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Volume 46, Issue 6, June 2016, Pages 643–754

INTERNAL MEDICINE JOURNAL

Spine-width: 3.7mm

Paper-type: UPM Classic 64

Volume

46

Issue

6

June

2016

ISSN 1444-0903

INTER NAL MEDICINE JOUR NAL

BANDAID2: a mnemonic for treatment of heart failure Idiopathic pulmonary fibrosis in Australia Methamphetamine-associated cardiomyopathy Oral immunisation for H. influenzae in chronic obstructive pulmonary disease Food, lifestyle and inflammatory bowel disease Patient and healthcare worker attitudes to eHealth

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Honorary Advisory Board

Editor-in-Chief Jeff Szer, Melbourne

Continuing Education Deputy Editor-in-Chief Deputy Editor-in-Chief Zoltan Endre, Sydney

Paul Bridgman, Christchurch

Subspecialty Editors Cardiology (General) Paul Bridgman, Christchurch

Infectious Diseases David Gordon, Adelaide

Cardiology (Arrhythmias) Andrew McGavigan, Adelaide

Intensive Care Michael O’Leary, Sydney

Clinical Genetics Les Sheffield, Melbourne

Internal Medicine Ian Scott, Brisbane

Clinical Pharmacology Jenny Martin, Newcastle Yvonne Bonomo, Melbourne (Addiction Medicine)

Nephrology Zoltan Endre, Sydney

Continuing Education (Clinical Perspectives) Christopher Pokorny, Sydney Emergency Medicine Joseph Ting, Brisbane Endocrinology Morton Burt, Adelaide Anthony Russell, Brisbane Ethics Paul Komesaroff, Melbourne Gastroenterology David M. Russell, Melbourne Geriatric Medicine Leon Flicker, Perth Haematology (General) Peter Browett, Auckland

Peter Doherty, Melbourne Kar Neng Lai, Hong Kong Richard Larkins, Melbourne Sir Gustav Nossal, Melbourne Lawrie W. Powell, Brisbane Nicholas Saunders, Newcastle John Shine, Sydney Chorh Chuan Tan, Singapore Sir David Weatherall, Oxford Judith Whitworth, Canberra Editorial Ombudsman Graham Macdonald, Sydney Manager Virginia Savickis, Sydney

Neurology David Blacker, Perth Nuclear Medicine Frederick A. Khafagi, Brisbane Occupational and Environmental Medicine; Health Economics; Editorials Editor Des Gorman, Auckland Oncology Damien Thomson, Brisbane Palliative Medicine Janet Hardy, Brisbane

Editorial Assistant Aparna Avasarala, Sydney Previous Editors-in-Chief Internal Medicine Journal Edward Byrne (1999–2004) The Australian and New Zealand Journal of Medicine Graham Macdonald (1989–1999) Michael O'Rourke (1981–1989) Akos Z. Gyory (1975–1981) Charles Kerr (1970–1975) The Australasian Annals of Medicine Ronald Winton (1957–1970) Mervyn Archdall (1952–1956)

Public Health Medicine Mark Ferson, Sydney Respiratory Medicine Matthew Naughton, Melbourne

Haemostasis/Thrombosis Claire McLintock, Auckland

Rheumatology Peter Youssef, Sydney

Immunology and Allergy Marianne Empson, Auckland

Sexual Health Medicine Darren Russell, Cairns

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aims and scope The Internal Medicine Journal, formerly known as the Australian and New Zealand Journal of Medicine, is the official journal of the Adult Medicine Division of The Royal Australasian College of Physicians (RACP). Its purpose is to publish high-quality internationally competitive peer-reviewed original medical research, both laboratory and clinical, relating to the study and research of human disease. Papers will be considered from all areas of medical practice and science. The Journal also has a major role in continuing medical education and publishes review articles relevant to physician education. Except where otherwise stated, articles are peer reviewed.

abstracting and indexing This journal is indexed by Abstracts on Hygiene and Communicable Diseases, AgBiotech News and Information, AIDS Abstracts, Australian Medical Index, BIOBASE, Biological Abstracts (BIOSIS), Biomedical Reference (EBSCO), Cambridge Scientific Abstracts, Chemical Abstracts Service, Current Contents/Clinical Medicine (an ISI product), Derwent Biotechnology Abstracts, EMBASE/Excerpta Medica, Environmental Sciences and Pollution Management, Health and Safety Science Abstracts (Online version), Helminthological Abstracts, InPharma Weekly, International Pharmaceutical Abstracts (IPA), Journals @ Ovid, MEDLINE, Nutrition Abstracts and Reviews, Pharmacoeoconomics and Outcomes News, Reactions Weekly, Science Citation Index, SCOPUS, Tropical Diseases Bulletin, Vitis-Viticulture and Oenology Abstracts

(Online Edition), World Agricultural Economics and Rural Sociology Abstracts, and CINAHL.

address for editorial correspondence Editor-in-Chief, Internal Medicine Journal, The Royal Australasian College of Physicians, 145 Macquarie Street, Sydney, NSW 2000, Australia (tel: +61 2 9256 5431; fax: +61 2 9252 3310). For enquiries regarding ScholarOne Manuscripts (formerly known as ManuscriptCentral) submissions please email [email protected] (e.g. IMJ-0000-2014). General enquiries should be directed to Virginia Savickis, the Editorial Office, Internal Medicine Journal, using imj@ racp.edu.au Comments on published papers are welcomed. Authors are offered right of reply (no more than 500 words) at the discretion of the Editor and discussion will not be entered into. Given the current pressures on editorial space, however, invited comments are restricted to one reply.

disclaimer The Publisher, RACP and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed do not necessarily reflect those of the Publisher, RACP and Editors, neither does the publication of advertisements constitute any endorsement by the Publisher, RACP and Editors of the products advertised. Copyright © 2016 Royal Australasian College of Physicians.

For submission instructions, subscription and all other information visit www.wileyonlinelibrary.com/journal/imj This journal is available online at Wiley Online Library. Visit www.onlinelibrary.wiley.com to search the articles and register for table of contents and email alerts. Wiley’s Corporate Citizenship initiative seeks to address the environmental, social, economic, and ethical challenges faced in our business and which are important to our diverse stakeholder groups. We have made a long-term commitment to standardise and improve our efforts around the world to reduce our carbon footprint. Follow our progress at www.wiley.com/go/citizenship Access to this journal is available free online within institutions in the developing world through the HINARI initiative with the WHO. For information, visit www.healthinternetwork.org ISSN 1444-0903 (Print) ISSN 1445-5994 (Online) IMJ.JEBJan16

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June 2016, Volume 46, Issue 6

Editorial 651

684

Pining for the fjords

J. R. Hardy and C. M. Douglas

R. L. Clancy, M. L. Dunkley, J. Sockler and C. F. McDonald

Review 653

Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID2): an evidence-based mnemonic for the treatment of systolic heart failure

694

N. Chia, J. Fulcher and A. Keech

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Idiopathic pulmonary fibrosis: an Australian perspective

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A survey of Australian and New Zealand clinical practice with neoadjuvant systemic therapy for breast cancer

N. Zdenkowski, P. Butow, G. B. Mann, S. Fewster, C. Beckmore, R. Isaacs, C. Douglas and F. M. Boyle

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The clinical spectrum of omega-5-gliadin allergy

T. A. Le, M. Al Kindi, J.-A. Tan, A. Smith, R. J. Heddle, F. E. Kette, P. Hissaria and W. B. Smith 717

Influence of food and lifestyle on the risk of developing inflammatory bowel disease

O. Niewiadomski, C. Studd, J. Wilson, J. Williams, C. Hair, R. Knight, E. Prewett, P. Dabkowski, S. Alexander, B. Allen, D. Dowling, W. Connell, P. Desmond and S. Bell

Pleural infection in a New Zealand centre: high incidence in Pacific people and RAPID score as a prognostic tool

D. Wong and E. Yap

J. Prasad, A. E. Holland, I. Glaspole and G. Westall

Original Articles

The impact of intensive care in a private hospital on patients aged 80 and over: health-related quality of life, functional status and burden versus benefit

M. Levinson, A. Mills, J. Oldroyd, A. Gellie, J. Barrett, M. Staples and G. Stephenson

Clinical Perspectives 663

Multi-site placebo-controlled randomised clinical trial to assess protection following oral immunisation with inactivated non-typeable Haemophilus influenzae in chronic obstructive pulmonary disease

Current patient and healthcare worker attitudes to eHealth and the personally controlled electronic health record in major hospitals

R. Armani, L. E. Mitchell, J. Allen-Graham, N. R. Heriot, T. Kotsimbos and J. W. Wilson 723

Methamphetamine-associated cardiomyopathy: patterns and predictors of recovery

A. Voskoboinik, J. F. Ihle, J. E. Bloom and D. M. Kaye

Ethics in Medicine 728

Research misconduct: time for a re-think?

K. J. Breen

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June 2016, Volume 46, Issue 6

Brief Communications 734

746

Have the ‘black clouds’ cleared with new residency programme regulations?

Life-threatening hypocalcaemia associated with denosumab in advanced chronic kidney disease

J. P. Killen, K. Yong, G. Luxton and Z. Endre

A. J. Schissler and A. J. Einstein 747 737

Nephrotic syndrome as a complication of chronic graft-versus-host disease after allogeneic haemopoietic stem cell transplantation

E. Wong, M. Lasica, S. Z. He, A. Bajel, A. W. Roberts, K. D. Mason, D. S. Ritchie and J. Szer 742

A case of delayed onset pyroglutamic acidosis in the sub-acute setting

L. Mo, D. L. Liang, A. Madden and A. K. Aung General correspondence 750

The Australian and New Zealand regional neurology training survey

Pulmonary hypertension assessment on echocardiography: more than peak tricuspid regurgitation velocity assessment

J. Ramchand, E. Jones, M. Yudi and P. Calafiore

C. McAulay-Powell and A. Ranta 751

Author reply

M. Nikpour, D. Prior, S. Proudman and W. Stevens

Letters to the Editor Clinical-scientific notes 745

A case of granulomatosis with polyangiitis: rheumatoid arthritis overlap syndrome presenting as cervical cancer successfully treated with rituximab

C. Campochiaro, R. Scotti, S. Margari, V. Giorgione, R. Mellone, G. Mangili, A. Del Maschio and M. Tresoldi

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Methamphetamine-triggered Takotsubo syndrome and methamphetamineassociated cardiomyopathy: a continuum?

