAD In conclusion, outcomes in this population remain poor undergoing major surgery. with 60 per cent being readmitted and nearly a quarter of patients not surviving after 18 months post-discharge. Due to missing information in the medical record, there was insufficient data to conclude that guideline recommendations were adhered to. 10 | Annual Report 2009 INTERSTROKE Now that the Pilot Phase has been completed, there will Stroke is a major global health problem, yet few studies be a transition into the main study with up to 10 centres have examined the risk factors for stroke and its subtypes participating in Australia. INTERSTROKE will provide in different ethnic populations representing different essential information on conventional and emerging risk regions of the world. Compared to coronary heart disease, factors to help guide population health initiatives aimed traditional risk factors (eg hypertension, hypercholesterolemia) at preventing stroke in low and high income countries. appear to exert different magnitudes of risk for stroke and To be successful, INTERSTROKE will involve national within stroke subtypes. Any effective global strategy to and international collaboration. John Varigos, from CCRE reduce the risk of stroke mandates a systematic and Therapeutics, is the national coordinator and, together standardised study of the contribution of traditional and with Graeme Hankey from the Royal Perth Hospital, will emerging risk factors within defined ethnic groups and coordinate the Australian arm of the study. INTERSTROKE geographical locations for each of the stroke subtypes. will have enormous implications for our understanding of In order to provide reliable answers, these studies need the causes of stroke within Australia and around the world. to be very large, so as to include large numbers of cases of strokes of each subtype. Clinical Informatics and INTERSTROKE has been designed to achieve this by utilising a global research network of investigators centrally Data Management coordinated through the Public Health Research Institute in Hamilton, Ontario, Canada. Many members of this The Clinical Informatics and Data Management Unit research network completed a similar study in 2005 (CIDMU) provides key platform technologies for the for myocardial infarction (MI) called INTERHEART. conduct of epidemiological, clinical trial and health INTERHEART included 30,000 participants from services research. The platform technologies include; 52 countries and showed that nine modifiable risk factors accounted for over 90 per cent of the risk. • multi-centre clinical trials and registry data management; A similar study is necessary in stroke because: • web-based, e-CRF, fax and paper-based data capture facilities; 1. the causes of stroke are far more diverse than MI; • web-based or telephone-based 2. many of the common risk factors for stroke and MI randomisation services; (eg lipids) appear to exert very different magnitudes • trial and site management capabilities; of risk for stroke compared with MI; and • trial and site monitoring capabilities; and 3. there are limited epidemiological studies in stroke. • statistical data analysis and study design capabilities. This study compares risk factors in people with stroke The platform technologies have been developed in (cases) to people without stroke (controls) in a large, accordance with international regulatory and national international case control study that includes approximately privacy and ethical guidelines. The following projects 24,000 cases and controls from about 37 countries. are being managed and conducted by CIDMU. Countries will recruit the following ethnic groups: Caucasians, Chinese, South Asians, Africans and Melbourne Interventional Group (MIG) native South Americans. The Melbourne Interventional Group (MIG) remains the only Percutaneous Coronary Intervention (PCI) Registry The pilot phase of INTERSTROKE, conducted to collecting standardised procedural and follow up data demonstrate the feasibility of such a large study in on consecutive patients across multiple sites in Victoria. stroke, has recently been completed with more than The MIG registry helped to inform the ACPR pilot project 2800 participants recruited from 15 countries (Australia, that was undertaken in 2009, however as yet the ACPR Argentina, Brazil, Canada, Chile, China, Colombia, project is not funded in an ongoing fashion. The MIG study Denmark, Germany, Ghana, India, Mozambique, Poland, informed the dataset and many of the sites also South Africa and Uganda). Results from the Pilot Study participated as pilot ACPR sites. will be presented at the European Stroke Conference in Barcelona in May 2010. Current enrolment sits at 12,914 PCI procedures. Thirty day and twelve month follow up are undertaken routinely on all subjects. Longer term outcome data is now available as linkage with National Death Index has been undertaken in 2009. Centre of Cardiovascular Research and Education in Therapeutics | 11 This data will be reported upon in 2010 with abstract and ASCTS manuscripts planned that will extensively utilise this data. The Australian Society of Cardiothoracic Surgeons In 2009, MIG continued to present widely at national and (ASCTS) National Cardiac Database Program records international cardiology meetings. In addition to the details of all adult cardiac surgical procedures performed 13 manuscripts already published, several more are in participating units across Australia. The program either in review or well underway. publishes annual reports describing the activities and outcomes of participating units in a comparative, MIG continues to collaborate widely, especially with de-identified format. the cardiac surgeons and the ASCTS registry. Currently, 18 of 25 Public Hospital Units are members of Publications the program and four private hospitals are also participating Reid CM, Ajani AE, Eccleston D. Why we need a national in the registry. Since the instigation of the project in 2001, registry in interventional cardiology. Med J Aust. 2009 Feb the ASCTS web database portal contains over 35,000 2;190(3):162–3. records. To date, 13 manuscripts arising from the project have been published including papers on an Australian Yap CH, Yan BP, Akowuah E, Dinh DT, Smith JA, Risk Prediction Model for Coronary Surgery, on the short Shardey GC, Tatoulis J, Skillington PD, Newcomb A, and longer term outcomes and in collaboration with Mohajeri M, Pick A, Seevanayagam S, Reid CM. other interventions. Does prior percutaneous coronary intervention adversely affect early and mid-term survival after coronary artery Publications surgery? JACC Cardiovasc Interv, 2009; 8:758–64. Brasacchio D, Dinh DT, Billah B, Shardey G, Reid CM on behalf of the Australian Society of Cardiac and Thoracic Gurvitch R, Lefkovits J, Warren RJ, Duffy SJ, Clark DJ, Surgeons Database Project Steering Committee. Cardiac Eccleston D, Yan BP, Reid C, Brennan A, Andrianopoulos N, Surgery in Victorian Public Hospitals 2007-2008: Hospital Ajani AE. Clinical outcomes of drug eluting stent use in Report. Quality and Safety Branch, Department of Human high risk patients with ST elevation Myocardial Infarction. Services, Melbourne Victoria 2009. Int J Cardiol, 2009 (Epub ahead of print) Brasacchio D, Dinh DT, Billah B, Shardey G, Reid CM Lim H, Farouque O, Andrianopoulos N, Yan B, Lim C, on behalf of the Australian Society of Cardiac and Thoracic Brennan A, Reid C, Freeman M, Charter K, Black A New Surgeons Database Project Steering Committee. Cardiac G, Ajani A, Duffy S, Clark D. Survival of elderly patients Surgery in Victorian Public Hospitals 2007–2008: Report undergoing percutaneous coronary intervention for acute to the Public. Quality and Safety Branch, Department of myocardial infarction complicated by cardiogenic shock. Human Services, Melbourne, Victoria 2009. Journal of American College of Cardiology Interventions, 2009;2:146–152. Brasacchio D, Dinh DT, Billah B, Shardey G, Reid CM on behalf of the Australian Society of Cardiac and Thoracic Freeman M, Clark D, Andrianopoulos N, Duffy S, Lim H, Surgeons Database Project Steering Committee. Cardiac Brennan A, Charter K, Shaw J, Horrigan M, Ajani A, Surgery in Australian Hospitals 2007–2008: National Sebastain M, Reid C, Farouque O. Procedural and clinical Report. Melbourne, Victoria 2009. outcomes of percutaneous coronary intervention for ostial lesions in proximal coronary arteries. Catheterization and Dinh DT, Di Giambattista K, Billah B, Shardey G, Cardiovascular Intervention, 2009;73:763–768. Reid CM on behalf of the Australian Society of Cardiac and Thoracic Surgeons Database Project Steering Butler MJ, Eccleston D, Ajani A, Lefkovits J, Clark DJ, Committee. Cardiac Surgery in NSW Public Hospitals Andrianopoulos N, Brennan A, Reid CM, Farrington C, 2007– 2008: NSW Service Report. Greater Metropolitan Walton AS, Dart AM, Duffy SJ, on behalf of the Melbourne Clinical Taskforce, NSW Health, Melbourne, Victoria 2009. Interventional Group (MIG). The effect of intended duration of clopidogrel use on early and late mortality and major Yap C-H, Andrianopoulos N, Dinh DT, Billah B, Rosalion AM, adverse cardiac events in patients with drug-eluting stents. Reid CM. Short and mid-term outcomes of coronary American Heart Journal, 2009;157(5):899–907. artery bypass surgery performed by surgeons in training. The Journal of Thoracic and Cardiovascular Surgery. 2009;137:1088–1092. 12 | Annual Report 2009 Yan BP, Clark DJ, Buxton B, Ajani AE, Smith JA, Duffy SJ, including Australia. The further aim is to compare Shardey GC, Skillington PD, Farouque O, Yii M, Yap C-H, outcomes within different subject profiles and define Andrianopoulos N, Brennan A, Dinh D, Reid CM, predictors of risk for subsequent events. In Australia, on behalf of the Australasian Society of Cardiac and 2873 participants were recruited with excellent follow up Thoracic Surgeons (ASCTS) and the Melbourne of 99 per cent at Year 1 and 98 per cent at Year 2. Recent Interventional Group (MIG). Clinical characteristics and publications have focussed on one year clinical outcomes early mortality of patients undergoing coronary artery for Australian patients identifying the increased adverse bypass grafting compared to percutaneous coronary outcomes associated with those not following evidence- intervention: Insights from the Australasian Society of based guidelines in relation to the use of statins and Cardiac and Thoracic Surgeons (ASCTS) and the aspirin. Further work has been undertaken with a health Melbourne Interventional Group (MIG) registries. economic analysis of greater utilisation of clinical outcomes Heart Lung and Circulation. 2009;18(3):184–90. and looking at the impact of obesity on costs in the Australian community. Australian Rheumatology Association Database (ARAD) Publications The Australian Rheumatology Association Database Ademi Z, Liew D, Chew D, Conner G, Shiel L, Nelson M, (ARAD) is a national Australian database which collects Soman A, Steg G, Bhatt DL, Reid C; REACH registry important health information from individuals with investigators. Drug treatment and cost of cardiovascular inflammatory arthritis. The aim of the registry is to determine disease in Australia. Cardiovasc Ther. 2009 Fall;27(3): the short and long term effectiveness and safety of new 164–72. biological disease-modifying anti-rheumatic drugs used to treat inflammatory arthritis conditions. ANZIC-RC Collaborations The Clinical Informatics and Data Management Unit CCRE Therapeutics provides data management for provide data management services for a number of the ARAD registry. Information is collected via six monthly investigator-initiated clinical studies being undertaken completed questionnaires, which include questions about by the Australia and New Zealand Intensive Care Research medical history, medication history, responses to medication, Centre (ANZIC-RC). Actively recruiting studies during 2009 physical functioning and quality of life. CCRE Therapeutics included the STATInS study; a phase II randomised has recently developed a web-based system which allows controlled trial of atorvastatin therapy in intensive care individuals to complete their 6 monthly questionnaire patients with severe sepsis, and the INFINITE study; on-line, which has been very well received by participants. a 'real time' registry of all patients admitted with Influenza A to Australian and New Zealand ICUs between 1 June Patients and rheumatologists across Australia contribute 2009 to the end of winter 2010. New endorsed trials that to ARAD, with over 3000 participants actively completing are in development and due to commence in early 2010, questionnaires and over 200 rheumatologists referring include POLAR; a study of the early use of induced patients to ARAD. hypothermia in closed head injuries to improve outcomes, and EPO-TBI; determining the efficacy of erythropoietin in Publications improving neurological function after traumatic brain injury. Briggs AM, March L, Lassere M, Reid C, Henderson L, Murphy B, van den Haak R, Rischin A, Staples M, Sentinel Surveillance Study Buchbinder R. Baseline Comorbidities in a Population- The Sentinel Study is a linked sentinel survey of chlamydia, Based Cohort of Rheumatoid Arthritis Patients Receiving HIV, syphilis and hepatitis C in Victoria developed by the Biological Therapy: Data from the Australian Rheumatology Burnet Institute and undertaken in collaboration with the Association Database. Int J Rheumatol. 