This is Case Study Six for the Research Impacts study.
(Left to Right) Research Professor Chris Charles, Research Associate Professor Chris Pemberton, Professor Richard Troughton, Professor Vicky Cameron, Professor Mark Richards.
Participants interviewed for the case study
Professor Mark Richards
Director, Christchurch Heart Institute; Professor in Medicine, University of Otago
National Heart Foundation Professor of Cardiovascular Studies Consultant Cardiologist, Canterbury District Health Board
Professor Vicky Cameron
Group Leader, The Omics Laboratory, Christchurch Heart Institute
Deputy Dean, University of Otago Christchurch
Professor Richard Troughton
Co-Director Clinical Studies, Christchurch Heart Institute Consultant Cardiologist, Christchurch District Health Board
Research Associate Professor Chris Pemberton
Director, Translational Biodiscovery Laboratory, Christchurch Heart Institute
Professor James (Jim) Januzzi
Professor, Harvard Medical School
Cardiologist, Massachusetts General Hospital, United States of America
Summary of the impact
The world-leading research of the Christchurch Heart Institute (CHI), based at the University of Otago, Christchurch, has influenced international clinical practice in the area of heart failure (HF). The research team has undertaken pioneering work with B-type natriuretic peptide (BNP) and amino-terminal pro B-type natriuretic peptide (NT-proBNP), including the discovery of circulating NT-proBNP. Both biomarkers are now widely used and endorsed by all authoritative international guidelines for HF diagnosis, prognosis and management. NT-proBNP is the single most widely used blood test (measured hundreds of thousands of times per year) for HF diagnostics and prognostics globally, resulting in improved health outcomes for patients and wider economic benefit. The impact of the CHI is the result of 35 years of sustained high-quality research from the team of biomedical scientists and clinicians, through a desire to continuously improve patient outcomes and clinical practice.
“The BNP story has had a major impact – it’s changed how people diagnose and treat heart failure, and to some extent heart attack, not only in New Zealand, but internationally. It has put New Zealand on the map, a contribution to the global effort.”
Professor Vicky Cameron – Group Leader, The Omics Laboratory, Christchurch Heart Institute
The CHI was formerly named the Christchurch Cardioendocrine Research Group (CCERG) by Professor Richards when he recruited researchers from multiple disciplines to form a cohesive group in the 1990s. The CCERG represented a more formal alliance of previous looser collaborations between Christchurch academic cardiology and endocrinology investigators, which had its origins in the early 1980s. Over the past 35 years the CHI has played a leading role in characterising the biochemistry, bioactivity and biomarker value of a wide range of peptides, most notably the natriuretic peptides (NPs) - circulating hormones generated by the heart – and developing these as cardiac biomarkers (indicators of heart disease, such as HF). NPs participate in maintaining total body balance of fluid and electrolytes and are therefore essential to life.
HF occurs when the heart is unable to sustain an adequate circulation of blood to meet the body’s needs1. It is a leading cause of death and disability worldwide, affecting 80 000 New Zealanders2. HF has a high mortality rate, with up to 40 per cent of patients not surviving one-year post diagnosis3 and 15–50 per cent of patients readmitted to hospital within 6 months of discharge4. HF is the single most common cause of medical admissions to hospital in those aged over 60 years. Internationally HF is responsible for ~2 per cent of total healthcare costs, with hospitalisation being a major cost to health care systems.5, 6
The work of the CHI team is comprehensive, with over 200 research papers produced on cardiac biomarkers in heart failure. Selected highlights are described in the following paragraphs.
Professor Mark Richards came to Christchurch in 1983. Just prior to this, in 1981, the first direct evidence of the first NP to be discovered was published from a Canadian centre7. ANP (atrial natriuretic peptide, a type of NP produced mainly by the atria8) was sequenced in 1984 by Japanese workers. Richards worked with pioneering colleagues Professor Gary Nicholls, Emeritus Professor Eric Espiner, Professor Hamid Ikram and Associate Professor Tim Yandle to provide the first data on the integrated cardiovascular, kidney and hormonal effects of ANP in humans, and showing it was produced by heart tissue9.
BNP (another type of NP originating from the heart) was discovered in 1988 by Japanese scientists, and soon after this CHI researchers Professor Mark Richards, Emeritus Professor Eric Espiner and Associate Professor Tim Yandle developed an assay (a test to detect the protein). Associate Professor Tim Yandle and the cardiology team confirmed that BNP circulated in human plasma, and that there was a different predominant form of it in people with HF10. After studying different isoforms of NPs and developing measuring methods, the idea was born to measure NT-proBNP (the inert fragment of the pro-BNP hormone that is cleaved from the bioactive BNP peptide) levels as a biomarker of HF. The group first published evidence of circulating NT-proBNP in humans in 1995. Major commercial interest from Roche Pharmaceuticals in the CHI research sparked the creation of the NT-proBNP test.