J. E. Madias 753

Author reply

A. Voskoboinik

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Internal Medicine Journal (2016)

E D I TO R I A L

Pining for the fjords1

In recent years, the specialty of palliative medicine has placed a major emphasis on encouraging openness in discussions around death. The purpose is twofold: to encourage our medical colleagues to develop the communication skills necessary to support their patients in making decisions around end of life care; and to educate the broader community around the inevitability of death as a normal part of life. Without the ability to talk openly and honestly about the likelihood of death, it is not possible to progress advance care planning, the avoidance of futile investigations, treatments and unnecessary hospital admissions. Palliative Care Australia’s theme in 2015 was ‘Dying to talk, talk about dying won’t kill you’.2 Unless death is discussed and planned for openly, we cannot determine people’s wishes with respect to such important issues as who will provide end of life care, what is the preferred place of death, what is known around prognosis and likely outcome of the disease. How can this be if no-one uses the words ‘death’ or ‘dying’ anymore? It is very discouraging that the ‘d’ word, especially in the popular press and social media, is seen as somehow cruel and disrespectful, to be avoided at all cost. As a consequence, the word is fast disappearing from every day vernacular. Euphemisms for dying abound. People no longer ‘die’. Instead they ‘pass’, ‘expire’, ‘succumb’, ‘depart’ are ‘lost’ or ‘move on’. So often, cancer patients in particular ‘lose their battle’, suggesting they didn’t try hard enough in a fight they had no chance of ever winning. This seems especially true of ‘good people’ (who usually pass away) whereas bad people (such as terrorists) are often ‘dead or are killed and die’. A letter to the editor in The Irish Times, tells of how a pedestrian hit by a car was found to be in a ‘lifeless condition’.3 Even a dead and bloated cow, washed up on a beach was described as ‘deceased’ in the local press. Junior staff in the hospital will inevitably report that a patient has ‘passed away’ over night. One intern was horrified when it was suggested that the patient had in fact died, claiming the statement to be terribly insensitive even though this was a patient with advanced cancer on a palliative care ward. Articles written for hospitals or lay press are inevitably edited to remove any direct mention of ‘dying’. This issue was highlighted recently, when attempts were made to edit an article for this journal on death in a major metropolitan hospital4 by replacing the words ‘died’ and ‘dying’ with ‘expired’ and ‘terminally ill’. © 2016 Royal Australasian College of Physicians

When and why did this phenomenon of death avoidance start to happen? William B Bradshaw reviewed funeral notices, obituaries and news stories in the United States for his Huffington Post blog. He claims that the change from ‘died’ to ‘passed away’ occurred gradually in the 1970s. By 1980, ‘passed away’ was the norm for all obituaries used by funeral homes.5 The change in terminology has been attributed to a developing deathdenial culture in western societies. Medicalisation and marginalisation of death has meant that the doctor and not the priest is the presiding figure at death.6 Death has become to be seen as a failure of modern care and society has become less accepting of the finitude of life.7 ‘Death, so omnipresent in the past that it was familiar… would become shameful and forbidden’.8 In a study of the use of the word ‘death’ by American oncologists in cancer care, only 27% used the word ‘death’ or ‘dying’ frequently in discussions with patients with a limited prognosis and 37% used it infrequently or never. Surprisingly, a much higher proportion discussed death at a first visit but only 5% in the last month.9 Euphemisms for impending death included ‘time is limited’, ‘time to transition to hospice’ and ‘your cancer is getting worse’.9 Although oncologists in a teaching hospital in Australia were more likely than patients or family to use explicit language in discussing death, they generally coupled it with implicit language (euphemisms or indirect talk).10 Even in the setting of a hospice unit, ‘dying’ was infrequently used for patients in the last days of life, whereas the use of the term ‘deteriorating’ was widespread.11 There is the danger that if health professionals are not ‘up front’ in their terminology, not only patients and family, but also staff, might misinterpret meaning. Why does calling death something different make it any easier or less traumatic for others? Most people are understandably very uncomfortable about death; they so rarely encounter the event and it is hard to envisage it ever happening to them. Death no longer occurs at home with family, but in single rooms in hospitals or nursing homes. We acknowledge certain cultural sensitivities. Talking about death or the bearing of bad news may be considered a cause of terminal illness, a curse or a hastener of death in some cultures.12 ‘Finishing up’ is the culturally appropriate reference for ‘sorry business’ (death and dying) within the Indigenous population of Australia 651

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where the use of the terms death or dying may cause discomfort or offence.13,14 This is the only possible argument for generalising the practice in this country. It is possible to use direct language and have conversations around death in a sensitive and kind manner, to ensure better understanding on the part of the patient and their family and help them make end of life decisions. End of life decision-making has been shown to be facilitated by communication strategies that include the use of explicit words such as death and dying, the avoidance of euphemisms, spelling out goals and expectations, and being specific when using words such as ‘hope’ and ‘better’.15 Focus groups including patients, families and healthcare professionals have identified six important themes when communicating with dying patients:

References 1 Chapman G, Cleese J, Gilliam T, Idle E, Jones T, Palin M. Dead parrot sketch. In: Wilmut R, ed. The Complete Monty Python’s Flying Circus: All the Words, Volume One. New York, NY: Pantheon Books; 1989; p. 320 (Appendix). 2 Palliative Care Australia. Living well with chronic illness. 2016. [cited 2016 Mar 30]. http://palliativecare.org.au/ national-palliative-care-week/ 3 ‘Passed away’ letters to the editor (Sean O’Kiersey). The Irish Times. 2016 Jan 13. 4 Douglas C, Clarke M, Alexander S, Khatun M. A tertiary hospital audit of opioids and sedatives administered in the last 24 hours of life. Intern Med J 2016; 46: 325–31. 5 Huffington Post. Died, passed away or passed. 2014. [cited 2016 Mar 30]. http://www.huffingtonpost.com/ william-b-bradshaw/died-passed-awayor-passed_b_6240282.html 6 Phillips JB. The changing presentation of death in the obituary, 1899–1999. Omega 2007; 55: 325–46.

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talking in an honest and straightforward way, being willing to talk about death, giving bad news in a sensitive way, listening, encouraging questions and being sensitive to when patients are ready to talk about death.16 Death happens to us all and to have the best possible death, we need to plan and prepare for it, and call it for what it is. Received 31 March 2016; accepted 6 April 2016. doi:10.1111/imj.13105 1,2

J. R. Hardy

and C. M. Douglas3

1

Department of Palliative and Supportive Care, Mater Health Services, and 2Mater Research–University of Queensland, and 3 Palliative and Supportive Care Services, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

7 Anderson KA, Sielski CL, Miles EA et al. Gardens of stone: searching for evidence of secularization and acceptance of death in grave inscriptions from 1900–2009. Omega 2011; 63: 359–71. 8 Aries P. Western Attitudes Towards Death: From the Middle Ages to the Present. Baltimore, MD: John Hopkins University Press; 1974, 85. 9 Gill AS, Bhandari S, Gosain R, Abraham J et al. Use of the word ‘death’ in cancer care. J Clin Oncol 2014; 32 (Suppl. 15): e20510. 10 Rodriguez KL, Gambino FJ, Butow P, Hagerty R et al. Pushing up the daisies: implicit and explicit language in oncologist-patient communication about death. Support Care Cancer 2007; 15: 153–61. 11 Latten R, Gamble M, Williams EMI, Ellershaw JE. “He’s deteriorating”. Language used by palliative care staff providing care of dying patients. Palliat Med 2010; 24: S83. 12 Hannon B, Zimmerman C, Knaul FM, Powell RA et al. Provision of palliative

13

14

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care in low- and middle-income countries: overcoming obstacles for effective treatment delivery. J Clin Oncol 2016; 34: 62–8. Sad news, sorry business. Guidelines for Caring for Aboriginal and Torres Strait Islander People Through Death and Dying. [cited 2016 Mar 30]. Available from URL: http://www.health.qld.gov. au/atsihealth/documents/sorry_ business.pdf Ray R, Street A, Blackford J. Hear the right story and finish up in country: learning lessons from Aboriginal Australians implementing Advance Care Planning. BMJ Support Palliat Care 2011; 1: 90. Norton SA, Talerico KA. Facilitating end-of-life decision-making: strategies for communicating and assessing. J Gerontol Nurs 2000; 26: 6–13. Wenrich MD, Randall Curtis J, Shannon SE, Carline JD et al. Communicating with dying patients within the spectrum of medical care from terminal diagnosis to death. Arch Intern Med 2001; 161: 868–74.

© 2016 Royal Australasian College of Physicians

REVIEW

Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID2): an evidence-based mnemonic for the treatment of systolic heart failure N. Chia,1,2* J. Fulcher1,2,3* and A. Keech1,2,3 1

NHMRC Clinical Trials Centre, and 2Sydney Medical School, University of Sydney, and 3Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

Key words heart failure, treatment, review, evidence-based medicine, prevention, pharmacotherapy. Correspondence Jordan Fulcher, National Health and Medical Research Council (NHMRC), Clinical Trials Centre, Level 6 Medical Foundation Building, 92–94 Parramatta Road, Camperdown, NSW 2050, Australia. Email: [email protected] . doi:10.1111/imj.12839

Abstract Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline-based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID2, standing for beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega-3 fatty acids, statins or anti-thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence-based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition.

Introduction Heart failure is a chronic disease with significant morbidity and mortality. In Australia, its prevalence rises from 1% at age 50 years to over 50% at 85 years or older, and it is one of the most common reasons for physician consultation and hospital admission in people over 70 years of age.1 Between 20% and 30% of patients with mild to moderate heart failure and 50% of patients with severe heart failure die within a year.2 Several evidence-based *Co-first authors. Funding: This work was supported by funding from the Sydney Medical School and NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia. The sponsors played no role in study design, data collection, data analysis, manuscript preparation or manuscript submission. Conflict of interest: None.


treatments exist that provide both symptomatic and mortality benefits. However, treatment rates are substantially lower than expected rates of intolerance or contraindication – for example, observational data on patient discharges from a regional New South Wales hospital found angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) were prescribed in only 65% of heart failure patients.3 In time-pressured environments of patient care, simple strategies aimed at improving guideline-based prescribing rates are well placed to improve outcomes. Mnemonics are frequently adopted in medical education to recall lists of causes and treatments. The aim of this review was to examine systematically the current evidence base for chronic heart failure treatments in order to derive a contemporary mnemonic for best practice therapies to assist clinicians in their patient care.

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Chia et al.

Methods The primary search aim was to identify treatments that provide mortality, hospitalisation or symptomatic benefits, in comparison with placebo, in chronic systolic heart failure patients. A starting list of treatments (pharmacological and device based) was obtained after reviewing the most recent American College of Cardiology Foundation/American Heart Foundation (ACCF/AHA) Guidelines (2013),4 ESC Chronic Heart Failure Guidelines (2012)5 and Australian National Heart Failure Guidelines (2011).1 For the purpose of this review, highly specialised therapies such as ventricular assist devices and cardiac transplantation were not included. Both MEDLINE and EMBASE databases were used to obtain reference lists based on a structured search strategy (Supporting Information, Appendix S1, p. 1). Titles and abstracts were screened to exclude duplicates and unsuitable articles producing a list of studies in which the full text was assessed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to further determine suitability.6 Meta-analyses of individual patient data from randomised trials were identified as representative of the highest level of evidence. If these were not available, meta-analyses of published trial data were used, providing the baseline trial populations were considered equivalent. If meta-analyses were not available or suitable, individual randomised controlled trials were sought. Additional factors considered in article

selection included the date of publication, the potential for publication bias in meta-analyses, and randomised controlled trial evidence published subsequent to previous meta-analyses. Two co-authors independently performed a literature search, and results were jointly reviewed to derive an optimised reference list for each medication.