2009; Department of Human Services Victoria, the Victorian Epub ahead of print. Infectious Disease Reference Laboratory and the Melbourne Sexual Health Centre. REACH The REACH registry is an international prospective CCRE Therapeutics is undertaking data management for observational registry of subjects at risk of this project that will be used to monitor HIV, hepatitis C atherothrombotic events. In Australia, the CCRE and sexually transmitted infection incidence, prevalence, Therapeutics has been the national coordinating centre risk behaviour and testing patterns in order to inform and the study has been conducted at 274 sites in Victoria, and evaluate relevant public health strategies. In 2009, NSW, QLD, SA and WA. The primary aim of this study was there is ongoing data linkage between Melbourne Sexual to evaluate the long-term risk of atherothrombotic events Health Centre for quarterly data extraction in addition to globally as well as in different population sub-groups continuing data collection from 16 sites across Victoria. Centre of Cardiovascular Research and Education in Therapeutics | 13 Cabrini Colorectal Database Project Australian Cardiac Procedures Registry (ACPR) In collaboration with Associate Professor Paul McMurrick, The ACPR pilot began in 2008 with the purpose of this is a project to develop a web-based data collection monitoring the safety and quality of cardiac procedures. process for colorectal surgical cancer procedures at Funding for the pilot was provided by the Australian Cabrini Hospital. The aim of this project will be to enable Commission on Safety and Quality in Health Care a systematic collection of surgical and outcomes data (ACSQHC). The aim of the pilot was to test and validate which will be able to be linked with other clinical datasets the draft 'Operating Principles and Technical Standards to provide a facility for Cabrini to undertake clinical for Australian Clinical Quality Registries'. research activities in this area of surgery. It is anticipated that the establishment of the ACPR TRIAGE registry will lead to an improvement in clinical services The primary aim of the study is to improve the accuracy provided and provide the mechanism for the benchmarking and speed of diagnosis of congestive heart failure (CHF) of performance in the delivery of quality of care. and acute coronary syndromes (ACS) in the Emergency Department. The study will compare the Biosite Triage Minimum core datasets were developed across three SOB panel (using Troponin I, Myoglobin, CKMB, D-dimer, areas – Percutaneous Coronary Interventions (PCI), BNP) with clinical assessment (history and physical Cardiac Surgery and Implantable Cardioverter Defibrillator examination) for the presence or absence of CHF, (ICD) devices and Cardiac Resynchronisation Therapy ACS and pulmonary emboli in patients presenting (CRT) devices. The Surgery and PCI datasets were with breathlessness with or without chest pain. modelled on the Australian Society of Cardiothoracic The primary endpoint will be the presence of CHF Surgeons Victorian database project and the Melbourne and/or ACS as defined by standard criteria (chest Interventional Group PCI registry, with the device X-ray, ECG, laboratory-based CK plus CK-MB or dataset a new development. troponin, echocardiogram). Eleven sites across four states participated in the ACPR A total of 703 patients were enrolled through pilot, with data collection commencing in July 2009. eight metropolitan and regional hospitals nation-wide. Participant follow ups were conducted at 24 hour, The final report was delivered to the ACSQHC in 30 day and 6-to-12 month time periods. The final November 2009. The funding of the ACPR pilot project follow ups were completed in 2009 and this data by the ACSQHC has led to a number of key outcomes is currently being finalised. Abstracts utilising 30 day in the quest to provide information on the quality of care outcome data have been presented nationally and in the provision of high-cost, high-risk cardiac services in internationally with longer term outcome data to Australia. Firstly, it has provided the structure for clinical be presented in 2010. leadership and stakeholders to meaningfully engage in the process and secondly, it has provided the process through ASia Pacific Evaluation of which standardised data can be collected through a Chest pain Trial (ASPECT) secure web-based system developed and operating The purpose of this study is to validate a clinical pathway according to regulatory standards. ('accelerated chest pain algorithm') of using ECG and/or Risk Stratification Tools in conjunction with serial As part of the pilot a literature review on funding models biomarkers (with blood levels of Troponin I, CKMB for clinical quality registries was conducted. This review 'Delta', and Myoglobin 'Delta' measurements) in formed the basis of potential financial strategies for patients presenting with ACS. sustainable funding which are currently being investigated further. It is hoped that a sustainable funding model will Recruitment began at the end of 2008 and is almost inform the structure of future clinical quality registries. complete. Over 2900 subjects have been recruited out of an expected 3400. Funding Australian Commission on Safety and Quality in Healthcare Preliminary data has been presented at national and 2008 to 2009 – $931,686 international biomarker meetings. Site auditing commenced in late 2009 and will continue into 2010. All sites will be visited by CCRE staff who have been trained to undertake the audit activity. 14 | Annual Report 2009 Pharmacoepidemiology/ A strength of the clozapine and myocarditis study is that environmental and host risk factors which may modify Translational Research the genetic risk are being documented along with the characteristics of the myocarditis such as measures Clozapine and Myocarditis Study of severity and involvement of organs besides the heart. Clozapine is the most effective drug available for schizophrenia, and also the safest when mortality is The Cardiovascular Disease Epidemiological used as the measure. However, in about two per cent Modelling Project of patients, it causes a life-threatening adverse effect, This project is supported by an ARC-Linkage grant with called myocarditis, in the first few weeks of therapy. industry partner sanofi-aventis, and is being conducted in Myocarditis is inflammation of the heart muscle and collaboration with colleagues at Baker IDI and St Vincent's it occurs as a hypersensitivity reaction with clozapine. Hospital Melbourne. The Cardiovascular Disease Epidemiological Modelling Project uses innovative The purpose of this study is to identify risk factors for statistical modelling techniques to model the burden myocarditis, including a genetic marker. If the risk factors of cardiovascular disease, obesity and diabetes in are known, it will be possible to prescribe the drug more Australia, and also aims to examine the effectiveness freely to those not at risk. and cost-effectiveness of potential interventions to prevent these chronic diseases and their sequelae. The study has a case-control design with four controls The ARC-Linkage granting scheme has a strong focus for each case. Controls are matched to cases by the unit upon training of future research leaders and this grant at which they started clozapine and by approximate start includes scholarship funding for a PhD candidate, date to control for variations in prescribing practice. Cases Ella Zomer. During 2009, the calibre of Ella's research and controls are documented from the patient's medical was recognised with acceptance of two oral presentations records. Most patients start clozapine as inpatients which at the European Society of Cardiology Congress. means that comprehensive and detailed information is available on daily doses of clozapine, concomitant medication, Major activities of this project during 2009 included daily vital signs, pathology results, smoking status and validation and calibration of cardiovascular risk prediction concurrent disease. The cases and controls are required equations in a number of Australian population settings to meet strict criteria to ensure the integrity of the study. and development of a detailed model of examining risk of cardiovascular disease in an Australian population The aim is to include 100 cases and 400 controls. group with metabolic syndrome. At the end of 2009, 91 cases and 158 controls were fully documented and samples for DNA extraction had Funding been received from 34 individuals. ARC Linkage Grant 2007 to 2009 – $212,000 A preliminary analysis of data up to the end of 2008 (66 cases, 78 controls) suggests that concurrent sodium INTEGRATE valproate and high rates of clozapine dose titration may The INTEGRATE study is a clinical audit program examining predispose to myocarditis. Use of zuclopenthixol may the evidence-based management of hypertension in a be protective. These effects account for only about community setting, which is being conducted by CCRE 10 per cent of the risk of myocarditis. The vast majority in association with Bristol-Myers Squibb. The INTEGRATE of cases were initiated on clozapine according to the study has involved participation by both General Practitioners dosing protocol and were not taking sodium valproate. (GP) and their patients Australia-wide, and aims to While there may be other environmental and host examine the factors associated with achievement of factors influencing risk, this result suggests that genetic blood pressure targets in patients with hypertension. predisposition may account for as much as 50 per cent The INTEGRATE study included a GP education program of the risk of clozapine-induced myocarditis. designed to address issues relating to achievement of blood pressure targets, and following the roll-out of the Genetic factors for other drug hypersensitivity reactions education program in early 2009, the second and final have been identified. In three examples, 100 per cent phase of data collection was undertaken in mid-late of those developing the reaction had the genetic marker 2009 utilising web-enabled data capture technology. which was located on the HLA-B region of chromosome 6. In the fourth example, flucloxacillin-induced liver injury, the Funding predisposing genetic factor was also in the HLA-B region, BMS and 84 per cent of cases were positive for the genotype. 