CHI researchers began using measurement of BNP to test patients for acute heart failure in the Christchurch emergency department (ED) in 1993. Patients presenting with breathlessness were subjected to the test and Dr Mark Davis and the team showed that HF patients had high levels of BNP compared to those who did not have a cardiac problem. This was published in The Lancet in 199411, triggering many replication studies around the world confirming that BNP is diagnostic of acute HF in people with shortness of breath in the EDeg 12,13,14.
The important results from the CHI research were later expanded in 2004, when Professor Mark Richards and Professor James Januzzi from the Harvard Medical School formed the International Collaborative of NT-proBNP, or ICON research study15. This multi-centre, international study confirmed that NT-proBNP testing had high diagnostic value for detection of acute heart failure and in predicting the prognosis of patients with shortness of breath who were suspected or confirmed to have acute HF. Furthermore, it provided important cut-off values of NT-proBNP, now enshrined in international clinical guidelines, to guide clinical decision making.
The CHI conducted the first ever trial of heart failure management guided by serial measurement of NT-proBNP20. This demonstrated benefit and triggered more than one dozen further trials by centres around the world. A meta-analysis of worldwide studies involving over 2000 patients undertaken in 201416, led by Professor Richard Troughton (Co-director Clinical Studies, CHI), provided compelling evidence that using BNP or NT-proBNP as a clinical guide (NP-guided patients) resulted in reduced all-cause mortality in those less than 75 years old. Additionally, hospitalisation due to heart failure or cardiovascular disease was significantly lower in NP-guided patients.
A recent clinical trial17 has found that a new drug called Entresto, that acts in part by blocking the breakdown of BNP and ANP, resulted in a 20 per cent risk reduction in mortality and new hospitalisation for HF compared with those receiving current ACE-inhibitor therapy. This is the biggest improvement in HF therapies for 20 years.
The randomized clinical trial IMPERATIVE-HF, comparing peri-discharge management (adjusting treatment if NP levels are raised) of Acute Decompensated Heart Failure with usual clinical care, finished data collection in 202018. This trial will determine if NP-guided care, around the time of hospital admissions for episodes of worsening heart failure, has better outcomes compared to standard care.
Key research of the CHI group includes:
- The first group to demonstrate the biological actions of ANP in humans.
- Showing BNP can be used in the diagnosis of HF (1994) and as an indicator of disease status11.
- Discovery of NT-proBNP in 1995, which is part of the BNP precursor19.
- Being the first group to show that treatment for HF can be altered using NT-proBNP levels as a guide. This RCT was published in The Lancet (2000)20.
- Showing that NP levels increase after myocardial infarction (MI; heart attack), and can be used to predict outcomes in MI patients21.
- Further refining the use of NPs in HF diagnosis, for example by studying NP levels in different age groups.
- Improving the diagnostic performance of NP tests. They have found that supplementing NT- proBNP testing with mid-region pro-ANP or micro-RNA tests22 leads to improved diagnostic accuracy.
- Professor Richards has shown that BNP/NT-proBNP levels can identify patients who respond to heart failure treatments – in particular, he showed this for beta-blocker therapy in heart failure. It was shown that NT-proBNP and BNP above certain thresholds predict benefit from beta blocker therapy in coronary heart disease.
- Health Research Council (HRC) - continuous Programme Grant funding for the past 27 years, which has exceeded $20 million. Additionally, multiple HRC Project Grants have been funded, of which four are current, including the IMPERATIVE-HF study.
- NZ Heart Foundation - multiple fellowships and project grants are held by group members.
- Since 1997 the Heart Foundation has funded Professor Mark Richards in its Chair of Cardiovascular Studies, which provides resources including long-term salary support for key CHI clinical and laboratory staff members.
- Ministry of Business, Innovation and Employment
- Canterbury Medical Research Fellowship (project grants and fellowships)
- Lotteries Health
- Christchurch Heart Institute Trust
- The team has produced over 200 papers on cardiac biomarkers in heart failure.
- The article Treatment of heart failure guided by plasma amino-terminal brain natriuretic peptide (N-BNP) concentrations from 200017 has over 1200 citations23.
- CHI research on NT-proBNP has been cited in 117 granted patents in the United States and Australia (PatCite).
- There has been extensive news coverage on the research within New Zealand (for example, the New Zealand Herald24, the Otago Daily Times25 and the Press26, as well as overseas in Australia27, China28 and South Africa29.