Results The search strategy was performed for beta-blockers, ACE inhibitors, ARB, neprilysin inhibitors, hydralazine + isosorbide dinitrate (H-ISDN), diuretics, aldosterone antagonists, ivabradine, automatic implantable cardioverter defibrillator (AICD), cardiac resynchronisation therapy (CRT), digoxin, omega-3 fatty acids, antithrombotic therapies and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) reductase inhibitors (statins). The literature search identified 2527 primary articles after removing duplicates. Of these, 609 manuscripts were selected for full-text review (Fig. 1).

Beta-blockers Long-acting beta-blockers (carvedilol, metoprolol succinate, bisoprolol, bucindolol, nebivolol and atenolol) have a large body of evidence supporting their efficacy in symptomatic heart failure with reduced ejection fraction (EF) (≤40%). A meta-analysis of 22 trials involving over

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for search strategy results.

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Systolic heart failure review

10 000 patients found that beta-blockers (prescribed in addition to ACE inhibitors) reduced the odds of all-cause mortality by 35% (odds ratio (OR) 0.65, 95% confidence interval (CI) (0.53–0.80)) and hospitalisation for heart failure by 36%, compared with placebo.7 While individual randomised controlled trials for bucindolol, nebivolol and atenolol have not shown independently significant mortality reductions, a network meta-analysis including these trials concluded there is no significant difference between individual beta-blockers, and that the benefits of beta-blockers in heart failure are a class effect.8 Recently, a large meta-analysis of individual patient data suggested heart failure patients with atrial fibrillation, compared with those in sinus rhythm, may not gain mortality benefits with beta-blockers (interaction P < 0.0001).9 Although a highly significant interaction, this has not been a pre-specified outcome finding of any randomised controlled trial. Several baseline population differences exist between heart failure patients in sinus rhythm and atrial fibrillation, which may have influenced these findings. Beta-blockers are safest in symptomatic heart failure when initiated at the lowest possible dose and doubled at regular intervals of 2 weeks, helping to avoid common adverse effects such as worsening heart failure, hypotension and bradycardia.10 To manage symptomatic hypotension at low doses, the ESC Chronic Heart Failure Guidelines 2012 recommend switching between betablockers before reducing the dose of other hypotensive agents such as ACE inhibitors, diuretics or nitrates.5 Although patients with chronic airways disease were excluded in most clinical trials, cardioselective betablockers have demonstrated to be generally safe in the short term, although long-term trials are lacking.11

Angiotensin-converting enzyme inhibitors A systematic review of randomised controlled trials in moderate to severe heart failure patients (EF ≤ 35% or ≤40%) showed ACE inhibitors reduce the odds of allcause mortality by 23% (OR 0.77, 95% CI (0.67–0.88), P < 0.001) and readmissions for heart failure by 35%, compared with placebo.12 Mortality reductions from ongoing therapy have been demonstrated out to 12 years of follow up.13 The risk of developing atrial fibrillation also appears reduced by ACE inhibitors (or ARB) in heart failure.14 In patients with ischaemic heart failure, ACE inhibitors also reduce the risk of recurrent myocardial infarction (MI) by 21% compared with placebo.15 Overall treatment effects of ACE inhibitors have been shown to be consistent regardless of gender, race and diabetic status,16 and are additive to beta-blocker therapy. © 2016 Royal Australasian College of Physicians

Adverse effects associated with ACE inhibitors include cough, hypotension, hyperkalaemia and renal dysfunction.15 However, even in most patients with advanced chronic kidney disease they can be used effectively. In the minority of situations where adverse effects have required treatment cessation, such side-effects are reversible.

Angiotensin receptor blockers A Cochrane review of 17 900 pooled trial participants with EF ≤ 40% showed that ARB, compared with placebo, reduced the risk of all-cause mortality by 13% (risk ratio (RR) 0.87, 95% CI (0.76–1.00), P = 0.05) and readmissions for heart failure by 29%.17 Compared with ACE inhibitors, ARB provide similar benefits in terms of reducing the risk of all-cause mortality, total hospitalisations and, in ischaemic heart failure, recurrent MI, and have similar side-effects, except cough.17 When used in combination with ACE inhibitors, ARB further reduce the risk of readmission for heart failure by 19%, but there is no additional reduction in the risk of all-cause mortality or total hospitalisations.17 Moreover, compared with ACE inhibitor therapy alone, combination therapy is associated with a much greater risk of renal dysfunction (91% higher risk), hyperkalaemia (95%) and symptomatic hypotension (57%).18

Hydralazine and isosorbide dinitrate H-ISDN have been trialled in combination in heart failure based on their separate and theoretically complementary mechanisms of action – ISDN reduces preload and hydralazine reduces afterload.19 Together they have been shown to provide mortality benefits and symptomatic relief in systolic heart failure. The first VasodilatorHeart Failure Trial (V-HeFT I) demonstrated a 25% lower risk of all-cause mortality and improved exercise capacity with H-ISDN compared with placebo in heart failure patients already receiving digoxin and diuretics.20 However, V-HeFT II, comparing H-ISDN with enalapril, showed a significantly lower all-cause mortality rate with enalapril at 2 years (absolute risk reduction (ARR) 5.4%, P = 0.02), with a similar but non-significant result at the 2.5 year trial end (ARR 5.4%, P = 0.08).21 Some preliminary evidence has suggested African Americans may derive greater benefits from H-ISDN than ACE inhibitors, whereas in Caucasians the reverse appears true, but no statistically significant heterogeneity between race and treatment effect for either of these medications has been convincingly demonstrated.22 Headaches and dizziness (30%) are common sideeffects of this therapy.20,21 The evidence for using 655

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H-ISDN with an ACE inhibitor (or ARB) is sparse (with the exception of use in African Americans), but when the latter are contraindicated, H-ISDN appears a reasonable, possibly less efficacious alternative.

Diuretics Although diuretics have been used for decades to treat volume overload in heart failure, their efficacy is supported by mainly small and dated randomised controlled trials. A Cochrane review composed of both randomised controlled trials and withdrawal studies found that diuretics reduced the odds of all-cause mortality by 76% (OR 0.24, 95% CI (0.07–0.83), P = 0.02) and readmission for heart failure by 93%, while improving exercise capacity compared with placebo.23 This meta-analysis excluded trials of aldosterone antagonists on the basis that they are not ‘conventional diuretics’, and hence results reflect trials of mainly loop and hydrochlorothiazide diuretics. Adverse effects of diuretics can include electrolyte and renal function abnormalities.

Aldosterone antagonists The addition of an aldosterone antagonist (eplerenone or spironolactone) to ACE inhibitor, beta-blocker and other diuretic therapy is a more recently established core component of the standard therapeutic regimen in severe heart failure (EF ≤ 35%). A meta-analysis of eight randomised controlled trials showed that compared with placebo, aldosterone antagonists reduced the odds of allcause mortality by 26% (OR 0.74, 95% CI (0.63–0.86), P < 0.001), driven mostly by reductions in sudden cardiac deaths (23%).24 Another meta-analysis showed significant reductions in the odds of all-cause hospitalisation (27%) and improvements in New York Heart Association (NYHA) functional class and ejection fraction (3%) with aldosterone antagonists compared with placebo.25 Hyperkalaemia and renal impairment are well-known risks for these medications and as a result patients with hyperkalaemia (serum K ≥ 5.0 mmol/L) or renal impairment (eGFR < 30 mL/min/1.73 m2 or serum creatinine >221 μmol/L) were excluded from the large randomised trials. Endocrine side-effects from spironolactone include gynaecomastia, decreased libido and, in women, menstrual irregularities. These can be avoided with eplerenone, which has greater drug target specificity. Eplerenone is currently Pharmaceutical Benefits Scheme (PBS) subsidised in Australia for early ischaemic heart failure but not for other aetiologies. 656

Ivabradine Ivabradine reduces heart rate by specific inhibition of funny channels (If) in the sinus node. A meta-analysis of individual patient data from two large randomised controlled trials in 12 000 patients with a reduced ejection fraction (≤35% or ≤40%) and heart rate ≥70 bpm, found ivabradine did not reduce the overall risk of all-cause and cardiovascular mortality, but did reduce readmissions for heart failure by 19% and the risk of MI by 23% compared with placebo.26 In a pre-specified subgroup with baseline heart rate ≥75 bpm, the risks of both allcause mortality (hazard ratio (HR) 0.89, 95% CI (0.80– 1.00), P = 0.048) and cardiovascular mortality (HR 0.88, 95% CI (0.78–1.00), P = 0.049) were significantly reduced.26 The treatment effects of ivabradine were independent of NYHA class status and beta-blocker doses.26 Ivabradine is generally well tolerated, but adverse effects can include symptomatic bradycardia (4%) and the development of phosphenes (false sensations of seeing lights, 3%).26 These adverse effects rarely caused withdrawal from treatment in the randomised trials and are reversible when the drug is withdrawn. Current ESC Chronic Heart Failure Guidelines (2012) and Australian Heart Foundation Guidelines (2011) recommend considering ivabradine in symptomatic heart failure patients (EF ≤ 35%) with sinus rhythm and HR ≥ 70 bpm,1,5 noting that PBS authority in Australia restricts subsidies to people with baseline HR > 77 bpm, which was the subgroup in the ivabradine and outcomes in chronic heart failure (SHIFT) trial demonstrating mortality benefits.

Devices Automatic Implantable Cardioverter Defibrillators (AICD) AICD are used for the primary prevention of ventricular arrhythmias and sudden cardiac death in heart failure patients. In a meta-analysis of randomised controlled trials of NYHA II–III patients with sinus rhythm and EF ≤ 35%, AICD reduced the risk of all-cause mortality by 26% (RR 0.74, 95% CI (0.67–0.83), P < 0.00001) compared with medical therapy alone.27 A mortality benefit was not seen in patients who started therapy within 40 days of having a MI,28 and existing ACCF/AHA guidelines recommend implantation according to an ejection fraction determined more than 40 days postMI.4 The same guidelines also recommend AICD implantation in NYHA I ischaemic heart failure patients with a lower ejection fraction (≤30%).4 There is a lack of © 2016 Royal Australasian College of Physicians


evidence for AICD in NYHA class IV patients, which mainly reflects the poor prognosis and typical exclusion of such patients from these trials. The current consensus is that patients should have a prognosis of at least 12 months to warrant AICD insertion.5