2007 to 2009 – $389,499 Centre of Cardiovascular Research and Education in Therapeutics | 15 Caulfield Clinical Trial Centre The Caulfield Clinical Countering the potential beneficial effects of aspirin therapy are the risks associated with bleeding which Trial Centre acts as our are likely to increase as people age. With the composite endpoint of extension of disability-free life years, ASPREE community-based research will determine the balance of benefit versus risk of aspirin. If it is proved effective, the low cost of aspirin therapy clinic. Most of the studies would make it an affordable preventive agent for elderly involve working with populations in all countries. general practitioners During 2009, the National Institute on Aging which is one of the National Institutes of Health in the USA approved across Melbourne and a major funding application for ASPREE. This was a joint submission from Australian ASPREE researchers, headed Australia as well as with by Professor John McNeil, and colleagues from the USA, healthy volunteer subjects headed by Professor Richard Grimm of the Berman Center of Outcomes Research in Minneapolis. There will be who donate their valuable 25 hubs in the USA recruiting participants for ASPREE with a focus on minorities groups (African-Americans time to assisting with and Hispanics). our research. The NIH awarded USD$50 million over seven years and this funding will begin in 2010. During the scientific reviews by the NIH, the ASPREE Protocol and numerous other Project highlights for documents were revised and changed to incorporate 2009 are as follows: the US collaborators and their site-specific requirements. At the end of 2009, the NIH-constituted Data and Safety Monitoring Board reviewed all the ASPREE documents ASPirin in Reducing Events in the Elderly and approved the study to begin new recruiting early (ASPREE) in 2010. One hundred and seventy existing ASPREE ASPREE is a large-scale, double-blind randomised, participants will constitute a Vanguard group for the placebo-controlled trial of low dose aspirin for primary study in Australia, most of whom will have their first prevention of disease in healthy older people. The major annual visit in 2010. research question is 'does low-dose aspirin prolong healthy, disability-free life in those aged 70 years and Publications over?' ASPREE will be conducted in general practices Woods RL, Tonkin AM, Nelson MR, Reid CM. across Victoria, Tasmania and the ACT and will therefore Should aspirin be used for the primary prevention of represent the ageing population in urban and rural Australia. cardiovascular disease in people with diabetes [editorial]? Medical Journal of Australia, 2009;190:614–615. The ASPREE clinical trial will involve 19,500 participants who will be randomised to daily 100mg of enteric-coated Woods RL, Nelson MR, Tonkin AM, Reid CM. In reply: aspirin or placebo. Follow up is planned for an average Should aspirin be used for the primary prevention of of five years. The trial methods are based on the highly cardiovascular disease in people with diabetes [editorial]? successful Second Australian National Blood Pressure Medical Journal of Australia, 2009;191(6):356–357. study (ANBP2) that was based in general practices in Australia with the practitioner as co-investigator. Low-dose Funding aspirin may be one of the most chemo-effective agents in NIH (USA) Grant older people to prevent or delay the onset of cardiovascular 2009 to 2015 – US$50,445,006 disease, stroke, dementia and certain cancers, particularly bowel cancer. These diseases are the most common NHMRC Project Grant causes of physical and mental disability and hospitalisations 2005 to 2009 – $3,503,500 amongst the elderly Australian population. 16 | Annual Report 2009 ASPREE Healthy Ageing Biobank The ASPREE Healthy Ageing Biobank Cluster The ASPREE Healthy Ageing Biobank is a unique Management Committee held its first meeting in opportunity to evaluate new preventive biomarkers of November 2009 with all cluster parties in attendance. disease in the elderly. Healthy participants aged 70 and Parties include CSIRO, Monash University, University over will be followed annually to ascertain cardiovascular of Melbourne, University of Tasmania (Menzies Research events, cognitive decline, cancer incidence, physical Institute) and Australian National University. disability and other chronic diseases. The ASPREE Biobank study aims to collect blood and urine samples at baseline on all participants to establish a repository of blood and urine from healthy older people who have not developed major diseases. Partners in this venture are the CSIRO, the University of Melbourne, the University of Tasmania and the Australian National University. The ASPREE Biobank will be particularly well suited for the evaluation of new predictive biomarkers for several reasons: • the large number of older subjects will produce statistically significant results within a much shorter time-frame than cohorts with younger participants; • repeated cognitive function assessments will provide a unique opportunity to identify biomarkers for Alzheimer's disease and other causes of dementia; • the annual or biennial clinical review will provide an excellent opportunity to accurately identify Funding other clinical endpoints eg, colon cancer; and NHMRC Equipment 2009 – $90,000 • the prospective design will allow biological samples to be collected, processed and stored in the most Aspirin for the prevention of cognitive decline favourable fashion for analysis of new biomarkers in the Elderly: a Neuro-Vascular Imaging Study and potential diagnostics for chronic diseases, (ENVISion) particularly those prevalent in the elderly. ENVISion is a sub-study of the large-scale clinical trial, ASPREE, and involves collaboration between researchers 2009 Progress from the Department of Epidemiology and Preventive In addition to the completion of renovations at The Clinical Medicine, and Chief Investigators Professor Elsdon Storey Trial Centre (CTC) at Caulfield Hospital, two additional (Monash University), Associate Professor Marc Budge regional Biobank processing centres were established in (Australian National University (ANU), and Professor 2009. Collaborations with ASPREE researchers at ANU Tien Wong (Centre for Eye Research Australia (CERA), and the University of Melbourne and pathology providers University of Melbourne). Awarded an NHMRC Project at Canberra Hospital and Goulburn Valley Health facilitated Grant in 2007, the ENVISion study is examining whether set up of the ASPREE Healthy Ageing Biobank in Canberra regular low-dose aspirin reduces the rate of increase of (ACT) and Shepparton (Regional Victoria). Plans are also brain Magnetic Resonance Imaging (MRI)-based white underway to set up an additional processing centre at matter hyperintensity and silent brain infarction volumes Hobart in collaboration with Professor Mark Nelson at in otherwise healthy elderly Australians. Brain MRI changes the Menzies Research Institute. correlate with white matter ischaemia, and may provide an efficient surrogate for cognitive decline. However, MRI is The Biobank protocol underwent a minor amendment relatively costly and is not universally accessible, making it in 2009 to include the collection of a urine sample from impractical for population screening. The retinal vasculature participants. The collection of urine will allow for testing shares many features with that of the brain. If changes in of biomarkers in the future that cannot be tested for in the two were found to be highly correlated, retinal digital the blood components that are being collected and photography would provide the opportunity to combine a stored. Three participants were enrolled in the study relatively inexpensive, widely available tool with automated in late 2009. analysis to select those likely to benefit most from a Centre of Cardiovascular Research and Education in Therapeutics | 17 preventative intervention (eg regular low-dose aspirin was employed to identify individuals likely to develop treatment). The sub-study will also examine whether chronic heart failure (CHF) focusing on risk factors structural changes in brain and/or retinal vasculature such as coronary artery disease, valvular heart disease, correlate with a decline in cognitive function. ENVISion hypertension and diabetes. is being conducted in 600 people who have consented to participate in ASPREE (300 participants in Canberra CHF is a major burden on the community due to the poor and 300 in Melbourne). quality of life and premature death of affected individuals, as well as the costs of care. CHF prevalence is increasing During 2009, recruitment of ENVISion study participants due to the ageing of the population and the improved was halted pending the outcome of a grant re-submission survival from myocardial infarction (MI) and CHF. to the NIH seeking international funding for the parent The increasing prevalence of obesity and diabetes, study, ASPREE. With the recent announcement in October coupled with uncontrolled hypertension, is also likely of significant funds (USD $50 million), and the subsequent to accelerate CHF incidence. Effective therapies for the review and approval of the ASPREE study protocol by the treatment and prevention of CHF are readily available, NIH's appointed Data Safety and Monitoring Board, and there is great potential to cost-effectively improve the stage is now set in 2010 to resume active recruitment the application of these therapies through improved of ASPREE and ENVISion participants. Despite this delay identification of two key patient groups: those with to recruitment, there has been ongoing ENVISion activity unrecognised CHF, and those at greatly increased risk in the past year: members of the ENVISion Steering of CHF due to LVD. Thus, early detection of disease Committee attended monthly teleconferences (as well could lead to more effective use of beneficial therapies, as one face-to-face meeting) to discuss and resolve reducing the total burden of symptomatic heart failure operational issues; the ENVISion Collaborative Agreement and thus the need for high cost devices. between ANU, Monash University and CERA was executed; standard operating procedures were amended to include Forty-four thousand clients of the health insurance company, the reporting and follow up of any MRI or retinal vascular HBA, and members of the general public, aged 60 and imaging abnormalities; a training workshop was conducted over, were invited to participate in the study if they had during the two-day official launch of the ASPREE and not been previously diagnosed with heart failure but had ENVISion studies in February to ensure standardisation one or more risk factors for heart failure (such as a heart in the administration of neuropsychological assessments; attack, stroke, diagnosed hypertension or diabetes). and a GP dinner was held in Canberra in November to Approximately 11,000 HBA clients responded to the promote the studies and to facilitate GP recruitment. study invitation and just over 4000 study participants were In Melbourne, ENVISion participants currently visit the successfully recruited for the study from mid-2007 to 2009, Clinical Trial Centre, Caulfield for retinal photography attending study visits in Melbourne and Shepparton and and cognitive function assessments (in addition to NT-proBNP, routine bloods and information relating to ASPREE-related measurements), with brain MRI medical history, concomitant medications, physical and conducted at the Alfred Hospital. demographic information was collected. Those with NT-proBNP in the upper quintile (approximately Funding 700 participants) were further assessed for cardiac NHMRC Project Grant function via ECG and echocardiographic examination. 2008 to 2012 – $1,271,102 The cross-sectional study was supported by BUPA Australia Group (comprising BUPA Australia Health Pty Ltd SCREEN-HF and MBF Australia Pty Ltd). This cross-sectional study will (SCReening Evaluation of the Evolution undergo final analysis in 2010. Highlights of 2009 were of New Heart Failure) presentations at 57th Annual Scientific Meeting CSANZ This prospective, cross-sectional study aims to assess and European Society of Cardiology meetings. the utility and cost-effectiveness of NT-B-type natriuretic peptide (NTpro-BNP) in the determination of left ventricular SCREEN-HFL – a longitudinal study dysfunction in patients at high-risk for this condition but The study investigators, in collaboration with St Vincent's without known cardiac dysfunction, symptoms of heart Research Institute and St Vincent's Health, were successful failure or previous diagnosis of either condition. in gaining funding from the NH&MRC to allow a five-year NT-proBNP is a hormone released from the heart in longitudinal follow-up of the entire SCREEN-HF study response to pressure or stretch and as such, it is a useful cohort and early in 2009 ethics approval was gained marker of left ventricular dysfunction (LVD), even in the to commence the longitudinal study. The objective of absence of accompanying symptoms. A simple strategy this longitudinal study is to establish the utility of plasma 18 | Annual Report 2009 NT-proBNP level, and change in NT-proBNP level, in the ANBP2 was conducted in general practices throughout identification of individuals with CV risk factors destined Australia, with recruitment taking place between April to develop CHF and/or echocardiographic evidence 1995 and June 1998. In total, 6083 subjects (mean age of LVD during five years of observation. of 71.9 years at baseline) were enrolled in the study from 1594 general practices and followed for a median of All of the 4000 participants from the SCREEN-HF 4.1 years. The results of ANBP2 showed that initial cross-sectional study are to be approached to take part treatment based on ACE inhibitor therapy provided in the longitudinal and by the end of 2009, 1117 had an 11 per cent reduction on all cardiovascular events consented to participate in the longitudinal study. They or death from any cause in comparison to basing have attended either CTC or St Vincent's