Details of the impact
Heart Failure treatment guidelines
Research from the CHI has appeared in multiple international guidelines, including:
- The American Heart Association (AHA) Guideline for the Management of Heart Failure30 have made Class I (strong) recommendations for the use of biomarkers in diagnosis and prognosis. The AHA has also released a Scientific Statement on the Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure, citing CHI work31.
- UK National Institute for Health and Care Excellence (NICE) Guidelines on Acute Heart Failure32.
- The European Society of Cardiology Acute and Chronic Heart Failure Guidelines33.
- The National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Guidelines for the Prevention, Detection, and Management of Heart Failure in Australia34.
- NT-proBNP is the single most widely used blood test (measured hundreds of thousands of times per year) for HF diagnostics and prognostics globally.
- NT-proBNP is used as an inclusion criterion and as a surrogate endpoint for HF trials. It helps to select the right participants for trials and to indicate presence or lack of benefit from innovative therapies.
- Use of NT-proBNP has been shown to be cost effective in multiple international studies3, 35–37. One study showed the use of NT-proBNP decreases the lifetime cost of care per patient by $176 000 USD for men, and $101 000 USD for women35. Another showed NT-pro BNP use reduces the medical costs of ED visits, hospitalisations and outpatient services37.
- Patients are diagnosed with HF faster and more accurately, leading to shorter hospital stay30, 33, reduced stay in ED31, fewer readmissions to hospital31 and reduction of the mortality rate 3, 32.
- Patients experience better quality of care, improved quality of life, and improved wellbeing 3, 35, 36.
- There is a reduction in hospitalisations and intensive care admissions38.
- Major commercial interest was received from Roche Diagnostics, who led the development of NT-proBNP as a test.
- Professor Mark Richards is a founder, and Associate Professor Chris Pemberton is a founder and Chief Scientific Officer of the spin-out company Upstream Medical Technologies. This company is developing tests to speed up the diagnosis of another heart condition, unstable angina25.
- Thousands of papers have now been written on BNP and NT-proBNP from a worldwide network of people, which is incrementally adding to CHI research. The Medline database shows 13,799 articles have been written on BNP since 199039.
- The CHI team is engaged in postgraduate supervision and the teaching of advanced degrees across preclinical basic science and in clinical areas in order to develop the next generation of researchers, who will further improve clinical outcomes for patients.
Pathway to impact
- The research environment and infrastructure has been important to enhance the collaborative nature of CHI studies, in particular the recent NT-proBNP studies, which have been nested within clinical care and integrated with the Canterbury District Health Board and Christchurch Hospital.
- The CHI has a strong working relationship with Professor Rob Doughty’s group at the University of Auckland (and prior to that Professor Norman Sharpe). For example, IMPERATIVE-HF is a two-centered study conducted in partnership with Auckland.
- There has been an excellent link between endocrine and cardiology researchers, basic scientists and clinicians within the CHI, resulting in ongoing fruitful cross-disciplinary conversation and mutual support.
- In 2016–17, the CHI launched a charity partnership with Ryman Healthcare and received $330,000 of funding to undertake a study about cardiovascular disease risk in New Zealand’s retirement healthcare sector40. Residents take part in research trials and benefit from education and improved care through this process.
- Other researchers actively seek to collaborate with CHI. Currently, 29 per cent of CHI research output on BNP has been done with collaborating authors (SciVal).
- The CHI has strong international collaborative links. Being located in New Zealand, away from large centers of cardiovascular research presents challenges. In recent years Professor Richards has spent a proportion of his time at the National University of Singapore, as founder of that University’s Cardiovascular Research Institute (CVRI), enabling access to large cohorts of Asian patients and expanding collaboration for the CHI. The CHI is also been a part of major international research studies, for example the ICON, GREAT, MAGGIC, GIANT and BIOS biomarker and heart failure research consortia15.
“What sets them apart from a lot of very successful research teams is their collaborative nature, which has increased the impact of the research that they’ve done.”
Professor James Januzzi – Harvard Medical School Cardiologist, Massachusetts General Hospital, USA.
- Community engagement is a large part of the CHI ethos. The senior leaders of the group have given over 90 public lectures in the past five years, including to the University of the Third Age, Probus, Rotary, and talks in conjunction with the Heart Foundation and Ryman Healthcare.
- Hui are arranged with Māori participants, and studies are designed to oversample Māori and Pacific participants.
“We must give talks to the general public. Don’t be shy about saying ‘this is what I do, and this is how your money is being used.’”
Research Associate Professor Chris Pemberton – Director, Translational Biodiscovery Laboratory, Christchurch Heart Institute
Planning for impact
- Undertaking basic work on the biology of NPs and then in parallel subsequently developing their application as clinically useful biomarkers is an excellent example of translational (bench to bedside and back) research.