Cardiac resynchronisation therapy CRT provides an individually optimised pacing of both ventricles to improve pump performance. An individual patient data meta-analysis examined randomised controlled trials of NYHA II–IV participants with sinus rhythm, EF ≤ 35%, increased QRS duration (≥120 ms) and optimal medical therapy. It found CRT, compared with control (AICD/pacemaker/optimal medical therapy) was associated with a reduced risk of all-cause mortality by 34% (HR 0.66, 95% CI (0.57–0.77)) and a reduced risk of the combined end-point of all-cause mortality and hospitalisation for heart failure.29 Benefits were independent of AICD presence, aetiology of heart failure and QRS morphology, noting the vast majority of subjects had left bundle branch block (LBBB). Analyses according to QRS duration have identified greater clinical benefits with longer durations, starting from QRS duration ≥140 ms.29 Conversely a small metaanalysis found a higher mortality risk for CRT in patients with QRS < 130 ms compared with medical therapy (RR 1.63, 95% CI (1.07–2.47), P = 0.023), despite echocardiographic evidence of dyssynchrony in most patients.30 QRS morphology also appears to influence prognosis. A meta-analysis of four CRT trials (n = 5356) found CRT significantly reduced composite clinical events in LBBB patients but had no benefits in non-LBBB patients.31 Long-term follow up of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) identified significant reductions in the risk of all-cause mortality (41%) and non-fatal heart failure events (62%) out to 7 years in patients with LBBB, but increased risks of both outcomes with CRT in patients without LBBB.32 More data for outcomes in patients with non-LBBB conduction abnormalities are required to help clarify these findings. CRT and AICD share similar adverse effects including lead problems, infection and mechanical complications. AICD also risk inappropriate shocks, the psychological stress from which can sometimes significantly impair the quality of life. Currently, major guidelines recommend CRT for NYHA III–IV patients with EF ≤ 35%, sinus rhythm, LBBB and QRS duration ≥120 ms. For patients without LBBB, the ACCF/AHA Guidelines (2013) and ESC Chronic Heart Failure Guidelines (2012) recommend CRT at QRS duration (≥150 ms). For NYHA II patients © 2016 Royal Australasian College of Physicians

international guidelines differ slightly, and the notably harmful findings from long-term MADIT-CRT follow up in non-LBBB patients suggests the appropriateness of CRT may be limited to more symptomatic patients.32 Only ACCF/AHA Guidelines (2013) include CRT for NYHA I patients, suggesting consideration in patients with severe ischaemic EF impairment (≤30%), LBBB and a broad QRS (>150 ms).

Digoxin Digoxin has traditionally been used in the setting of atrial fibrillation and advanced heart failure. A Cochrane review showed that digoxin did not reduce all-cause and heart failure mortality but did reduce heart failure symptoms and readmissions for heart failure by 32% (OR 0.68, 95% CI (0.61–0.75), P < 0.00001).33 Benefits appeared greater in patients with severely reduced ejection fraction (≤25%) or NYHA III–IV functional class.34 Post-hoc subgroup analyses by serum digoxin concentrations (SDC) found patients within the range 0.5–0.8 ng/ mL had their risk of all-cause mortality reduced by 20% (HR 0.80, 95% CI (0.68–0.94), P = 0.005). Increased arrhythmic complications have been identified in patients with SDC concentrations ≥1.2 ng/mL.35 If used in the context of any renal impairment, digoxin requires very careful dose and level monitoring to prevent toxicity.

Drugs with limited evidence Omega-3 fatty acids Evidence for fish oil supplementation in heart failure patients is limited but modestly supportive. One randomised controlled trial found that 1 g (850–882 mg of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in 1.5:1) of omega-3 fatty acids per day, compared with placebo, reduced the risk of all-cause mortality by 9% (HR 0.91, 95% CI (0.833–0.998), P = 0.041) at 2 years but did not affect rates of hospitalisation.36 A meta-analysis of prospective observational studies examining incident heart failure according to fish oil intake demonstrated a linear protective association, with a 5% lower risk per 15 g of fish consumed daily.37 Nausea is the most common side-effect but typically does not prompt drug discontinuation.

Antithrombotic therapy in sinus rhythm Left ventricular systolic dysfunction is associated with an increased risk of thromboembolism in patients with sinus rhythm, but the evidence for benefit from antithrombotic therapy is not definitive. In a Cochrane review of 657

Chia et al.

trials including heart failure patients in sinus rhythm, warfarin non-significantly reduced the risk of all-cause mortality (OR 0.66, 95% CI (0.36–1.18), P = 0.16) compared with placebo.38 Other larger randomised trials of heart failure have shown no difference between warfarin, aspirin and clopidogrel for mortality risk and reported conflicting findings regarding heart failure readmissions.39,40 Warfarin has been shown in heart failure patients to reduce the risk of ischaemic stroke by 48% compared with aspirin39 and the risk of any stroke compared with either aspirin or clopidogrel.40 Factored against these benefits, the risk of major haemorrhage is significantly increased with warfarin use compared with placebo (OR 5.98, 95% CI (1.71–20.93), P = 0.0052),38 aspirin (OR 2.21, 95% CI (1.42–3.47), P < 0.001)39 or clopidogrel (RR 2.48, CI not presented, P = 0.007).40

Statins Statins (HMG-CoA reductase inhibitors) are widely used to treat ischaemic heart disease, but there is limited evidence for their use in all heart failure patients. A metaanalysis of 10 randomised controlled trials with symptomatic heart failure and standard baseline therapies showed no significant effects with statin therapy versus placebo on the risk of all-cause mortality (OR 0.89, 95% CI (0.72–1.10), P = 0.27) or hospitalisations for heart failure, without any excess in adverse events.41 Current evidence suggests statin prescription should not routinely be given to these patients unless they have other indications such as ischaemic heart or cerebrovascular disease.

ARB and neprilysin inhibitor combination LCZ696 (valsartan and sacubitril) is a promising novel combination therapy based on results from a large single phase III randomised controlled trial. The recently published trial included NYHA II–IV patients with reduced ejection fraction (≤40%) and baseline treatment with beta-blockers, diuretics, digoxin and aldosterone antagonists. It found that compared with ACE inhibitor therapy, LCZ696 reduced the risk of all-cause mortality by 16% (HR 0.84; 95% CI (0.76–0.93), P < 0.001) and hospitalisation for heart failure by 21%.42 While data are preliminary and continue to accrue, results are encouraging.

Discussion Heart failure is a condition with substantial morbidity and mortality, and there is an acknowledged deficiency between evidence-based recommended treatments and everyday prescribing patterns. Mnemonics represent a simple way to assist clinicians in their treatment of 658

patients, and in this paper, we have sought to review the contemporary evidence base for systolic heart failure treatments to devise a mnemonic summarising these treatments. Based on this review we propose use of the mnemonic BANDAID2 – representing beta-blocker, ACE inhibitor/ARB, nitrate-hydralazine (or potentially neprilysin inhibitor in the future), diuretics, aldosterone antagonist, ivabradine, devices and digoxin in approaching the treatment of systolic heart failure (Tables 1, 2). There is strong evidence to support the use of betablockers, ACE inhibitors and ARB in systolic heart failure, noting a choice of either ACE inhibitor or ARB is generally preferable to the use of both. Treatment with H-ISDN is effective, but inferior to ACE inhibitors (and to ARB by indirect comparison) in the general population. The novel combination therapy LCZ696 (valsartan and sacubitril (a neprilysin inhibitor)) has promising preliminary results, but more research is required. The evidence for diuretics is limited, but supports a mortality reduction and their symptomatic benefits in treating fluid overload are undisputed. Aldosterone antagonists significantly reduce mortality and hospitalisations in heart failure patients. Ivabradine reduces hospitalisations for heart failure in sinus rhythm patients with HR ≥ 70 bpm and, in patients with resting heart rate ≥75 bpm, reduces both all-cause and cardiovascular mortality. However, beta-blockers should be used prior to ivabradine, when possible, on account of more definitive mortality benefits. AICD reduce the risk of sudden cardiac death in medically stabilised, NYHA II–III patients with EF ≤ 35% in sinus rhythm, noting some recommendations for use in NYHA I ischaemic heart failure patients. CRT-D reduces mortality among NYHA III–IV patients with EF ≤ 35% in sinus rhythm, with recommendations according to QRS morphology and duration – for LBBB ≥ 120 ms and for non-LBBB > 150 ms, noting use among NHYA II and I patients is more controversial because of evidence of harm in some non-LBBB settings. Recommendations for digoxin are less definitive because of a lack of clear mortality benefit despite reductions in hospitalisations. Most guidelines therefore recommend digoxin as the last line of treatment for heart failure, irrespective of rhythm. Importantly, most of these medications or device interventions were trialed in patients receiving existing standards of care of the time for heart failure. This provides reassurance that risk reductions from treatments should in most instances be additive when used in combination in appropriately selected patients (Fig. 2). An area not examined in this review is the critical role of heart failure outpatient services in providing the frequent monitoring and consultation patients with advanced heart failure require. Prevention of © 2016 Royal Australasian College of Physicians


Table 1 Effects of systolic heart failure treatments included in the BANDAID2 mnemonic on total mortality and hospitalisation rates Drug Beta-blocker

ACE inhibitor

Comparison Placebo

7

Placebo12

Trial type Meta-analysis

Meta-analysis

End-points Total mortality (22 RCT, n = 10,135) Hospitalisation for HF (22 RCT, n = 10,076) Total mortality (32 RCT, n = 7105)

HR/RR/OR OR 0.65, 95% CI (0.53–0.80)

ARR for mortality 4.4% at 1 year

OR 0.64, 95% CI (0.53–0.79) OR 0.77, 95% CI (0.67–0.88), P < 0.001

≤3 months: 5.4%; 3 months to 4 years: 5.8%

ARB

Placebo17

ACE inhibitor17

ARB + ACE inhibitor

Nitratehydralazine (H-ISDN) LCZ696 (ARB + Neprilysin inhibitor) Diuretic

Aldosterone antagonist

Meta-analysis

Meta-analysis

Hospitalisation for HF (3 RCT, n = 2590) Total mortality (8 RCT, n = 5201) Hospitalisation for HF (3 RCT, n = 4310) Total mortality (7 RCT, n = 8260) Hospitalisation for HF (4 RCT, n = 8108)

ACE inhibitor17

OR 0.65, 95% CI (0.57–0.74), P < 0.001 RR 0.87, 95% CI (0.76–1.00), P = 0.05

7.1% at 1.3 years

RR 0.71, 95% CI (0.61–0.82), P < 0.00001 RR 1.05, 95% CI (0.91–1.22), P = 0.48

NA

RR 0.96, 95% CI (0.83–1.11), P = 0.58 RR 0.98, 95% CI (0.90–1.06), P = 0.60

NA

RR 0.81, 95% CI (0.74–0.89), P < 0.00001

Placebo20 ACE inhibitor21

RCT RCT

Total mortality (n = 642) Total mortality (n = 804)

RR 0.66, 95% CI (0.46–0.96), P < 0.028 RR 1.39 (CI not stated), P = 0.016

5.3% at 2 years −5.4% at 2 years

ACE inhibitor42

RCT

Total mortality (n = 10521)

HR 0.84, 95% CI (0.76–0.93), P < 0.001

4.7% at 2.3 years

HR 0.79, 95% CI (0.71–0.89), P < 0.001

Meta-analysis

Hospitalisation for HF (n = 10521) Total mortality (3 studies (1 RCT), n = 202) Hospitalisation for HF

Placebo23

Placebo

Meta-analysis Meta-analysis

Ivabradine

Total mortality or hospitalisation for HF (30 RCT, n = 6988) Total mortality (9 RCT, n = 4643)

Placebo26

Meta-analysis

2 withdrawal studies, n = 169 Total mortality24 (7 RCT, n = 11,826) All-cause hospitalisation25 (7 RCT, n = 8699) Total mortality (2 RCT, n = 7632)

Hospitalisation for HF

OR 0.24, 95% CI (0.07–0.83), P = 0.02

8% at ∼6 months

OR 0.07, 95% CI (0.01–0.52), P = 0.01 OR 0.74, 95% CI (0.63–0.86), P < 0.001

10.4% at 2.2 years

RR 0.73, 95% CI (0.63–0.84), P < 0.0001 HR 0.96, 95% CI (0.87–1.05), P = NS (Overall population) HR 0.89, 95% CI (0.80–1.00), P = 0.048. (HR ≥ 75 bpm subgroup) HR 0.78, 95% CI (0.70–0.87) P < 0.0001

NA 2% at 1.8 years

RR 0.74, 95% CI (0.67–0.83), P < 0.00001

6.5% at 2 years

HR 0.66, 95% CI (0.57–0.77)

2.9% at 1 year

(2 RCT, n = 7632) AICD

Medical therapy27

Meta-analysis

CRT

AICD or

Meta-analysis

(5 RCT, n = 3872)

medical therapy29

Digoxin

Placebo33

Total mortality (7 RCT, n = 4981) Total mortality

Meta-analysis

Total mortality or hospitalisation for HF (5 RCT, n = 3872) Total mortality (8 RCT, n = 7755) Hospitalisation for HF (4 RCT, n = 7262) Improved clinical status 12 studies, n = 123.