Hospital for the treatment on a diuretic. study assessments including ECG and echocardiographic examination. It is anticipated that there will be approximately The ANBP2 Follow-up Study is examining the risk 3500 participants in the longitudinal study and that study of heart failure in older Australians with hypertension visits in Shepparton will occur during 2010. Blood samples (high blood pressure). This study is designed to undertake are collected and stored for later measurement of novel a prospective cohort 10 year follow up study of all subjects cardiovascular biomarkers. in ANBP2 (who consented to follow up) with the primary aim being to determine the rate of all-cause and The main features of the five-year SCREEN-HF cardiovascular mortality and morbidity in this elderly longitudinal study are: hypertensive population. In addition, the study will determine the progression from hypertension to CHF • All SCREEN-HF study participants will be invited to of the population and the effect of initiating treatment participate in the five year longitudinal study, which will based on ACE inhibitor versus that based on diuretic on collect five years of longitudinal data, with a second subsequent CHF, together with healthcare utilisation and echocardiographic and clinical examination performed costs associated with this management of these elderly three years after the first examination. The second Australian hypertensives. This will permit modelling of echocardiographic examination will be performed healthcare resource requirements in an ageing cohort approximately three years after the first because it will and quantification of disease burden in an elderly take three years to perform 3500 echocardiographic Australian cohort. examinations, and we aim to complete the second examination for all 3500 subjects within the five-year The ANBP2 participants, who gave consent at the duration of this project. end of the ANBP2 study for further contact, were sent questionnaires in the mail to complete and were also • The SCREEN-HF study participants will be invited to asked to give a questionnaire to their general practitioner undergo echocardiographic, ECG, clinical examination to complete and return. One thousand, seven-hundred and quality of life assessments and be reviewed in and twenty-six participants and 1222 GPs returned regards to cardiovascular events, symptoms of questionnaires which will allow determination of the heart failure and current medications. long-term cardiovascular consequences of antihypertensive treatment, comparing outcomes in those randomised to Funding treatment with ACE-inhibitors with those treated with NHF Grant-in-Aid diuretic agents. Through data linkage with the National 2008 to 2009 – $126,671 Death Index and re-contacting of participants 10 years after completion of the original study, it was ascertained The Second Australian National Blood Pressure that approximately 32 per cent of the original study (ANBP2) Follow up Study participant cohort have died. In 2010, Melbourne The Second Australian National Blood Pressure Study metropolitan participants will be invited to attend the (ANBP2) was a randomised controlled trial designed and CTC for further follow-up including an ECG and conducted by the High Blood Pressure Research Council echocardiographic examination. of Australia. It was designed to determine if there was any difference in outcome (defined by total cardiovascular Funding events and mortality) between elderly hypertensive NHMRC General Practice Clinical Research Program patients, aged 65 to 84 years, who were randomised to 2008 to 2009 – $192,000 active treatment with an angiotensin-converting enzyme (ACE)-inhibitor based-regimen or treatment with a diuretic-based antihypertensive regimen. Centre of Cardiovascular Research and Education in Therapeutics | 19 ARMCAD (Alternative Risk Markers in Coronary CLEAR (Cardiovascular Longitudinal Evaluation Artery Disease) and Assessment of Risk) This prospective observational study recruited 550 patients This study is a cross-research database to incorporate referred for invasive coronary angiography in three Melbourne current and future investigator-driven studies at CCRE. cardiology centres, irrespective of co-morbidities. The aims The aims are to improve data collection, standardise of the project are: cardiovascular risk information and enhance recruitment into research projects. Future CCRE studies will 1. to better understand the effects of risk factor incorporate the use of standardised case report forms. modification on prediction and stratification of Participants, at the time of recruitment, will be consented the risk of coronary artery disease (CAD); and to include their study data in the CLEAR database, allowing long-term follow up of cardiovascular morbidity 2. the clinical impact of novel and non-invasive markers and mortality. Currently, clinical trials have a finite follow up such as pulse wave analysis, heart rate variability and period; the CLEAR study involves lifetime follow up and pulse wave velocity. will establish a cohort of volunteers suitable for recruitment into future studies. The project commenced in 2007 with Diagnostic coronary angiography is the gold-standard for the incorporation of the ARM-CAD and SCREEN-HF studies. identifying coronary atherosclerosis. Risk factor assessment combined with stress-testing and nuclear imaging is often HOPE-3 (Heart Outcomes Prevention Evaluation) used for risk-stratification and to determine the need and HOPE-3 is a five-year multinational double blind longitudinal priority for coronary angiography. These tests require study to evaluate the effects of the 'polypill', namely substantial resources and despite their use, significant combined cholesterol and blood pressure lowering, coronary artery disease is absent in up to half of patients. in approximately 11,000 study participants who are Angiography itself is associated with serious adverse without vascular disease at baseline. The study is expected events, including death (0.1 per cent), myocardial to identify safe and effective CV prevention strategies infarction (0.1 per cent) and vascular injury or bleeding which could substantially reduce the risk of CVD in large (4 to 8 per cent). proportions of the adult population worldwide. Our results have highlighted the important risk factors The trial participants are those who do not have a clear associated with CAD and how novel risk markers can indication or contraindication to lipid lowering or blood be used in a clinical environment to diagnose or exclude pressure lowering with any of the study drugs. In order coronary disease. Results from cross-sectional analysis to exclude very low risk people, in addition to age, one of angiographic disease have been presented at a number additional CV risk factor is required for eligibility in the trial. of international conferences and final manuscripts are The inclusion criteria for the study are women aged over currently under peer-review in major cardiology journals. 60 years and men aged over 55 years, with one additional The ARM-CAD study is also recruiting a lower-risk cohort CV risk factor (such as current or recent smoker, waist/hip at the Caulfield Clinical Trial Centre and assessing follow ratio over 0.90 in men and over 0.85 in women, family up of participants to identify incident cardiovascular events history of premature CHD in first degree relatives (age and the predictive capacity of novel risk markers. under 55 years in men or under 65 years in women). The primary outcome is the composite of CV death, Publications nonfatal myocardial infarction (MI), nonfatal ischemic Kotecha D, Flather M, McGrady M, Pepper J, New G, stroke, resuscitated cardiac arrest and arterial Krum H, Eccleston D. Contemporary predictors of revascularisations. Follow-up study visits occur coronary artery disease in patients referred for angiography. every six months for an average of at least five years. Eur J Cardiovasc Prev Rehabil. 2009 Oct 24. [Epub ahead of print] 20 | Annual Report 2009 CTC is recruiting study participants as well as coordinating SAVE (Sleep Apnea cardioVascular Endpoints) other sites in Australia: The George Institute for International The SAVE study is a collaborative, Phase III, multi-centre, Health, Sydney; The George Institute for International open-label randomised controlled trial of continuous Health, School of Rural Health Research Centre, Dubbo; positive airway pressure (CPAP) for the treatment of and Dr Geoffrey Robinson (GP practice, Mt Beauty, obstructive sleep apnoea (OSA) to prevent cardiovascular Victoria). In 2010, Dr John Amerena, Geelong and disease. The primary objective of the study is to evaluate Canberra Hospital will also begin recruiting study the hypothesis that in patients with moderate to severe OSA, participants. To date in Australia, twenty-four patients have CPAP added to standard care will reduce the incidence of been randomised at CTC, eight at The George in Dubbo major and minor CV events relative to standard care alone, and two at The George in Sydney. Recruitment for this as measured by the composite endpoint cluster of CV study has been slower than expected worldwide with death, myocardial infarction, stroke, hospitalisation for a total of 6320 participants worldwide being randomised heart failure and hospitalisation for an acute ischaemic to the study by the end of 2009. HOPE-3 will recruit study cardiac event or cerebral event. participants from about 150 centres in about nine countries. Recruitment has now been extended to June 2010. OSA is a condition in which a person, because of This investigator-initiated study is conducted by the relaxation of throat muscles, stops breathing for several Population Health Research Institute, McMaster University seconds at a time, many times over, during sleep. and Hamilton Health Sciences, Canada. Research indicates that it may lead to high blood pressure and increase the risk of heart attacks and strokes. One of HOPE-3 arterial compliance sub-study the current treatments available for severe OSA is the use Funding was obtained from the National Heart Foundation of CPAP. CPAP involves the use of a small mask placed (NHF) to conduct a sub-study to assess the independent over the nose or nose and mouth, during sleep where air and the combined effects of blood pressure lowering and is gently pushed into the lungs and allows people to lipid lowering on arterial stiffness in approximately 300 continue breathing normally. CPAP has been shown of the HOPE-3 study participants who attend CTC. to effectively reduce snoring, obstructive episodes and daytime sleepiness. Some short-term research studies Prior to receipt of study medication, those subjects willing have shown that CPAP may help to reduce blood pressure. to participate in the sub-study will undertake arterial stiffness This CPAP device is approved in Australia and internationally assessment at the Clinical Trial Centre. Pulse wave velocity for use in the treatment of sleep apnoea. Participants are (PWV) is measured between the carotid artery and the eligible for the study if they have at least one of the following femoral artery using non-invasive applanation tonometry. risk factors for OSA: a previous heart attack; heart disease Systemic arterial compliance is a non-invasive test of the requiring bypass graft surgery, angioplasty or stenting; elasticity of the arteries and involves measurements of stroke, or a transient ischaemic attack (TIA); or angina. blood pressure and blood flow using ultrasound transducers positioned above the sternum to image This study is being carried out in about 5000 patients the ascending aorta. Three study participants have world-wide and will last up to five years. Recruitment is been recruited to the sub-study. continuing and 13 sites in Australia have randomised 53 patients and sites in China have randomised 280 patients. Funding CTC is the 5th highest recruiting Australian site with seven NHF Grant-in-Aid study participants. This investigator initiated study is being 2008 to 2009 – $120,126 conducted by an international group of researchers based in China, Europe, USA and Australia. The SAVE International coordinating entre is based at the Adelaide Institute for Sleep Health, Adelaide, South Australia. Centre of Cardiovascular Research and Education in Therapeutics | 21 STABILITY KANYINI –GAP (Kanyini Guidelines Adherence (The STabilisation of Atherosclerotic plaque with the Polypill Study) By Initiation of darapLadIb TherapY This is a prospective, open, randomised controlled clinical This is a randomised, placebo-controlled, double-blind, trial (n=1000 non-Indigenous and