- CHI researchers actively take opportunities to publicise their work. For example, Professor Mark Richards has spoken to members of learned societies on over 280 occasions.
- By disseminating research results, traction is gained for further research and for application of the research. For example, with BNP, American and European interest was generated in the early 2000s, resulting in translation to treatment guidelines and the NT-proBNP test being created by Roche Diagnostics.
- The CHI uses the media team at the University of Otago to distribute press releases. This helps to inform the public and other scientists about the research they are doinge.g. 41. The CHI leadership also independently interacts with print and visual media and co-ordinates its own newsletter and Facebook account.
- Research Associate Professor Chris Pemberton and Dr Andree Pearson are leading a study called CHAMPIONZ looking at cardiovascular risk in residents in the Ryman rest homes.
- The current HRC Programme Grant is wrapping up, so planning is underway for the area of focus for the next Programme Grant, which will be on acute coronary heart disease and its management. Coronary heart disease is the major precursor to heat failure. This work will take advantage of the improved integration of health data sets and information, including the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry. The other theme of this work will be tailoring treatment to fit individual patients.
- Health Navigator New Zealand, Heart Foundation of New Zealand. Heart failure 2019.
- Foundation NZH. NZ-led heart failure findings debunk world medical view. 2018.
- Pufulete M, Maishman R, Dabner L, Mohiuddin S, Hollingworth W, Rogers CA, et al. Effectiveness and cost-effectiveness of serum B-type natriuretic peptide testing and monitoring in patients with heart failure in primary and secondary care: an evidence synthesis, cohort study and cost-effectiveness model. Health technology assessment (Winchester, England). 2017;21(40):1-150.
- Adlbrecht C, Huelsmann M, Berger R, Moertl D, Strunk G, Oesterle A, et al. Cost analysis and cost-effectiveness of NT-proBNP-guided heart failure specialist care in addition to home-based nurse care. European journal of clinical investigation. 2011;41(3):315-22.
- Bundkirchen A, Schwinger RH. Epidemiology and economic burden of chronic heart failure. European Heart Journal Supplements. 2004;6 (suppl_D):D57-D60.
- McMurray JJ, Stewart S. Epidemiology, aetiology, and prognosis of heart failure. Heart. 2000;83(5):596-602.
- de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sciences. 1981;28(1):89-94.
- Vivo pathophysiology. Atrial naturetic hormone. 2018.
- Richards A, Ikram H, Yandle T, Nicholls M, Webster M, Espiner E. Renal, haemodynamic, and hormonal effects of human alpha atrial natriuretic peptide in healthy volunteers. The Lancet. 1985;325(8428):545-9.
- Yandle T, Richards A, Gilbert A, Fisher S, Holmes S, Espiner E. Assay of brain natriuretic peptide (BNP) in human plasma: evidence for high molecular weight BNP as a major plasma component in heart failure. The Journal of Clinical Endocrinology & Metabolism. 1993;76(4):832-8.
- Davis M, Espiner E, Yandle T, Richards G, Town I, Neill A, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. The Lancet. 1994;343(8895):440-4.
- O’Donoghue M, Chen A, Baggish AL, Anwaruddin S, Krauser DG, Tung R, et al. The effects of ejection fraction on N-terminal ProBNP and BNP levels in patients with acute CHF: analysis from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Journal of cardiac failure. 2005;11(5):S9-S14.
- Barcarse E, Kazanegra R, Chen A, Chiu A, Clopton P, Maisel A. Combination of B-type natriuretic peptide levels and non-invasive hemodynamic parameters in diagnosing congestive heart failure in the emergency department. Congestive Heart Failure. 2004;10(4):171-6.
- Harrison A, Morrison LK, Krishnaswamy P, Kazanegra R, Clopton P, Dao Q, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Annals of emergency medicine. 2002;39(2):131-8.
- Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J, Santalo-Bel M, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. European heart journal. 2005;27(3):330-7.
- Troughton RW, Frampton CM, Brunner-La Rocca H-P, Pfisterer M, Eurlings LWM, Erntell H, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. European Heart Journal. 2014;35(23):1559-67.
- McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. The New England Journal of Medicine. 2014;371:993-1004.
- Registry ANZCT. Trial registered on ANZCTR. 2014.
- Hunt P, Richards A, Nicholls M, Yandle T, Doughty R, Espiner E. Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clinical Endocrinology. 1997;47(3):287-96.
- Troughton RW, Frampton CM, Yandle TG, Espine EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. The Lancet. 2000;355(9210):1126-30.
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- Ellis KL, Cameron VA, Troughton RW, Frampton CM, Ellmers LJ, Richards AM. Circulating microRNAs as candidate markers to distinguish heart failure in breathless patients. European Journal of Heart Failure. 2013;15(10):1138-47.
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