HR 0.65, 95% CI (0.58–0.74) OR 0.98, 95% CI (0.89–1.09), P = 0.76

NA at 3 years

OR 0.68, 95% CI (0.61–0.75), P < 0.00001 OR 0.31, 95% CI (0.21–0.43), P < 0.00001

HR/RR/OR methods give similar estimates when event rates are relatively low. ACE, angiotensin-converting enzyme; AICD, automatic implantable cardioverter defibrillator; ARB, angiotensin receptor blocker; ARR, absolute risk reduction; CRT, cardiac resynchronisation therapy; HF, heart failure; H-ISDN, hydralazine-isosorbide dinitrate; HR, hazard ratio; NA, not applicable; OR, odds ratio; RCT, randomised controlled trial; RR, risk ratio.


659

660 ACCF/AHA: A ESC: B ACCF/AHA: B (ACCF/AHA: A for African

• EF ≤ 40% • Alternative to ACE inhibitor/ARB (General population)OR

• Last line therapy for symptomatic relief

CRT • QRS ≥ 120 ms • Refer to specific criteria for each NYHA class in guidelines

• Prognosis ≥1 year

• Medical therapy ≥3 months

• Sinus rhythm

AICD • NYHA II–III • EF ≤ 35%

ACCF/AHA: I NHF: A

ESC: B ACCF/AHA: B

ESC: IIb ACCF/AHA: IIa NHF:B

NHF: A

ESC: I¶ ACCF/AHA: I

ESC: I

ESC: IIa ACCF/AHA: N/A NHF: B

NHF: B

• Renal dysfunction

• Extensive lateral LV wall scarring (CRT)

• Poor prognosis

• Hypersensitivity

• Unsuitable vascular anatomy

• HR < 50 • Uncontrolled systemic infection

• AV or SA block • Combination with cytochrome P450 3A4 inhibitors • Severe psychiatric conditions

• Sick sinus syndrome • End-stage renal failure

• Incessant VT/VF

• Hypersensitivity • Moderate-severe hepatic failure

• Stage 3 + CKD


• Hypotension

• Stage 1–2 CKD

• Hyperkalemia (>5.0 mmol/L)

• Hypotension

ESC: I ACCF/AHA: I

NHF: D

• Hyponatraemia • Hypokalemia

ACCF/AHA: A

ESC: A ACCF/AHA: A§


• Hypotension


• Pregnancy

• Hypotension

• Intolerable headache


• Renal dysfunction

†Ivabradine is recommended for HR ≥ 70 bpm in Australian National Heart Foundation Guidelines (2011), but PBS subsidies are only provided for HR ≥ 77 bpm. ‡Level B for non-ischaemic causes of heart failure. §Level of evidence and class of recommendation varies according to criteria. ¶Class IIa for non-LBBB QRS morphology. ACCF, American College of Cardiology Foundation; ACE, angiotensinconverting enzyme; AHA, American Heart Association; AICD, automatic implantable cardioverter defibrillator; ARB, angiotensin receptor blocker; AV, atrioventricular; CKD, chronic kidney disease; CRT, cardiac resynchronisation therapy; EF, ejection fraction; ESC, European Society of Cardiology; H-ISDN, hydralazine-isosorbide dinitrate; HR, heart rate; LBBB, left bundle branch block; LV, left ventricle; NHF, National Heart Foundation (Australia); NYHA, New York Heart Association; OR, odds ratio; PBS, Pharmaceutical Benefits Scheme; SA, sinoatrial; VF, ventricular fibrillation; VT, ventricular tachycardia.

Digoxin

Devices

• Maximum tolerable beta-blocker dose

• HR ≥ 70 bpm

• Sinus rhythm

• EF ≤ 35%

• Decompensated heart failure

• Reversible airways disease


Absolute

• Symptomatic hypotension or bradycardia

Relative

Contraindications

• Conduction disease

ESC: I ACCF/AHA: I

(ACCF/AHA: I for African Americans)

ACCF/AHA: I NHF: A ESC: IIb ACCF/AHA: IIa NHF: B

ESC: I

ESC: I ACCF/AHA: I NHF: A

Class/grade of recommendation

ESC: A‡‡

ESC: B ACCF/AHA: N/A

• NYHA II–IV

Ivabradine†

ESC: A ACCF/AHA: A

• NYHA II–IV

Aldosterone antagonist • EF ≤ 35%

ESC: N/A ACCF/AHA: C

Diuretic

• EF ≤ 35%

• NYHA III–IV

• Addition to ACE inhibitor (African Americans) Americans)

ESC: A

• NYHA I–IV

• EF ≤ 40%

ESC: A ACCF/AHA: A

Level of evidence

• NYHA II–IV

Indications

• Volume overload

Nitrate-hydralazine (H-ISDN)

ACE inhibitor/ARB

Beta-blocker

Treatment

Table 2 Indications, contraindications and major society recommendations for systolic heart failure treatments

Chia et al.



Figure 2 Effects on total mortality in patients with systolic heart failure, by treatment allocation compared with placebo. *Combination pharmacotherapy represents a broad estimate of the potential clinical benefits from combining treatments marked with an asterisk. The effect of diuretics has not been included due to a broad CI. †Trial result comparing angiotensin receptor blocker (ARB) + Neprilysin inhibitor to angiotensin converting enzyme (ACE) inhibitor. ( ) 95% OR, ( ) 95% CI. HR/RR/OR methods give similar estimates when event rates are relatively low. ACE, angiotensinconverting enzyme; AICD, automatic implantable cardioverter defibrillator; CRT, cardiac resynchronisation; H-ISDN, hydralazine-isosorbide dinitrate; HR, hazard ratio; OR, odds ratio; RR, risk ratio.

hospitalisations and associated morbidity can successfully be achieved by titrating medication doses, particularly diuretics, early in the course of deteriorating symptoms or increasing weight. Similarly, advances in remote ICD/ permanent pacemaker monitoring allow expedited responses to rhythm, rate and other physiological changes, which can effectively prevent patient deteriorations. Beyond achieving standards in pharmacological and device therapeutics, the importance of frequent monitoring and review in heart failure patients cannot be overstated.

References 1 Krum H, Jelinek MV, Stewart S, Sindone A, Atherton JJ. 2011 Update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. Med J Aust 2011; 194: 405–9. 2 National Heart Foundation of Australia. A Systematic Approach to Chronic Heart Failure Care: A Consensus Statement. Melbourne: National Heart Foundation of Australia; 2013. 3 Yao D-K, Wang L-X, Curran S, Ball P. Adherence to treatment guidelines in the pharmacological management of chronic heart failure in an Australian population. J Geriatr Cardiol 2011; 8: 88–92.


Conclusion It is essential that patients are prescribed optimal evidence-based therapies in both hospital and community settings, as effective management of heart failure can substantially reduce morbidity and mortality. Consideration of BANDAID2, representing a current evidence-based treatment mnemonic for patients with systolic heart failure, could improve prescribing rates and therefore patient outcomes in this complex chronic disease.

4 Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128: e240–327. 5 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur J Heart Fail 2012; 14: 803–69. 6 Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. Ann Intern Med 2009; 151: 264–9. 7 Brophy JM, Joseph L, Rouleau JL. Betablockers in congestive heart failure. A

Bayesian meta-analysis. Ann Intern Med 2001; 134: 550–60. 8 Chatterjee S, Biondi-Zoccai G, Abbate A, D’Ascenzo F, Castagno D, Van Tassell B et al. Benefits of (beta) blockers in patients with heart failure and reduced ejection fraction: network meta-analysis. BMJ 2013; 346: f55. 9 Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JGF et al. Efficacy of (beta) blockers in patients with heart failure plus atrial fibrillation: an individual-patient data metaanalysis. Lancet 2014; 384: 2235–43. 10 Gottlieb SS, Fisher ML, Kjekshus J, Deedwania P, Gullestad L, Vitovec J et al. Tolerability of β-blocker initiation and titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Circulation 2002; 105: 1182–8.

661

Chia et al.

11 Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005; CD003566. 12 Garg R, Yusuf S, Bussmann W, Sleight P, Uprichard A, Massie B et al. Overview of randomized trials of angiotensinconverting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995; 273: 1450–6. 13 Jong P, Yusuf S, Rousseau MF, Ahn SA, Bangdiwala SI. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study. Lancet 2003; 361: 1843–8. 14 Zhang Y, Zhang P, Mu Y, Gao M, Wang JR, Wang Y et al. The role of reninangiotensin system blockade therapy in the prevention of atrial fibrillation: a meta-analysis of randomized controlled trials. Clin Pharmacol Ther 2010; 88: 521–31. 15 Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACEInhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355: 1575–81. 16 Shekelle PG, Rich MW, Morton SC, Atkinson CS, Tu W, Maglione M et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a metaanalysis of major clinical trials. J Am Coll Cardiol 2003; 41: 1529–38. 17 Heran BS, Musini VM, Bassett K, Taylor RS, Wright JM. Angiotensin receptor blockers for heart failure. Cochrane Database Syst Rev 2012; CD003040. 18 Kuenzli A, Bucher HC, Anand I, Arutiunov G, Kum LC, McKelvie R et al. Meta-analysis of combined therapy with angiotensin receptor antagonists versus ACE inhibitors alone in patients with heart failure. PLoS ONE 2010; 5: e9946. 19 Cole RT, Kalogeropoulos AP, Georgiopoulou VV, Gheorghiade M, Quyyumi A, Yancy C et al. Hydralazine and isosorbide dinitrate in heart failure: historical perspective, mechanisms, and

662

20

21

22

23

24

25

26

27

28

future directions. Circulation 2011; 123: 2414–2. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative study. N Engl J Med 1986; 314: 1547–52. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303–10. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail 1999; 5: 178–87. Faris RF, Flather M, Purcell H, PooleWilson PA, Coats AJ. Diuretics for heart failure. Cochrane Database Syst Rev 2012; CD003838. Bapoje SR, Bahia A, Hokanson JE, Peterson PN, Heidenreich PA, Lindenfeld J et al. The effects of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with left ventricular systolic dysfunction: a meta-analysis of randomized controlled trials. Circ Heart Fail 2013; 6: 166–73. Ezekowitz JA, McAlister FA. Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials. Eur Heart J 2009; 30: 469–77. Fox K, Komajda M, Ford I, Robertson M, Böhm M, Borer JS et al. Effect of ivabradine in patients with leftventricular systolic dysfunction: a pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials. Eur Heart J 2013; 34: 2263–70. Nanthakumar K, Epstein AE, Kay GN, Plumb VJ, Lee DS. Prophylactic implantable cardioverter-defibrillator therapy in patients with left ventricular systolic dysfunction: a pooled analysis of 10 primary prevention trials. J Am Coll Cardiol 2004; 44: 2166–72. Hohnloser SH, Kuck KH, Dorian P, Roberts RS, Hampton JR, Hatala R et al. Prophylactic use of an implantable cardioverter–defibrillator after acute myocardial infarction. N Engl J Med 2004; 351: 2481–8.