Indigenous individuals) parallel-group, multi-centre, event-driven trial of an of a polypill-based strategy compared to usual care investigational product called darapladip, in people with among individuals at high risk of cardiovascular events chronic coronary heart disease receiving standard practice based in general practices and Indigenous specific health care at the time of entry into the study. Coronary Heart services, augmented by a cost-effectiveness analysis and Disease (CHD) is a condition in which deposits of fat and a formal process evaluation. cholesterol, called plaque, build up over time in the heart or the blood vessels that supply blood to the heart muscle. The Kanyini GAP study comprises of two collaborations: This build up of plaque is part of a process called The Kanyini Vascular Collaboration (KVC) is a five year 'atherosclerosis', or hardening of the arteries. People health services research program, established between with CHD are at risk of having a heart attack or stroke. Indigenous and non-Indigenous health service and clinical researchers and conducted in close collaboration with Darapladip reduces the activity of a naturally occurring several Aboriginal Community Controlled Health Services chemical in the body, an enzyme, called lipoprotein- (ACCHS) in metropolitan, rural and remote communities associated phospholipase A2, or Lp-PLA2. Elevated in NSW, NT, and QLD and one government funded plasma levels of an enzyme known as Lp-PLA2 are Indigenous health service in QLD. The Guidelines associated with an increased risk of cardiovascular events. Adherence with the Polypill collaboration has been formed Clinical studies of darapladip have shown dose-dependent between the George Institute for International Health, inhibition (the higher the dose the greater the inhibition) of the Department of General Practice, Western Clinical both plasma and intra-plaque Lp-PLA2 activity. Stopping School, University of Sydney and CTC, Monash University. the production of this enzyme may be beneficial to These three groups have developed a research collaboration cardiovascular patients who are also taking standard comprising of a diverse network of general practices in therapies such as lipid lowering medication called statins. NSW and Victoria. The CTC is responsible for recruiting approximately 100 non-Indigenous study participants This international study aimed to recruit 15,500 in the Melbourne area in association with local general participants randomised to one of two groups. practices. Ethics approval was obtained for this study Approximately 7750 participants will be allocated to at the end of 2009 and recruitment will start in 2010. the darapladip group and will receive 160mg of enteric coated darapladip daily, 7750 participants will receive a The aim of the study is to assess whether provision of placebo daily and will be followed for up to three years. a polypill (containing low dose aspirin, a statin and two The study recruitment was achieved in October 2009, blood pressure lowering medicines) compared to usual with 306 participants at 16 sites in Australia (23 participants cardiovascular medications improves adherence to were recruited by the Clinical Trial Centre – the second indicated therapies and clinical outcomes among high-risk highest recruiting site in Australia). Study participants patients. Secondary aims are to measure prescription of will be followed every six months for approximately combination therapy, barriers to adherence, quality of life, three-and-a-half years. This study is funded by safety, cardiovascular events, prescriber acceptability, the pharmaceutical company, GlaxoSmithKline. and healthcare resource consumption. The study will be conducted within mainstream general practices and the Funding participating health service partners in the Kanyini Vascular GlaxoSmithKline Australia Pty Ltd Collaboration. This is an investigator initiated study 2009 to 2010 – $219,600 sponsored by The George Institute for International Health and is funded by an NHMRC grant. 22 | Annual Report 2009 ABIDING (Ankle Brachial Index Determination Oscillometric devices allow Ankle-Brachial Index (ABI) by oscillometric method IN General practice) measurement without a Doppler device. We wish to The ABIDING Study will investigate if the oscillometric validate these devices in Australian general practice. determination of ankle brachial index (ABI) by general Secondary aims of the study are to establish the change practice nurses is a valid and reliable method. Practice in prevalence over time of PAD in a defined high risk nurses have been chosen rather than GPs as, with the general practice population, to ascertain the utility of current GP workforce shortage and the promotion of oscillometric devices for the diagnosis of PAD and to the concept of a 'primary care team' supported by monitor the change since baseline of the ABI using the MBS item numbers for nurses, this is more likely to be standard technique, BMI, waist circumference measure implementable. GPs have ready access to oscillometric and Edinburgh Claudication score. Ethics approval for the sphygmomanometers as recently oscillometric study was obtained and the study began recruiting in late sphygmomanometers were distributed to GPs through 2009, with 13 study participants completing study visits. the High Blood Pressure Research Council of Australia. This study is funded by an NHMRC grant and is being led by Professor Mark Nelson, University of Tasmania. The REACH Registry Australian DMC, located at the Department of Epidemiology and Preventive Medicine, Monash University, will be used to recruit GP practices to participate in the study. The REACH Registry was an international register of those with established cardiovascular disease or at high risk of it. It was demonstrated in the REACH Registry that peripheral arterial disease (PAD) is prevalent in high risk individuals in the Australian primary care environment. In addition, it was shown that those with the condition had the highest level of Cardiovascular Disease (CVD) morbidity and mortality over the subsequent year. Centre of Cardiovascular Research and Education in Therapeutics | 23 Research training and education Research student reports 500 adults, in diverse geographical settings from Alice Springs Town to remote communities and town camps, will undergo full cardiovascular assessment including Fourth Year echocardiograph and ECG. To date, over 170 participants are enrolled and preliminary data shows there is a high Dr Michele McGrady prevalence of heart failure risk factors along with MBBS, FRACP ventricular dysfunction and rheumatic heart disease. Thesis title Current progress Epidemiology of Left Ventricular Dysfunction Recruitment in both these cohorts is complete and and Heart Failure in High Risk Populations. final reporting is underway along with data analysis and preparation of manuscripts to report findings. Background Heart failure is a major health problem throughout the Ms Zanfeni Ademi world, with high morbidity, mortality and cost to the MPharm, MPH healthcare system. Population estimates of heart failure prevalence vary between 2 and 10 per cent, depending Thesis title on the population, and rises significantly as we age. Using the real world data to inform policy decision makers Fifty per cent or greater of those with identifiable left on the cost of illness and cost effectiveness of treatment ventricular dysfunction are asymptomatic, undiagnosed for cardiovascular disease. and often untreated. Prevalence rates may be even greater in selected populations, particularly those with a very high A number of registries have been performed over the years prevalence of known risk factors for the condition, such as in the field of cardiovascular disease. However, not many hypertension, myocardial ischemia, diabetes mellitus, cardiovascular patient registries report the cost data. chronic kidney disease and obesity. Effective therapies Therefore, our aim is to emphasize the significance of exist to treat both symptomatic and asymptomatic left these registries on estimating the cost effectiveness of ventricular systolic dysfunction. We have limited data in treatment as a tool to inform policy decision makers in Australia on the prevalence of heart failure, asymptomatic order to maximise technical and allocative efficiency. left ventricular dysfunction and the underlying causes and We recommend that to expand their spectrum of still have much to learn about early diagnosis. importance and relevance and to fill these gaps in evidence, cardiovascular registries must report costs data alongside Aim other epidemiological outcomes. The objective was to To document the epidemiology and underlying identify the main drivers of healthcare costs from the characteristics of heart failure and asymptomatic perspective of the government as the main payer. LV dysfunction in two high risk populations as follows: The study applied the bottom up costing approach SCReening Evaluation of the Evolution of New Heart to health expenditures using one year and two year Failure (SCREEN HF) – An elderly high risk population follow up data from Australian subjects recruited into the (over 60 years, plus more than one heart failure risk factor) international REACH Registry. It applied regression and without a previous diagnosis of known HF or left count models to ascertain the impact of cardiovascular ventricular dysfunction. Following initial screening risk factors and outcomes in healthcare costs, and have (n=3500), the 700 participants with NT-proB natriuretic explored the causes of any difference found. In addition, peptide (NT-proBNP) in the highest quintile undergo it used decision analysis tree model to show the difference assessment of cardiac structure and function by ECG in treatment gap between clinical practice and and echocardiogram. recommendations with regard to cardiovascular disease. The study has reported these results as the Incremental Heart of the Heart – a population based study of Cost effectiveness ratio per event prevented. heart failure and underlying aetiology in the Indigenous population of Central Australia. This population has three times the mortality from heart failure as the general population and a high prevalence of rheumatic heart disease. 24 | Annual Report 2009 Dr Suree Lekawanvijit As AST-120 can reduce a circulating IS level which is MD (Hons 1), FRCPath increased more in MI animals compared to sham animals. Another animal project using an MI model and AST-120 Thesis title as treatment has also been conducted alongside the renal Cardiorenal Syndrome: Pathophysiology and Role failure with AST-120 project. of Protein-Bound Uremic Toxins and Biomarkers. Third Year Background Heart Failure (HF) and Chronic Kidney Disease (CKD) Ms Lavinia Tran are closely interrelated. Failure of one organ can cause BBiomedSci (Hons) dysfunction of the other which in turn accelerates failure of both, leading to the term 'cardiorenal syndrome'. Thesis title However, the pathophysiology is still unclear. Therapeutic targeting of signalling pathways in heart failure. In the setting of CKD, traditional cardiovascular risk factors Background such as hypertension, diabetes and hyperlipidemia alone Heart failure is a major health burden worldwide and are not enough to explain the unacceptably high places substantial stress on the health care system. cardiovascular death observed. Since protein-bound uremic toxins, a subgroup of toxins accumulated in Lavinia's PhD project spans across both clinical and basic patients with CKD, are ineffectively removed by current science research to determine the mechanisms involved conventional hemodialysis, we hypothesized that such in the progression of heart failure and to target these toxins may have adverse cardiac effects. Indoxyl Sulfate pathways with novel drugs. The clinical study involves (IS), one of those toxins, has been demonstrated pro- an Iontophoresis trial with heart failure patients and healthy fibrotic and pro-hypertrophic effects on cultured cardiac controls to test the effects of potential drugs on forearm cells, for the first time, as well as a pro-inflammatory effect vascular blood flow. The basic science component utilizes on monocytic cells. Thus, IS might be implicated in animal models and primary cell culture to investigate drug cardiovascular diseases and accelerated death in the effects. The current findings of this study have been setting of CKD. This work was presented at AHA Scientific presented both nationally and internationally. Sessions 2008 and won the AHA Best Scientific Poster Lavinia plans to submit her PhD by publication in 