29 Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, Claude Daubert J et al. An individual patient metaanalysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart J 2013; 34: 3547–56. 30 Shah RM, Patel D, Molnar J, Ellenbogen KA, Koneru JN. Cardiacresynchronization therapy in patients with systolic heart failure and QRS interval ≤ 130 ms: insights from a metaanalysis. Europace 2015; 17: 267–73. 31 Sipahi I, Chou JC, Hyden M, Rowland DY, Simon DI, Fang JC. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: metaanalysis of randomized controlled trials. Am Heart J 2012; 163: 260–7000. 32 Goldenberg I, Kutyifa V, Klein HU, Cannom DS, Brown MW, Dan A et al. Survival with cardiac-resynchronization therapy in mild heart failure. N Engl J Med 2014; 370: 1694–701. 33 Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of heart failure in patients in sinus rhythm. Cochrane Database Syst Rev 2014; CD002901. 34 Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525–33. 35 Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289: 871–NaN. 36 Gissi-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1223–30. 37 Djousse L, Akinkuolie AO, Wu JHY, Ding EL, Gaziano JM. Fish consumption, omega-3 fatty acids and risk of heart failure: a meta-analysis. Clin Nutr 2012; 31: 846–53. 38 Lip GY, Shantsila E. Anticoagulation versus placebo for heart failure in sinus rhythm. Cochrane Database Syst Rev 2014; CD003336. 39 Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR et al. Warfarin and aspirin in


patients with heart failure and sinus rhythm. N Engl J Med 2012; 366: 1859–69. 40 Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and

Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation 2009; 119: 1616–24. 41 Lipinski MJ, Cauthen CA, BiondiZoccai GGL, Abbate A, Vrtovec B, Khan BV et al. Meta-analysis of randomized controlled trials of statins versus placebo in patients with heart

failure. Am J Cardiol 2009; 104: 1708–16. 42 McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993– 1004.

Supporting information Additional supporting information may be found in the online version of this article at the publisher’s web-site: Appendix S1 Search strategy.

C L I N I C A L P E R S P E CT I V E S

Idiopathic pulmonary fibrosis: an Australian perspective J. Prasad,1,2 A. E. Holland,1,3 I. Glaspole1 and G. Westall1,2 1

Allergy Immunology and Respiratory Medicine, Alfred Hospital, 2Clinical School of Medicine, Monash University, and 3Department of Physiotherapy, La Trobe University, Melbourne, Victoria, Australia

Key words idiopathic pulmonary fibrosis, IPF review, IPF treatment, IPF exacerbation, IPF MDM, IPF transplant. Correspondence Jyotika Prasad, Allergy, Immunology and Respiratory Medicine, Alfred Hospital, 55 Commercial Road, Melbourne, Vic. 3004, Australia. Email: [email protected]

Abstract Idiopathic pulmonary fibrosis is a progressive interstitial lung disease of unknown aetiology with a dismal median survival of 3 years. Patients typically develop progressive dyspnoea and increasing exercise limitation. With a rising incidence and prevalence, an unpredictable disease course and limited treatment options, it is rapidly becoming an important public health concern. To date, lung transplantation has been the sole viable hope for treatment for those who qualify. However, the landscape of idiopathic pulmonary fibrosis management is changing, with the recent emergence of novel pharmacotherapy shown to have a favourable influence on the natural history of this disease.

Received 30 August 2015; accepted 13 December 2015. doi:10.1111/imj.13078

Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing idiopathic interstitial pneumonia (IIP) with an unknown cause, primarily affecting older patients.1 An initial airway epithelial injury to an unknown environmental Funding: None. Conflict of interest: I. Glaspole: Boehringer and Intermune. G. Westall: CSL.


stimulus leads to a dysregulated healing response that results in progressive lung injury and extensive fibrosis. Fibroblasts are the key cells in the pathogenesis of IPF.2 Clinically, IPF is associated with progressive exertional dyspnoea and a restrictive ventilatory deficit on lung function testing and characteristic usual interstitial pneumonia (UIP) features on both computed tomography scans and histology. The disease course may be variable and heterogeneous between individuals. It has both a

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rising incidence and prevalence over the past decade, and the prognosis remains dismal. In this review, we provide an Australian perspective on the current diagnostic and management issues that confront the care of patients with IPF.

Incidence IPF is the most common of the IIP. Determining the true incidence and prevalence of IPF has remained a challenge worldwide due to diagnostic imprecision, changing classification of disease and the heterogeneous diagnostic criteria used in different trials. In Australia, the ability to provide an accurate estimate of the disease burden has been hindered by the geographical enormity and healthcare variability as well as the rarity of this disease.3 The global prevalence of IPF varies significantly based on geographical location of study population as well as the use of narrow or broad case definition. Prevalence is estimated at 14–63 cases per 100 000 in the United States, 1.25–23.4 cases per 100 000 in Europe and 2.9 cases per 100 000 in Japan, while the annual incidence varies from 6.8 to 17.4 per 100 000 in United States and 0.22–7.4 per 100 000 in Europe.4 Currently, there is no accurate estimation of the incidence or prevalence of IPF in Australia. However, the 2014 Lung Disease in Australia report highlighted that during 2011–2012, ILD contributed to 4050 hospitalisations and 1161 deaths (5.2 per 100 000 population), with the male gender accounting for 681 (58.7%) of the deaths.5 To address a lack of collaboration and systematic approach to the management of IPF in Australia, the IPF registry was set up in 2012 by the Lung Foundation Australia to meet the specific goals of providing further insight into the epidemiology and natural history of IPF in Australia as well as to collect information on patient reported outcomes, burden of disease and current management strategies.3

Risk factors Most studies suggest that IPF is more common amongst men, with an incidence that increases with age.1 Familial cohorts of IPF have been described and account for 0.2–2.0% of all cases of IPF.6 Genetic polymorphism of hTERT2 and hTR,7 genes involved in controlling telomere length that plays a pivotal role in controlling cell death and ageing, are described in this population. Other risk factors include a smoking history, gastrooesophageal reflux (GER) disease and exposure to wood and metal dust. Cigarette smoking is strongly associated with IPF, with an odds ratio of 2.3 (95% 664

confidence interval 1.3–3.8) for smokers with a 20–40pack per year history.8 GER disease is present in a large proportion of patients with IPF but often occurs without symptoms.9 Certain infectious agents, particularly viruses like Hepatitis C, Epstein–Barr virus and adenovirus, have been implicated.10 Susceptibility may be due to genetic polymorphisms relating to epithelial damage and abnormal healing as well as environmental exposures.

Natural history Patients typically present with gradual worsening of dyspnoea on exertion and/or dry cough. Symptoms generally precede diagnosis by 6 months to 2 years.6 Delay in diagnosis is usually due to consideration of other more common comorbidities in that age range. Symptoms such as weight loss, fever and arthralgia are unusual in IPF and should prompt investigation for other causes. Physical examination findings are basal crackles and finger nail clubbing, which may be present in 50% of the patients.1 In advanced stages of the disease, there may be signs of cor pulmonale. Retrospective studies suggest that the median time of survival from diagnosis is 3 years, which may previously have been overestimated due to inclusion of other forms of IIP, such as non-specific interstitial pneumonia, which may be more treatment responsive. Despite this, the course of the disease may be highly variable where some patients experience a rapid decline, while others either maintain relative stability or have episodes of acute exacerbation.1 Acute exacerbation, a distinct clinically recognised entity, is defined as the subjective worsening of dyspnoea within the prior 30 days, new bilateral opacities on high resolution computed tomography (HRCT) of the chest and no evidence of infection and exclusion of other alternative causes.11 The incidence of acute exacerbations is estimated at 5–10% annually10 and is associated with a high mortality rate.

Diagnostic work up There are no specific laboratory tests in IPF. However, an elevated erythrocyte sedimentation rate and a low positive antinuclear antibody may be present. Connective tissue disorder-related interstitial lung disease (ILD) should be considered if other serological tests, such as double-stranded DNA antibody, extractable nuclear antigen antibodies or rheumatoid factor, are significantly elevated. With the advancing disease, polycythaemia in response to hypoxaemia may be present. © 2016 Royal Australasian College of Physicians

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Spirometry reveals a restrictive ventilatory deficit with a decreased forced vital capacity (FVC) and forced expiratory volume (FEV1). The ratio of FEV1/FVC may be normal or elevated due to reduced pulmonary compliance. Static lung volumes, particularly total lung capacity, can confirm the presence of restriction. Gas exchange is impaired in IPF, which is demonstrated by reduced diffusion capacity and may precede changes in lung volume.12 A 6-min walk test, which is a simple yet practical physiological assessment, and/or cardiopulmonary exercise testing, which is a more complex assessment of limitation of oxygen consumption, can both provide valuable prognostic information.10 Baseline physiological assessment as well as the longitudinal change in these parameters has been shown to predict mortality. A chest X-ray may be suggestive of fibrotic lung disease, however, lacks diagnostic accuracy and has been shown to have large inter-observer variability in identifying the correct pattern of fibrosis.6 A HRCT scan of the chest is the preferred method of imaging and detailed definition of the lung parenchyma. During the diagnostic process, HRCT of the chest, obtained with prone, inspiratory and expiratory views, reviewed by an experienced pulmonary radiologist enables discrimination between the ‘typical’ radiographical features of IPF from other types of ILD. Typical appearance of IPF on HRCT consists of patchy, predominantly subpleural and bibasilar reticular opacification (Fig. 1) and honeycombing (Fig. 2).10 Ground glass changes may be present but scant. Traction bronchiectasis suggests established fibrosis. A UIP pattern on HRCT is not unique to IPF. This pattern of fibrosis can be seen in other conditions, such as

Figure 1 The apicobasal gradient with basal predominant changes of fibrosis.