2010. Award (Basic Science). The paper has been accepted for publication in the European Heart Journal 2010. Significance of this study This project has the potential to uncover novel therapeutic Next to this project is to discover how to eliminate the drugs for the treatment of heart failure and provide further adverse effects of indoxyl sulfate on the heart by conducting understanding of the mechanisms that may be relevant in an in vivo study (renal failure model), using a compound other cardiovascular diseases. named AST-120. This compound is an oral adsorbent having IS-lowering effect in the gut. The aim of this study Scholarship – National Heart Foundation Postgraduate is to determine whether AST-120 can improve heart Research Scholarship. function and structural changes in relation to its IS-lowering effect. In the setting of HF, the other direction to study cardiorenal syndrome, study of how the diseased heart affects the kidney is extremely rare. Therefore, an in vivo project to systematically study of pathophysiology has been conducted. Aims are to evaluate changes at structural and molecular levels in the kidney following Myocardial Infarction (MI) over time and to identify biomarkers for early kidney injury in this setting. Renal dysfunction, progressive renal interstitial fibrosis and an increased Kidney Injury Molecule-1 (KIM-1) have been identified. This work was presented at AHA Scientific Sessions 2009. Centre of Cardiovascular Research and Education in Therapeutics | 25 Ms Ella Zomer CSL Symposium: Modern Management BBiomedSci(Hons) of Heart Failure Chair: Professor Henry Krum Thesis title Epidemiological modelling of metabolic syndrome The first speaker was Professor Andrew Coats, Deputy and cardiovascular disease in Australia. Vice Chancellor (Community) at the University of Sydney whose talk titled 'Heart Failure: Modern Understanding Metabolic Syndrome (MetS) is a group of factors that of Epidemiology and Treatment' addressed the growing significantly increase the risk of developing cardiovascular problem of treating heart failure in the elderly. His disease and type two diabetes mellitus. With no clear presentation was followed by Dr Marcus Flather, definition it is underpinned by insulin resistance, cardiologist and Director of the Clinical Trials and hyperinsulinemia and obesity together with other Evaluation Unit, Royal Brompton Hospital, London, cardiovascular risk factors. It currently affects who then addressed the issue of 'Beta Blockers in Heart approximately 20 to 30 per cent of the Australian Failure: New Data in the Elderly'. Dr Flather (together with population and estimated to continue to rise with the Professor Coats) is a member of the Steering Committee aging population and increasing rates of obesity. As there of the multinational SENIORS study and, in his presentation, are many risk factors comprising MetS, confusion surrounds he provided new data from this study on the effects of what component to treat first. This project aims to develop nebivolol in patients with preserved ejection fraction and and use epidemiological (including economic) modelling impaired renal function. Following the presentations, to (i) determine the future landscape of metabolic Professor Krum led an interesting question and answer syndrome and cardiovascular disease in Australian session and discussion. and (ii) identify the most effective and cost effective means of preventing and treating cardiovascular disease Astra Zeneca Symposium: The Role of Biomarkers in patients with metabolic syndrome. in Cardiovascular Disease (CVD) Risk Assessment Chair: Professor Andrew Tonkin Findings from this study have been presented both nationally as a student finalist oral presentation at Professor Tonkin started the proceedings by presenting the High Blood Pressure Research Council 2008, an 'Overview of the Global Burden of CVD' and this was and internationally as an oral presentation at the followed by Dr Paul M Ridker, Director of the Center for European Society of Cardiology 2009. Cardiovascular Disease Prevention at the Brigham and Women's Hospital, Boston, and Principal Investigator for the recently published JUPITER Study. Dr Ridker Meetings and symposia presented information from the JUPITER study on the effects of lowering high levels of CRP a protein marker Cardiac Society of Australia and New Zealand for inflammation in the blood with rosuvastatin, and the Sydney, 13 to 16 August, 2009 effect on heart attack risk. The Cardiac Society of Australia and New Zealand Annual Scientific Meeting is the major event on the Australian Professor Stefan Blankenberg from the Department Cardiology calendar. of Medicine, Johannes Gutenberg University, Mainz in Germany, presented information of the role of 'Biomarkers In line with its commitment to education in therapeutics, in Diagnostic and Risk Assessment'. These presentations CCRE Therapeutics continued its sponsorship of satellite were followed by a lively discussion, chaired by Professor symposia at this event and, in conjunction with CSL Tonkin, on the case for CRP in CVD risk assessment Biotherapies and Astra Zeneca (Australia), put together versus the case for the multiple biomarker approach. an expert team of local and international speakers for two very interesting symposia. Both Symposia brought together local and international experts who presented valuable information from recent clinical and laboratory research and offered an opportunity for discussion in a more intimate environment. 26 | Annual Report 2009 Financial report CCRE Therapeutics continues to stand alone following the end of our original NHMRC CCRE infrastructure grant of $2 million in 2007. Further success with NHMRC, NHF and ARC grants as well as industry funding has ensured financial viability and sustainable growth. Not appearing on the graph below is National Institute of Health (NIH) support. A successful Rapid Access to Investigational Drugs (RAID) grant secured in-kind support of US$2.9 million. The NIH also awarded CCRE Therapeutics US$50 million over seven years for the large-scale ASPREE study which will begin new recruitment in 2010. Centre of Cardiovascular Research and Education in Therapeutics | 27 Grants NHMRC NHF P Davidson, P Macdonald, D Curnow, P Newton, DL Hare, D Clarke, H Krum D Leung, G Tofler, H Krum The Melbourne Depression in Heart Failure Oxygen to relieve dyspnoea in non-hypoxaemic Collaborative Medication trial patients with end-stage heart failure 2008–2012 $893,581 (NHF and Beyond Blue) 2007–2009 $300,000 (Palliative Care) H Krum, DJ Campbell, C Reid, S Stewart S Stewart, P Scuffham, T Marwick, J Horowitz, H Krum, Randomised, placebo-controlled clinical trial of P Davidson, P Macdonald, C Reid pharmacological intervention in high risk subjects Which Heart failure Intervention is most Cost-effective with elevated BNP to prevent new heart failure and consumer friendly in reducing Hospital care: 2008–2009 $126,671 (Grant-in-Aid) The WHICH study, 2007–2011 $878,702 (Health Services) Reid CM, Cameron J, Kingwell B, Dart A J McNeil, A Tonkin, L Beilin, C Reid, H Krum, M Nelson Independent and combined effects of blood pressure ASPirin in Reducing Events in the Elderly (ASPREE) lowering and lipid lowering on vascular stiffness 2005–2009 $3,503,500 (Project) 2008–2009 $120,126 (Grant-in-Aid) H Krum, D Kelly, S Itescu A Owen, C Reid, P McLennan, H Krum Novel therapeutic strategies to reduce the burden Omega-3 fatty acid status and cardiovascular risk of chronic heart failure in older Australians 2005–2009 $4,634,965 (Program) 2009–2010 $130,800 (Grant-in-Aid) J Simes, D Ghersi, M Stockler, T Keech, S Green, ARC Linkage Grant D Henderson-Smart, H Krum, G Jennings A National Clinical Trials Register D Liew, C Reid, A Owen, J Shaw, D Magliano 2005–2010 $1,500,000 (Enabling) Epidemiological modelling of cardiovascular disease and diabetes in Australia R Buchbinder, L March, M Lassaire, C Reid 2007–2009 $212,000 The Australian Rheumatology Association Database (ARAD) 2006–2010 $1,250,000 (Enabling) Industry Nelson MR, Reid CM, Ryan P, Tonkin AM, Wing LMH BMS Absolute risk prediction of subsequent cardiovascular Integrate Project events in elderly Australian with hypertension 2007–2009 $389,499 2008–2009 $192,000 (General Practice Clinical Research Program) Glaxo Wellcome Australia H Krum, A Kompa CM Reid Therapeutic Efficacy of Soluable Epoxide Hydrolase Senior Research Fellowship Inhibition in a Post-MI model of Cardiac Remodelling 2008–2012 $537,500 2009 $108,081 Budge M, Storey E, Tonkin AM, Wong T, Reid CM, Ames D Pfizer (CVL Grant) Aspirin for the prevention of cognitive decline in the Elderly M McGrady, H Krum (EnVISION) The prevalence of heart failure in Aboriginal 2008–2012 $1,271,102 communities in Central Australia 2009 $55,000 J McNeil, C Reid, H Krum, A Tonkin, R Woods Mobile Assessment Centre and blood GlaxoSmithKline Australia Pty Ltd processing laboratory H Krum 2009 $90,000 (Equipment) A Clinical Outcomes Study of Darapladib versus Placebo in Subjects with Chronic Coronary Heart Disease to H Krum, P Scammells, B Wang Compare the Incidence of Major Adverse Cardiovascular Development of novel anti-inflammatory compounds Events (MACE) – STABILITY Trial 2009 $196,250 (Development) 2009–2010 $219,600 28 | Annual Report 2009 National Institute of Health (USA) Rapid Access to Investigational Drugs (RAID) R Gilbert, D Kelly, H Krum, S Williams Treatment of Diabetic Nephropathy Using a Purpose-Designed Anti-Fibrotic Drug 2008–2010 US$2,900,000 (in-kind support) R Grimm, J McNeil, A Tonkin, C Reid, M Nelson, R Woods ASPirin in Reducing Events in the Elderly (ASPREE) 2009–2015 US$50,445,006 RACP Collaborative Research Initiative Grant F Ierino, N Isbel, H Krum A randomised controlled trial of the beta-blocker carvedilol versus placebo to reduce cardiovascular morbidity and mortality in patients receiving dialysis 2008–2010 $704,400 Government C Reid, A Ajani, B Billah, A Brennan, D Dinh, A Hannaford, H Krum, J McNeil, G Shardey, A Tonkin Testing and validating draft 'Operating Principles and Technical Standards for Australian Clinical Quality Registries 2008–2009 $931,686 Centre of Cardiovascular Research and Education in Therapeutics | 29 Publications Ritz E, Krum H, Schlaich M, Whitbourn R, Sobotka PA, Leet A, Richardson M, Senior JA, Funston R, Skiba M, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Bailey M, Krum H. A bioavailability study of cyclosporine: Thambar S, Abraham WT, Esler M, Wang Y, Tsun Z, comparison of Neoral versus Cysporin in stable heart Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, transplant recipients. J Heart Lung Transplant. Machura K, Park JK, Beck FX, Müller DN, Derer W, Goss J, 2009 Sep; 28(9):894–8. Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Rasmussen HH, Figtree GA, Krum H, Bundgaard H. Titze J. New approaches to pathogenesis and The use of beta3-adrenergic receptor agonists in the management of hypertension. Clin J Am Soc Nephrol. treatment of heart failure. Curr Opin Investig Drugs. 2009 Dec;4(12):1886–91. 2009 Sep;10(9):955–62. Krum H. Optimising management of chronic heart failure. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Lancet 2009 Nov 28;374(9704):1808–1809. (invited editorial) Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med. 2009 Aug 27; Zammit SC, Cox AJ, Gow RM, Zhang Y, Gilbert RE, Krum H, 361(9):932–4. (letter) Kelly DJ, Williams SJ. Evaluation and optimization of antifibrotic activity of cinnamoyl anthranilates. Gheorghiade M, Khan S, Blair JE, Harinstein ME, Krum H, Bioorg Med Chem. 2009 Dec 15;19(24):7003–6. Mukherjee R, Pitt B; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) Chan CC, Reid CM, Aw TJ, Liew D, Haas SJ, Krum H. Investigators. The effects of eplerenone on length of stay Do COX-2 inhibitors raise blood pressure more than and total days of heart failure hospitalization after myocardial nonselective NSAIDs and placebo? An updated meta- infarction in patients with left ventricular systolic analysis. J Hypertens, 2009;Dec 27(12):2332–2341. dysfunction. Am Heart J. 2009 Sep;158(3):437–43. Thom O, Taylor DM, Wolfe RE, Cade J, Myles P, Krum H, Ezekowitz JA, Hernandez AF, Starling RC, Yancy CW, Wolfe R. Comparison of a supra-sternal cardiac output Massie B, Hill JA, Krum H, Diaz R, Ponikowski P, Metra M, monitor (USCOM) with the pulmonary artery catheter. Howlett JG, Gennevois D, O'Connor CM, Califf RM, Br J Anaesth. 2009 Dec;103(6):800–4. Fonarow GC. Standardizing care for acute decompensated heart failure in a large megatrial: The approach for the Kotecha D, Flather M, McGrady M, Pepper J, New G, Acute Studies of Clinical Effectiveness of Nesiritide in Krum H, Eccleston D. Contemporary predictors Subjects with Decompensated Heart Failure of coronary artery disease in patients referred for (ASCEND-HF). Am Heart J, 2009;157:219–228. angiography. Eur J Cardiovasc Prev Rehabil. 