Figure 2 Classic feature of subpleural reticulation with coarse honeycombing (marked with

).

asbestosis, chronic hypersensitivity pneumonitis and rheumatoid-related lung disease. As establishing the diagnosis is challenging, a thorough and detailed history reflecting these potential exposures is critical to obtain. In case of a patient presenting with a ‘definite’ UIP pattern on HRCT, a histopathologic assessment may not be necessary. However, if required, a surgical lung biopsy is considered ‘gold standard’. On histopathologic specimens, patchy areas of fibrosis and honeycombing alternating with less affected or normal lung parenchyma can be seen.13 The hallmark histopathologic feature of IPF is specialised structures known as fibroblastic foci, which consist of extracellular matrix and proliferating fibroblasts and myofibroblasts.6 Inflammation is mostly absent from the UIP pathological pattern, except for occasional lymphoid follicles that are confined to regions of end-stage fibrosis.14 A UIP pattern contains no hyaline membranes, granulomas or organised alveolar exudates. In acute exacerbation of IPF diffuse, alveolar damage, hyaline membrane formation, hyperplastic type II cells and interstitial thickening secondary to oedema and infiltration of inflammatory cells may be present.14 As IPF is commonly associated with emphysema, pulmonary hypertension, lung cancer, sleep apnoea and GER,4,6 clinical vigilance and appropriate assessment with additional investigations, such as an echocardiogram and sleep studies, may be warranted. GER is a commonly observed comorbidity in patients with IPF, with retrospective studies highlighting that aggressive management of this condition can potentially change the natural history of the disease and improve survival.9,15 665

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Multi-disciplinary meeting The use of a multi-disciplinary team (MDT) meeting to formulate a diagnosis in ILD has been advocated in several consensus statements10,16; however, no clear guidelines exist for the proper constitution and governance of MDT, and the effect of heterogeneity on their diagnostic output is unclear. A multi-disciplinary meeting is defined as dynamic, close communication between the clinician, radiologist and, if appropriate, the pathologist based on an integrated presentation of clinical data, lung function, laboratory findings, radiological findings and histology.16 Its reported benefits are its ability, in expert hands, to recognise a broader range of ILD, achieve greater inter-observer agreement and assist in the clarification of poorly recognisable or unclassifiable disease.17,18 The importance of the accurate characterisation of ILD is clear when considered using a linked effectiveness approach.19 A wide range of therapeutic choices exist for ILD, such as antigen avoidance in hypersensitivity pneumonitis, anti-fibrotic therapy in IPF, immune suppression in CTD-ILD and vasculitis, lung transplantation, palliative approaches or best supportive care. It is no longer the case that a similar approach can be applied to most ILD, with differences in therapeutic approaches potentially having starkly different outcomes for the patient. For example, as is discussed below, anti-fibrotic therapy has been confirmed as effectively reducing disease progression in IPF, but if immune suppression is prescribed instead, an increased risk of disease progression and mortality would be expected.20–22 The MDT can also provide commentary on casespecific classification of disease behaviour, treatment goals and monitoring strategy.16 This can be beneficial in making challenging treatment decisions in patients with IPF who represent a fairly heterogeneous group, particularly when it comes to disease progression.

Treatment options Non-pharmacological management of IPF Despite promising new pharmacotherapies, IPF remains a progressive disease that is characterised by distressing dyspnoea, reduced functional capacity and poor quality of life. There is evidence of peripheral muscle weakness, particularly in the lower limbs, and reduced physical activity in daily life, which worsens as the disease progresses.23 Mood disorders such as anxiety and depression are common. The emergence of new treatments raises the possibility that patients will live longer with high levels of disability. Supportive care interventions, offered 666

concurrently with appropriate pharmacological treatments, should be considered to improve symptoms and well-being in people with IPF. Pulmonary rehabilitation involves exercise training and self-management education, usually delivered in a group setting at an outpatient facility. A recent Cochrane review concluded that pulmonary rehabilitation resulted in clinically meaningful improvements in exercise capacity, symptoms and quality of life in people with IPF.24 The UK-based NICE guidelines concluded that because of its positive impact on health status, pulmonary rehabilitation is cost effective in IPF and should be offered every 6–12 months.25 There is some evidence that outcomes of pulmonary rehabilitation are more favourable if it is delivered early in the disease course.26 In Australia, people with IPF are accepted into most pulmonary rehabilitation programmes. Due to the prevalence of exercise-induced hypoxaemia and pulmonary hypertension, a programme that has the capacity to administer supplemental oxygen during exercise training is desirable. Acute administration of supplemental oxygen therapy improves maximal exercise performance, prolongs exercise endurance, reduces dyspnoea and shortens recovery time in IPF. Although there have been no randomised controlled trials (RCT) of longer-term oxygen supplementation in IPF and no studies demonstrating a survival benefit, it is commonly prescribed to ameliorate hypoxaemia and reduce symptoms. The American Thoracic Society guidelines provide a strong recommendation in favour of long-term oxygen therapy in patients with IPF who have clinically significant hypoxaemia, drawing on evidence from other chronic lung diseases.10 This recommendation is consistent with Australian practice. In most Australian states, people with IPF will also be eligible for ambulatory oxygen therapy if they have evidence of significant exertional desaturation. The information and support needs of people with IPF should be carefully considered. In a qualitative study, people with IPF expressed a strong preference for more information about their disease, including an understanding of expected prognosis, management of medication side-effects, dealing with symptoms such as dyspnoea and cough and planning for end-of-life care.27 They were happy to receive this information from any knowledgeable health professional, suggesting that a range of clinicians could be involved in providing patient support and education, including physicians, specialist IPF nurses, pulmonary rehabilitation staff and palliative care teams. Referral to palliative care for assistance with symptom management (both dyspnoea and cough) and access to advance care planning should be considered © 2016 Royal Australasian College of Physicians

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and discussed with patients as early as possible. Although limited evidence suggests that formal education and disease management programmes are not useful,28 some patients may value involvement in a support group, such as those run by the Lung Foundation Australia.

Pharmacological therapy Over the past two decades, the pharmacological approach to IPF has moved from an anti-inflammatory and immunosuppressant focus to a reliance on antifibrotic agents, a shift that has reflected the changing views of the underlying pathophysiology of the condition. Initially thought to be a predominantly inflammatory condition, early IPF RCT of drugs such as prednisolone, azathioprine, acetylcysteine and interferon gamma were disappointingly negative.10 Today, we view IPF as a pro-fibrotic condition in which an initial airway injury that is associated with dysregulated alveolar epithelial function and recruitment of fibroblasts leads to scarring of lung parenchyma and irreversible loss of lung function. In May 2014, with the publication in the New England Journal of Medicine of the INPULSIS-1 and INPULSIS-2 trials20 and the ASCEND trial,21 we had evidence for the first time that pharmacological management of IPF could favourably influence its natural history. These new agents have been shown to slow down the progression of disease but not reverse or stop the disease process to date. Pirfenidone is an orally administered anti-fibrotic drug that inhibits multiple growth factors and cytokines, including platelet-derived growth factor, transforming growth factor-beta and tumour necrosis factor-alpha. Initial RCT of pirfenidone29 demonstrated conflicting efficacy but sufficient promise for the drug to be licensed for treatment of IPF in Germany, the United Kingdom, China and India. The publication of the ASCEND study has led to approval for treatment by the US Food and Drug Administration (FDA) and in Australia through the Therapeutic Goods Association (TGA) Special Access Scheme (SAS). The ASCEND study included patients recruited from Australia and showed that pirfenidone compared with placebo significantly reduced the 1-year rate of decline of FVC.21 In a pre-specified analysis combining the results of the ASCEND study with earlier trials,29 pirfenidone also reduced mortality in patients with IPF. The INPULSIS trials were two identical simultaneously run RCT comparing nintedanib with placebo in patients with IPF.20 As per the ASCEND study, the primary end point, a reduction in the rate of decline of FVC was achieved. Nintedanib is an intracellular inhibitor of © 2016 Royal Australasian College of Physicians

multiple tyrosine kinases, such as vascular endothelial growth factor, fibroblast growth factor and plateletderived growth factor. Whilst these studies represent a landmark in the pharmacological management of IPF, enthusiasm is tempered by commonly encountered sideeffects that include diarrhoea (seen in 61% of patients on nintedanib). Both the ASCEND and INPULSIS studies recruited patients with mild to moderate disease (FVC > 50% predicted and diffusion capacity > 30%) who were followed for 12 months. Efficacy beyond 1 year or in patients with more advanced IPF remains unknown. Linking basic scientific understandings of the pathophysiology of the fibrotic pathways underlying IPF to drug discovery is now leading to clinical translation with the availability and use of proven anti-fibrotic drugs. Other implicated pathophysiological mechanisms that are currently being targeted in clinical trials include agents against interleukin-13, integrins and lysl oxidaselike 2.30 Mesenchymal stem cells may enhance epithelial repair, and a first-in-man Australian dose-escalation study of intravenous mesenchymal stem cells was associated with a good short-term safety profile.31 There was no evidence of efficacy in the trial as it was uncontrolled.

Lung transplantation Australian consensus statements on transplant recipient criteria comment with regard to suitability for lung transplantation state that ‘the presence of multiple comorbidities in patients over 65 years of age will exclude the majority of such patients from consideration’. This is pertinent given that the median age of presentation with IPF is 66 years. Appropriate, usually younger IPF patients should be considered for lung transplantation, with good outcome achievable with both single and double lung transplantation. Given the predictable decline in most patients with IPF, the everpresent risk of acute exacerbations and expected delays in identifying suitable donor organs and suitable IPF patients should be referred early in their disease course for consideration of transplantation.

Future direction The IPF landscape in Australia is changing with increasing population awareness of this disease as well as the introduction of novel pharmacotherapy. However, IPF remains a poorly understood progressive respiratory disease with extremely poor survival. Ongoing molecular, translational and clinical research is required to improve our understanding of this disease and provide a structured evidence-based approach to management. 667

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References 1 Kim HJ. Natural history of idiopathic pulmonary fibrosis. Respir Med 2015; 109: 661–70. 2 Yang IV. Epigenomics of idiopthic pulmonary fibrosis. Epigenomics 2012; 4: 195–203. 3 Moodley Y, Goh N, Glaspole I, Macansh S, Walters EH, Chapman S et al. Australian Idiopathic Pulmonary Fibrosis Registry: vital lessons from a national prospective collaborative project. Respirology 2014; 19: 1088–91. 4 Lee AS. The burden of idiopathic pulmonary fibrosis: an unmet public health need. Respir Med 2014; 108: 955–67. 5 Poulos LM, Correll PK, Toelle BG, Reddel HK, Marks GB. Lung Disease in Australia. Sydney: Woolcock Institute of Medical Research, University of Sydney; 2014. [cited 2016 May 1]. Available from URL: http://lungfoundation.com. au/wp-content/uploads/2014/10/ LUNG-DISEASE-IN-AUSTRALIAREPORT_Final_22October14.pdf 6 Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis 2008; 3: 8. 7 Povedano Juan M, Martinez P, Flores Juana M, Mulero F, Blasco MA. Mice with pulmonary fibrosis driven by telomere dysfunction. Cell Rep 2015; 12: 286–99. 8 Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1997; 155: 242–8. 9 Lee JS, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184: 1390–4. 10 Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidencebased guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788–824.