2009 Oct 24. [Epub ahead of print] Krum H. Consider beta blockers for patients with heart failure. BMJ, 2009;338:1384–1385. Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Renal Denervation as a Therapeutic Approach Krum H, Iyngkaran P, Lekawanvijit S. Pharmacologic for Hypertension: Novel Implications for an management of the cardiorenal syndrome in heart failure. Old Concept. Hypertension, 2009 Dec;54(6):1195–1201. Current Heart Failure Reports, 2009;6:105–111. Kemp W, Kompa A, Phrommintikul A, Herath C, Zhiyuan J, Krum H, Sanders P. Expanding indications for pacing Angus P, McLean C, Roberts S, Krum H. Urotensin II in chronic heart failure. MJA, 2009; 190;470–471. modulates hepatic fibrosis and portal hemodynamic (invited editorial) alterations in rats. Am J Physiol Gastrointest Liver Physiol. 2009 Oct;297(4):G762–7. Martin JH, Connelly KA, Boyle A, Kompa A, Zhang Y, Kelly D, Gilbert RE, Krum H. Effect of atorvastatin on cardiac Weber MA, Black H, Bakris G, Krum H, Linas S, Weiss R, remodelling and mortality in rats following hyperglycemia Linseman JV, Wiens BL, Warren MS, Lindholm LH. and myocardial infarction. Int J Card, 2009 April 21. A selective endothelin-receptor antagonist to reduce blood [Epub ahead of print] pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Connelly KA, Kelly DJ, Zhang Y, Prior DL, Advani A, Cox AJ, Lancet, 2009 Oct 24;374(9699):1423–31. Thai K, Krum H, Gilbert RE. Inhibition of protein kinase C-ß by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy. Circ Heart Fail, 2009;2:129–137. 30 | Annual Report 2009 Krum H, Swergold G, Curtis SP, Kaur A, Wang H, Reid CM, Ajani AE, Eccleston D. Why we need Smugar SS, Weir MR, Laine L, Brater DC, Cannon CP. a national registry in interventional cardiology. Factors associated with blood pressure changes in Med J Aust. 2009 Feb 2;190(3):162–3. patients receiving diclofenac or etoricoxib: results from the MEDAL study. J Hypertension, 2009;27:886–893. Joubert J, Reid C, Barton D, Cumming T, McLean A, Joubert L, Barlow J, Ames D, Davis S. Integrated care Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski improves risk-factor modification after stroke: initial results J, Bartus K, Kapelak B,Walton A, Sievert H, Thambar S, of the Integrated Care for the Reduction of Secondary Abraham WT, Esler M. Catheter-based renal sympathetic Stroke model. J Neurol Neurosurg Psychiatry. 2009 denervation for resistant hypertension: a multicentre safety Mar;80(3):279–84. and proof-of-principle cohort study. Lancet, 2009;373:1275–1281. Reid C, Billah B, Dinh DT, Skillington PD, Smith JA, Yii M, Seevanayagam S, Pick A, Mohajeri M, Shardey GC. Krum H, Curtis SP, Kaur A, Wang H, Smugar SS, Weir MR, An Australian Risk Prediction Model for 30-day Mortality Laine L, Brater DC, Cannon CP. Baseline factors after Isolated Coronary Artery Bypass – the AusSCORE. associated with congestive heart failure in patients J Thorac Cardiovasc Surg, 2009; 138: 904–10. receiving etoricoxib or diclofenac: multivariate analysis of the MEDAL program. Eur J Heart Fail, 2009; Jun Yap CH, Yan BP, Akowuah E, Dinh DT, Smith JA, 11(6):542–50. Shardey GC, Tatoulis J, Skillington PD, Newcomb A, Mohajeri M, Pick A, Seevanayagam S, Reid CM. Does prior Becker MC, Wang TH, Wisniewski L, Wolski K, Libby P, percutaneous coronary intervention adversely affect early Luscher TF, Borer JS, Mascette AM, Husni ME, Solomon DH, and mid-term survival after coronary artery surgery? Graham DY, Yeomans ND, Krum H, Ruschitzka F, Lincoff AM, JACC Cardiovasc Interv, 2009; 8:758–64. Nissen SE for the PRECISION Investigators. Rationale, design, and governance of Prospective Randomized Owen AJ, Retegan C, Rockell M, Jennings G, Reid CM. Evaluation of Celecoxib Integrated Safety versus Ibuprofen Inertia or inaction? Blood pressure management and Or Naproxen (PRECISION), a cardiovascular end point trial cardiovascular risk in diabetes. Clin Exp Pharmacol of nonsteroidal anti-inflammatory agents in patients with Physiol. 2009 Jul;36(7):643–7. arthritis. Am Heart J, 2009;157:606–12. Walls HL, Peeters A, Son PT, Quang NN, Hoai NT, Loi do D, McGrady M, Krum H. Screening: the new frontier in heart Viet NL, Khai PG, Reid CM. Prevalence of underweight, failure management. Cardiovasc Ther. 2009;27(1):1–3. overweight and obesity in urban Hanoi, Vietnam. Asia Pac J Clin Nutr. 2009;18(2):234–9. Schneider H, Lam L, Lokuge A, Krum H, Naughton MT, Smit P, Bystrzycki A, Eccleston D, Cowan BR, Young AA, Anderson C, Doughty RN, Federman J, Flannery G, Cameron P. B-type natriuretic Krittayaphong R, Lonn E, Marwick TH, Reid CM, peptide testing, clinical outcomes, and health services Sanderson JE, Schmieder RE, Teo K, Wadham AK, use in emergency department patients with dyspnea. Worthley SG, Yu CM, Yusuf S, Jennings GL. Ann Intern Med, 2009;150:365–371. The cardiac MRI substudy to ongoing telmisartan alone and in combination with ramipril global endpoint trial/ Krum H, Abraham WT. Heart failure. Lancet, telmisartan randomized assessment study in ACE- 2009;373:941–955. (invited review) intolerant subjects with cardiovascular disease: analysis protocol and baseline characteristics. Clin Res Cardiol. Kemp W, Colman J, Thompson K, Madan A, Vincent M, 2009 Jul;98(7):421–33. Chin-Dusting J, Kompa A, Krum H, Roberts S. Norfloxacin treatment for clinically significant portal Cowan BR, Young AA, Anderson C, Doughty RN, hypertension: results of a randomised double-blind Krittayaphong R, Lonn E, Marwick TH, Reid CM, placebo-controlled crossover trial. Liver International, Sanderson JE, Schmieder RE, Teo K, Wadham AK, 2009;29(3):427–433. Worthley SG, Yu CM, Yusuf S, Jennings GL; ONTARGET Investigators. Left ventricular mass and volume with Brady SR, de Courten B, Reid CM, Cicuttini FM, telmisartan, ramipril, or combination in patients with de Courten MP, Liew D. The role of traditional previous atherosclerotic events or with diabetes mellitus cardiovascular risk factors among patients with (from the ONgoing Telmisartan Alone and in Combination rheumatoid arthritis. J Rheumatol. 2009 Jan;36(1):34–40. With Ramipril Global Endpoint Trial [ONTARGET]). Am J Cardiol. 2009 Dec 1;104(11):1484–9. Centre of Cardiovascular Research and Education in Therapeutics | 31 Briggs AM, March L, Lassere M, Reid C, Henderson L, Freeman M, Clark D, Andrianopoulos N, Duffy S, Lim H, Murphy B, van den Haak R, Rischin A, Staples M, Brennan A, Charter K, Shaw J, Horrigan M, Ajani A, Buchbinder R. Baseline Comorbidities in a Population- Sebastain M, Reid C, Farouque O. Procedural and clinical Based Cohort of Rheumatoid Arthritis Patients Receiving outcomes of percutaneous coronary intervention for ostial Biological Therapy: Data from the Australian Rheumatology lesions in proximal coronary arteries. Catheterization and Association Database. Int J Rheumatol. 2009; Cardiovascular Intervention, 2009;73:763–768. Epub ahead of print. Butler MJ, Eccleston D, Ajani A, Lefkovits J, Clark DJ, Ademi Z, Liew D, Chew D, Conner G, Shiel L, Nelson M, Andrianopoulos N, Brennan A, Reid CM, Farrington C, Soman A, Steg G, Bhatt DL, Reid C; REACH registry Walton AS, Dart AM, Duffy SJ, on behalf of the Melbourne investigators. Drug treatment and cost of cardiovascular Interventional Group (MIG). The effect of intended duration disease in Australia. Cardiovasc Ther. 2009 Fall;27(3): of clopidogrel use on early and late mortality and major 164–72. adverse cardiac events in patients with drug-eluting stents. American Heart Journal. 2009;157(5):899–907. Brasacchio D, Dinh DT, Billah B, Shardey G, Reid CM on behalf of the Australian Society of Cardiac and Thoracic Yap C-H, Andrianopoulos N, Dinh DT, Billah B, Rosalion AM, Surgeons Database Project Steering Committee. Cardiac Reid CM. Short and mid-term outcomes of coronary Surgery in Victorian Public Hospitals 2007–2008: Hospital artery bypass surgery performed by surgeons in training. Report. Quality and Safety Branch, Department of Human The Journal of Thoracic and Cardiovascular Surgery. Services, Melbourne, Victoria 2009. 2009;137:1088–1092. Brasacchio D, Dinh DT, Billah B, Shardey G, Reid CM Yan BP, Clark DJ, Buxton B, Ajani AE, Smith JA, Duffy SJ, on behalf of the Australian Society of Cardiac and Thoracic Shardey GC, Skillington PD, Farouque O, Yii M, Yap C-H, Surgeons Database Project Steering Committee. Andrianopoulos N, Brennan A, Dinh D, Reid CM, on Cardiac Surgery in Victorian Public Hospitals 2007–2008: behalf of the Australasian Society of Cardiac and Thoracic Report to the Public. Quality and Safety Branch, Surgeons (ASCTS) and the Melbourne Interventional Department of Human Services, Melbourne VIC 2009. Group (MIG). Clinical characteristics and early mortality of patients undergoing coronary artery bypass grafting Brasacchio D, Dinh DT, Billah B, Shardey G, Reid CM compared to percutaneous coronary intervention: Insights on behalf of the Australian Society of Cardiac and from the Australasian Society of Cardiac and Thoracic Thoracic Surgeons Database Project Steering Committee. Surgeons (ASCTS) and the Melbourne Interventional Cardiac Surgery in Australian Hospitals 2007–2008: Group (MIG) registries. Heart Lung and Circulation. National Report. Melbourne VIC 2009. 2009;18(3):184–90. Dinh DT, Di Giambattista K, Billah B, Shardey G, Zwahlen D, Andrianopoulos N, Matheson B, Duchesne G, Reid CM on behalf of the Australian Society of Cardiac Millar J. High-Dose-Rate brachytherapy in combination and Thoracic Surgeons Database Project Steering with conformal external beam radiotherapy in the Committee. Cardiac Surgery in NSW Public Hospitals treatment of prostate cancer. Brachytherapy. 2007–2008: NSW Service Report. Greater Metropolitan 2009;9(1):27–35. Clinical Taskforce, NSW Health, Melbourne VIC 2009. Yap CH, Sposato L, Akowuah E, Theodore S, Dinh DT, Gurvitch R, Lefkovits J, Warren RJ, Duffy SJ, Clark DJ, Shardey GC, Skillington PD, Tatoulis J, Yii M, Smith JA, Eccleston D, Yan BP, Reid C, Brennan A, Andrianopoulos Mohajeri M, Pick A, Seevanayagam S, Reid CM. N, Ajani AE. Clinical outcomes of drug eluting stent use in Contemporary results show repeat coronary artery high risk patients with ST elevation Myocardial Infarction. bypass grafting remains a risk factor for operative Int J Cardiol 2009 (Epub ahead of print) mortality. Ann Thorac Surg, 2009; 87(5): 1386–91. Lim H, Farouque O, Andrianopoulos N, Yan B, Lim C, Piercy M, McNicol L, Dinh DT, Story DA, Smith JA. Brennan A, Reid C, Freeman M, Charter K, Black A New G, Major complications related to the use of transesophageal Ajani A, Duffy S, Clark D. Survival of elderly patients echocardiography in cardiac surgery. J Cardiothorac Vasc undergoing percutaneous coronary intervention for acute Anesth, 2009; 23(1): 62–5. myocardial infarction complicated by cardiogenic shock. Journal of American College of Cardiology Interventions, 2009; 2:146–152. 32 | Annual Report 2009 Soderberg S, Colquhoun D, Keech A, Yallop J, Barnes E, Ashton E, Windebank E, Skiba M, Reid C, Schneider H, Pollicino C, Simes RJ, Tonkin A, Nestel P, for the LIPID Rosenfeldt F, Tonkin A, Krum H. Why did high-dose Study Investigators. Leptin but not adiponectin is a predictor rosuvastatin not improve cardiac remodelling in chronic of recurrent cardiovascular events in men: results from the heart failure? Mechanistic insights from the UNIVERSE Long-term Intervention with Pravastatin in Ischaemic study. Int J Cardiol (in press). Disease (LIPID) Study. Int J Obes, 2009;33:123–30. Stewart JI, Washbrook E, Tonkin A. Cardiovascular Barr EL, Boyko EJ, Zimmet PZ, Wolfe R, Tonkin AM, risk management. 4. Moderate- to low-risk patients Shaw JE. Continuous relationships between non-diabetic – management recommendations. Eur J Gen Practice hyperglycaemia and cardiovascular disease and all-cause (in press). mortality: the AusDiab Study. Diabetologia, 2009;52: 415–424. Chen L, Tonkin AM, Moon L, Mitchell P, Dobson A, Giles G, Hobbs M, Phillips P, Shaw JE, Simmons D, Simons LA, Tonkin A, Forbes A, Haas SJ. The evidence on trial: Fitzgerald AP, De Backer G, De Bacquer D. Recalibration Cholesterol lowering and cancer. Heart Asia, 2009;1:6–10. and validation of the SCORE risk chart in the Australian population: the AusSCORE chart. Eur J Cardiovasc Prev Barr EL, Tonkin AM, Welborn TA, Shaw JE. Validity of Rehab (in press, accepted April 2009). self-reported cardiovascular disease events in comparison to medical record adjudication and a statewide hospital Beauchamp A, Peeters A, Wolfe R, Turrell G, Harriss L, morbidity database: the AusDiab study. Int Med J, Giles GG, English DR, McNeil J, Magliano D, Harrap S, 2009;39:49–53. Liew D, Hunt D, Tonkin AM. Inequalities in cardiovascular disease mortality: the role of behavioural, physiological and Tonkin AM, Chen L. Where on the Healthcare continuum social risk factors. J. Epidemiology and Community Health should we invest? The case for primary care? Heart Lung (in press). and Circ, 2009;18:108–113. Chen L, Magliano DJ, Balkau B, Colagiuri S, Zimmet PZ, Tonkin AM, Boyden AN, Colagiuri S. Maximising the Tonkin AM, Shaw JE. An Australian diabetes risk effectiveness and cost-effectiveness of cardiovascular assessment tool based on demographic, lifestyle and disease prevention in the general population. simple anthropometric measures. Med J Aust (in press). Med J Aust, 2009;191:300–302. Barr EL, Cameron AJ, Balkau B, Zimmet PZ, Welborn T, Cameron AJ, Dunstan DW, Owen N, Zimmet PZ, Barr Tonkin AM, Shaw JE. HOMA insulin sensitivity index, ELM, Tonkin AM, Magliano D, Murray SG, Welborn TA, hyperglycaemia and the risk of all-cause mortality and Shaw JE. Health and mortality consequences of cardiovascular disease in the general population abdominal obesity: evidence from the AusDiab study. – the AusDiab study. Diabetologia (in press). Med J Aust, 2009;191:202–208. Dennekamp M, Akram M, Abramson MJ, Tonkin AM, Tonkin AM, Beauchamp A, Stevenson CN. Sim MR, Fridman M, Erbas B. The role of outdoor air The importance of extinguishing secondhand smoke. pollution as a trigger for an out-of-hospital cardiac arrests. Circulation, 2009;120:1339–1341. Epidemiology (in press). Cui J, Forbes A, Kirby A, Simes J, Tonkin A. Cameron AJ, Sicree RA, Zimmet PZ, Albert KGMM, Laboratory and non-laboratory based risk prediction Tonkin AM, Balkau B, Tuomilhto J, Chitson P, Shaw JE. models for secondary prevention of cardiovascular Cutpoints for abnormal waist circumference in Europids disease: the LIPID study. Eur J Cardiovasc Prev Rehabil, and South Asians: An evaluation of methods and 2009;16:660–668. re-assessment of association with incident Type 2 diabetes. Obesity (in press). Driscoll A, Worrall-Carter L, Hare DL, Davidson PM, Riegel B, Tonkin A, Stewart S. Evidence-based chronic Rostambeigi N, Tonkin A, Atkins R, Ghanbarian A, heart failure management programs: reality or myth? Cameron A, Forbes A, Momenan AA, Hadaegh F, Qual Saf Health Care, 2009; 18: 450–5. Mirmiran P, Zimmet P, Azizi F, Shaw J. Waist circumference has heterogenous impact on the metabolic syndrome related outcomes in different ethnicities. Diabetes Res Clin Prac (in press). Centre of Cardiovascular Research and Education in Therapeutics | 33 Kritharides L, Brown A, Jeremy R, Tonkin A, Walsh W, Thrift AG, Dewey HM, Sturm JW, Srikanth VK, Gilligan AK, White H. Overview and determinants of CV disease Gall SL, Macdonnell RAL, McNeil JJ, Donnan GA. in Indigenous populations. Heart Lung and Circulation Incidence of Stroke Subtypes in the North East Melbourne (in press). Stroke Incidence Study (NEMESIS): Differences between Men and Women. Neuroepidemiology, 2009;32(1):11–18. Curtis AJ, Stoelwinder JU, McNeil JJ. Management of waiting lists needs sound data. Walls HL, McNeil JJ, Peeters A. Population Versus Med J Australia, 2009;191(8):423–424. High-risk Interventions for Obesity. Epidemiology, 2009;20(6):929–930. Evans SM, Cameron PA, McNeil JJ. Reforming NSW Health: the importance of using Walls H, Wolfe R, Haby M, Magliano D, de Courten M, credible data. Med J Aust, 2009;190(9):515. Reid C, McNeil JJ, Shaw, J. Trends in BMI of Urban Australian Adults, 1980–2000. Public Health Nutr. Gabbe BJ, Bailey M, Cook JL, Makdissi M, Scase E, 2009;22:1–8 (Epub ahead of print). Ames N, Wood T, McNeil JJ, Orchard JW. The association between hip and groin injuries in the elite junior football Myles PS. What's new in trial design: propensity scores, years and injuries sustained during elite senior competition. equivalence, and non-inferiority. J Extra Corpor Technol. Br J Sports Med, 2009; [Epub ahead of print]. 2009 Dec;41(4):P6–10. Haller G, Stoelwinder J, Myles P, McNeil JJ: Leslie K, Myles PS, Forbes A, Chan MT. The Effect Quality and Safety indicators in Anesthesia: of Bispectral Index Monitoring on Long-Term Survival Anesthesiology, 2009;110(5):1158–1175. in the B-Aware Trial. Anesth Analg. 2009 Nov 12 (Epub ahead of print). Lowthian JA, Diug BO, Evans SM, Maxwell EL, Street AM, Piterman L, McNeil JJ. Who is responsible for the care Leslie K, Chan MT, Myles PS, Forbes A, McCulloch TJ. of patients treated with warfarin therapy? Med J Aust, Posttraumatic Stress Disorder in Aware Patients from 2009;190(12):674–677. the B-Aware Trial. Anesth Analg. 2009 Oct 27 (Epub ahead of print). Ngo DT, Sverdlov AL, McNeil JJ, Horowitz JD. Correlates of arterial stiffness in an ageing population: Haller G, Myles PS, Taffé P, Perneger TV, Wu CL. role of asymmetric dimethylarginine. Pharmacol Res. Rate of undesirable events at beginning of academic year: 2009;60(6):503–507. retrospective cohort study. BMJ. 2009 Oct 13;339:b3974. Ngo DT, Sverdlov AL, Willoughby SR, Nightingale AK Story DA, Fink M, Leslie K, Myles PS, Yap SJ, Beavis V, Chirkov YY, McNeil JJ, Horowitz JD. Determinants of Kerridge RK, McNicol PL. Perioperative mortality risk score occurrence of aortic sclerosis in an aging population. using pre- and postoperative risk factors in older patients. JACC Cardiovasc Imaging, 2009;2(8):919–927. Anaesth Intensive Care. 2009 May;37(3):392–8. Nichol AD, Cooper DJ. POLAR Study Investigators on Todd MM, Hindman BJ, Clarke WR, Torner JC, Weeks JB, behalf of the ANZICS-Clinical Trials Group; EPO Study Bayman EO, Shi Q, Spofford CM; IHAST Investigators. Investigators on behalf of the ANZICS-Clinical Trials Group. Perioperative fever and outcome in surgical patients with Can we improve neurological outcomes in severe aneurysmal subarachnoid hemorrhage. Neurosurgery. traumatic brain injury? Something old (early prophylactic 2009 May;64(5):897–908. hypothermia) and something new (erythropoietin). Injury, 2009;40(5):471–478. Haller G, Stoelwinder J, Myles PS, McNeil J. Quality and safety indicators in anesthesia: a systematic review. Polizzotto MN, Phillips LE, Cannell P, Cohney S, Davies C, Anesthesiology. 2009 May;110(5):1158–75. Opat SS, McNeil JJ, Wood EM. The Thrombotic thrombocytopenic purpura registry: a new national Myles PS, Daly D, Silvers A, Cairo S. Prediction of resource to inform patient care and medical research. neurological outcome using bispectral index monitoring Internal Medicine Journal, 2009;39(1):72–73. in patients with severe ischemic-hypoxic brain injury undergoing emergency surgery. Anesthesiology. Ronaldson KJ, McNeil JJ. Improving drug safety by 2009 May;110(5):1106–15. locating genetic markers for hypersensitivity reactions. Med J Aust, 2009;190(11):641–643. 34 | Annual Report 2009 Myles PR, Hubbard RB, McKeever TM, Pogson Z, Smith CJ, Myles PS, Leslie K, Peyton P, Paech M, Forbes A, Gibson JE. Risk of community-acquired pneumonia and Chan MT, Sessler D, Devereaux PJ, Silbert BS, Jamrozik the use of statins, ace inhibitors and gastric acid K, Beattie S, Badner N, Tomlinson J, Wallace S. Nitrous suppressants: a population-based case-control study. oxide and perioperative cardiac morbidity (ENIGMA-II) Pharmacoepidemiol Drug Saf. 2009 Apr;18(4):269–75. Trial: rationale and design. ANZCA Trials Group. Am Heart J. 2009 Mar;157(3):488–494.e1. Buchanan FF, Myles PS, Cicuttini F. Patient sex and its influence on general anaesthesia. Anaesth Intensive Care. Story DA, Fink M, Leslie K, Myles PS, Yap SJ, Beavis V, 2009 Mar;37(2):207–18. Review. PubMed PMID: Kerridge RK, McNicol PL. Perioperative mortality risk score 19400484. using pre- and postoperative risk factors in older patients. Anaesth Intensive Care, 2009 May;37(3):392–8. Myles PS. Bispectral index monitoring in ischemic-hypoxic brain injury. J Extra Corpor Technol. 2009 Mar;41(1):P15–9. Ramchandra R, Hood SG, Denton DA, Woods RL, McKinley MJ, McAllen RM, May CN. Basis for the Myles PS, Leslie K, Peyton P, Paech M, Forbes A, preferential activation of cardiac sympathetic nerve activity Chan MT, Sessler D, Devereaux PJ, Silbert BS, in heart failure. Proceedings of the National Academy of Jamrozik K, Beattie S, Badner N, Tomlinson J, Wallace S; Science USA, 2009;106(3):924–928. ANZCA Trials Group. Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: rationale and design. Woods RL, Tonkin AM, Nelson MR, Reid CM. Should Am Heart J. 2009 Mar;157(3):488–494.e1. aspirin be used for the primary prevention of cardiovascular disease in people with diabetes [editorial]? Medical Journal Silbert BS, Myles PS. Is fast-track cardiac anesthesia of Australia, 2009;190:614–615. now the global standard of care? Anesth Analg. 2009 Mar;108(3):689–91. Woods RL, Nelson MR, Tonkin AM, Reid CM. In reply: Should aspirin be used for the primary prevention of Pasternak JJ, McGregor DG, Lanier WL, Schroeder DR, cardiovascular disease in people with diabetes [editorial]? Rusy DA, Hindman B, Clarke W, Torner J, Todd MM; Medical Journal of Australia, 2009;191(6):356–357. IHAST Investigators. Effect of nitrous oxide use on long-term neurologic and neuropsychological outcome Driscoll A, Davidson P, Clark R, Huang N and Aho Z in patients who received temporary proximal artery on behalf of National Heart Foundation consumer occlusion during cerebral aneurysm clipping surgery. resource working group. Tailoring Consumer Resources Anesthesiology. 2009 Mar;110(3):563–73. To Enhance Self-Care In Chronic Heart Failure. Australian Critical Care Journal, 2009;22:133–140. Daly DJ, Myles PS. Update on the role of paravertebral blocks for thoracic surgery: are they worth it? Cameron J, Worrall-Carter L, Driscoll A, and Stewart S. Curr Opin Anaesthesiol. 2009 Feb;22(1):38–43. Measuring self-care in chronic heart failure: a review of the psychometric properties of clinical instruments. McIlroy DR, Myles PS, Phillips LE, Smith JA. Journal of Cardiovascular Nursing, 2009;24(6):10–22. Antifibrinolytics in cardiac surgical patients receiving aspirin: a systematic review and meta-analysis. Clark RA, Driscoll A, Davidson PM. Access and quality Br J Anaesth. 2009 Feb;102(2):168–78. of Heart Failure Management Programs in Australia. Australian Critical Care Journal, 2009; 22:111–116. Wallace S, Myles P. 2009 Solving the challenges of large multicenter trials in Anesthesia. 26th Aug HSR. Lee C, Riegel B, Driscoll A, Suwanno J, Moser DK, PROCEEDINGS. Lennie TA, Dickson VV, Cameron J, Worrall-Carter L. Gender Differences in Heart Failure Self-Care: A Leslie K, Myles PS, Forbes A, Chan MT. The Effect Multinational Cross-Sectional Study. International of Bispectral Index Monitoring on Long-Term Survival Journal of Nursing Studies 2009;46:1485–1495. in the B-Aware Trial. Anesth Analg. 2009 Nov 12. Riegel B, Driscoll A, Suwanno J, Moser D, Dickson VV, Leslie K, Chan MT, Myles PS, Forbes A, McCulloch TJ. Carlson B, Cameron J. An International Perspective on Posttraumatic Stress Disorder in Aware Patients from Heart Failure Self-Care. Journal of Cardiac Failure, the B-Aware Trial. Anesth Analg. 2009 Oct 27. 2009;15(6):508–516. Centre of Cardiovascular Research and Education in Therapeutics | 35 Books Tonkin A (ed.).Therapeutic Strategies in Lipid Disorders. Clinical Publishing, Oxford, 2009 Book chapters Haas SJ, Thien F, Tonkin AM, Kong DCM, Nelson MR, Demos L, Zimmet H, Krum H, Liew D, McNeil JJ. Clozapine-associated myocarditis and cardiomyopathy – It's the heart that is important, not the classification. In: P.H. Bruno and M.T. Giordano (editors). Cardiomyopathies: Effects, Causes and Treatments; Nova Science Publishers, Inc: Nova Biomedical Books, 2009 pp251–283. Chen L, Tonkin AM. Absolute risk assessment in the general population. In: Tonkin A (ed.) Therapeutic Strategies in Lipid Disorders. Clinical Publishing, Oxford 2009. Tonkin A. The expanded evidence base and translation to improved outcomes. In: Tonkin A (ed.) Therapeutic Strategies in Lipid Disorders. Clinical Publishing, Oxford 2009. 36 | Annual Report 2009 Centre of Cardiovascular Research and Education in Therapeutics | 37 Contact Centre of Cardiovascular Research and Education in Therapeutics Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine Monash University Level 6, The Alfred Centre 99 Commercial Road Melbourne, Victoria 3004 Telephone: +61 3 9903 0048 Fax: +61 3 9903 0556 Email: firstname.lastname@example.com Website: www.ccretherapeutics.org.au Disclaimer: The information in this report was correct at the time of publication. Monash University reserves the right to alter this information should the need arise. CRICOS provider: Monash University 00008C. May 2010. TSG262339
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