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11 Johannson K. Acute exacerbation of idiopathic pulmonary fibrosis: a proposal. Curr Respir Care Rep 2013; 2: 233–40. 12 Alhamad EH. Pulmonary function tests in interstitial lung disease. Clin Chest Med 2001; 22: 715–50. 13 Oldham JM. Idiopathic pulmonary fibrosis: early detection and referral. Respir Med 2014; 108: 819–29. 14 Leslie KO. Pathology of interstitial lung disease. Clin Chest Med 2004; 25: 657–703. 15 Fulton BG, Ryerson CJ. Managing comorbidities in idiopathic pulmonary fibrosis. Int J Gen Med 2015; 8: 309–18. 16 Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013; 188: 733–48. 17 Flaherty KR, Andrei AC, King TE Jr, Raghu G, Colby TV, Wells A et al. Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis? Am J Respir Crit Care Med 2007; 175: 1054–60. 18 Flaherty KR, King TE Jr, Raghu G, Lynch JP III, Colby TV, Travis WD et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med 2004; 170: 904–10. 19 Merlin T, Lehman S, Hiller JE, Ryan P. The “linked evidence approach” to assess medical tests: a critical analysis. Int J Technol Assess Health Care 2013; 29: 343–50. 20 Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2071–82. 21 King TE Jr, Bradford WZ, CastroBernardini S, Fagan EA, Glaspole I, Glassberg MK et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2083–92.

22 Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012; 366: 1968–77. 23 Wallaert B. Physical activity in daily life of patients with fibrotic idiopathic interstial pneumonia. Chest 2013; 144: 1652–8. 24 Dowman L, Hill CJ, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev 2014; 10: CD006322. 25 The diagnosis and management of suspected idiopathic pulmonary fibrosis. NICE Clinical Guideline 163; 2013 June. 26 Holland AE, Hill CJ, Glaspole I, Goh N, McDonald CF. Predictors of benefit following pulmonary rehabilitation for interstitial lung disease. Respir Med 2012; 106: 429–35. 27 Holland AE, Fiore JF Jr, Goh N, Symons K, Dowman L, Westall G et al. Be honest and help me prepare for the future: what people with interstitial lung disease want from education in pulmonary rehabilitation. Chron Respir Dis 2015; 12: 93–101. 28 Lindell KO, Olshansky E, Song MK, Zullo TG, Gibson KF, Kaminski N et al. Impact of a disease-management program on symptom burden and health-related quality of life in patients with idiopathic pulmonary fibrosis and their care partners. Heart Lung 2010; 39: 304–13. 29 Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760–9. 30 Woodcock HV, Maher TM. The treatment of idiopathic pulmonary fibrosis. F1000Prime Rep 2014; 6: 16. 31 Chambers DC, Enever D, Ilic N, Sparks L, Whitelaw K, Ayres J et al. A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology 2014; 19: 1013–8.


O R I G I N A L A RT I C L E S

Influence of food and lifestyle on the risk of developing inflammatory bowel disease O. Niewiadomski,1 C. Studd,2 J. Wilson,3 J. Williams,1 C. Hair,4 R. Knight,4 E. Prewett,4 P. Dabkowski,4 S. Alexander,4 B. Allen,4 D. Dowling,4 W. Connell,1 P. Desmond1 and S. Bell1 1

Department of Gastroenterology, The University of Melbourne, St Vincent’s Hospital, Melbourne, 4Gastroenterology Department, Barwon Health, Geelong, Victoria, 2Gastroenterology Department, Royal Hobart Hospital, Hobart, and 3Gastroenterology Department, North West Regional Hospital, Burnie, Tasmania, Australia

Key words inflammatory bowel disease, Crohn disease, ulcerative colitis, epidemiology, environmental factors, aetiology. Correspondence Dr Olga Niewiadomski, Department of Gastroenterology, University of Melbourne, St Vincent’s Hospital Fitzroy, Vic. 3065, Australia. Email: [email protected] Received 14 December 2015; accepted 23 March 2016. doi:10.1111/imj.13094

Abstract Background: The Barwon area in Australia has one of the highest incidence rates of inflammatory bowel disease (IBD) and therefore is an ideal location to study the impact of environmental exposures on the disease’s development. Aim: To study these exposures prior to the development of IBD in a population-based cohort. Method: One hundred and thirty-two incident cases (81 Crohn disease (CD) and 51 ulcerative colitis (UC)) from an IBD registry and 104 controls replied to the International Organization of Inflammatory Bowel Diseases environmental questionnaire. This included 87 questions about pre-illness exposures that included childhood illnesses, vaccinations, breastfeeding, house amenities, pets and swimming, diet and smoking. Results: The factors associated with CD included smoking (odds ratio (OR): 1.42, confidence interval (CI): 1–2.02, P = 0.029); childhood events, including tonsillectomy (OR: 1.74, CI: 1.15–2.6, P = 0.003) and chicken pox infection (OR: 3.89, CI: 1.61–9.4, P = 0.005) and pre-diagnosis intake of frequent fast food (OR: 2.26, CI: 1.76–4.33, P = 0.003). In UC, the risk factors included smoking (OR: 1.39, CI: 1.1–1.92, P = 0.026) and pre-diagnosis intake of frequent fast food (OR: 2.91, CI: 1.54–5.58, P < 0.001), and high caffeine intake was protective (OR: 0.51, 95% CI: 0.3–0.87, P = 0.002). Other protective exposures for UC included high fruit intake (OR: 0.59, CI: 0.4–0.88, P = 0.003) and having pets as a child (OR: 0.36, CI: 0.2–0.79, P = 0.001). Conclusion: This first Australian population-based study of environmental risk factors confirms that smoking, childhood immunological events and dietary factors play a role in IBD development; while high caffeine intake and pet ownership offer a protective effect.

Introduction The incidence of inflammatory bowel diseases (IBD) is on the rise globally and varies in different populations.1 Current understanding of the pathogenesis suggests an interplay between genetic susceptibility of the immune system to changes in microbiota, likely due to environmental exposures that trigger a dysregulated immune response.2,3 The changing epidemiology globally offers an opportunity to study the impact of environmental

Funding: This study is solely funded by a postgraduate university scholarship and the St Vincent’s Gastroenterology Deparment. Conflict of interest: None.


drivers on disease aetiology. The incidence of IBD has stabilised in places such as North America, Northern Europe and Australia after a marked increase over half a century1,4,5 in comparison to Denmark that shows a continual rise in incidence.6 Eastern Europe and Asia have historically had much lower rates of IBD, but as they become more westernised in diet and lifestyle, the rate of IBD is increasing.7–9 This rapid rise in incidence over a few decades strongly points to the environment playing a significant role in disease aetiology. Smoking10–13 and appendicectomy12,14,15 are the strongest exposures that have been shown in studies to be associated with IBD. Dietary factors are likely to have an impact, possibly through their role on gut microbiota, but studies so far show contradictory associations. It is 669

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intuitive to study such environmental associations when the disease pattern is changing or emerging at a rapid rate. We have previously documented that the Barwon area in Australia has one of the highest incidence rates of IBD in the world,16 and it is important to employ epidemiological tools in such a population to determine possible aetiological factors. In this study, we report the results of a case control study assessing environmental exposures prior to diagnosis of IBD in a population-based cohort in Barwon, Australia.

Methods Study population During a 4-year inclusion period (2007/2008, 2010–2013), all incidence cases of IBD from a welldefined geographical area, Barwon, were recruited to be part of a population-based prospective study. Cases were identified by a multifaceted approach to ensure complete population case identification, which has been previously described in detail.16,17 In brief, it involved case identification through local specialists, hospitals, pharmacies and the pathology centres (for histological diagnosis). The Barwon area, with Geelong as the major city, is located south-west of Melbourne in Victoria, Australia at latitude of 38 S. The most recent population estimate in 2011 was 293 426.18 A total of 278 incident cases of IBD was identified during the study. Of these, 16 (6%) patients were lost to follow-up, eight (3%) were re-diagnosed as not IBD, one (0.4%) was not a true incident case and one (0.4%) was not suitable for the study due to an unstable social situation. Two hundred and fifty-two patients were enrolled into the IBD clinical registry, which was used as a basis to collect outcome data on the natural history, quality of life impact, environmental factors and healthcare cost. A proportion of these patients (those diagnosed in 2011) has previously been used as a comparison to the Asia-Pacific ACCESS study.13

Definitions and disease classifications The diagnosis of Crohn disease (CD), ulcerative colitis (UC) and IBD undifferentiated was based on the Copenhagen Diagnostic criteria.6 Disease phenotype was defined by the Montreal classification.19

Environmental questionnaire The environmental questionnaire includes 87 questions and was completed by the patients retrospectively after 670

diagnosis with IBD. This questionnaire was developed in 1999 by the IOIBD (International Organization of Inflammatory Bowel Diseases). It covers 25 environmental risk factors associated with IBD. This questionnaire has been validated in a case control study12 and used in multiple IBD cohorts in the past.11,13,20 For statistical analysis, items were grouped into parameters: smoking status at diagnosis, appendicectomy and tonsillectomy before age 20, use of oral contraceptives, breastfeeding during infancy, childhood infections (measles, mumps, rubella, chickenpox, pertussis and/or scarlet fever), pet ownership, vaccinations (tuberculosis, pertussis, measles, rubella, diptheria, tetanus and polio), a high sugar diet (defined as ≥2 of the following: sugar in coffee, sugar in tea, daily intake of soft drinks, sugar on breakfast cereal/ porridge), a high-fibre diet (defined as daily intake of 3 or more of the following: fruit, vegetables, wholemeal bread, ≥slices of bread, cornflakes, muesli), frequent fast food consumption (at least weekly), high intake of caffeine (≥2 cups of coffee or tea per day), daily physical activity, sanitation conditions (access to running and hot water, flush toilets, mains drainage) and IBD in a first degree relative.12,20

Data collection Most patients completed the questionnaire within 6 months of diagnosis, except for those diagnosed in 2007/2008 (n = 21) who did so later. Patients were asked to answer the questionnaire either by mail or electronically. The principal researcher and three other Gastroenterology Advanced Trainees collected data on disease progress. The data included demographics, disease classification, disease activity, medical therapy, surgery, hospitalisation, malignancy and death. Healthy controls from the same geographical area as well as from greater Melbourne were also asked to complete the questionnaire. Controls were volunteers accessed through social networks and university affiliation, with no history of IBD and gastroenterological illness or family history of IBD. A total of 103 controls (56 females), median age 47.5 years (range: 24–70 years) completed the questionnaire. Controls were specifically chosen outside of the hospital setting to minimise the chance of comorbidities.

Statistical analysis Statistical analysis was performed using SPSS version 22 (IBM Corp. Armonk, NY, USA). Odds ratios (OR) with 95% confidence intervals were calculated to examine the difference between those diagnosed with CD and UC and controls on relevant environmental © 2016 Royal Australasian College of Physicians

Risks of developing inflammatory bowel disease

factors. All controls were pooled together. Separate binary logistic regressions were used.

1.15–2.6, P = 0.003), as shown in Table 2. History of a tonsillectomy as a child was more likely in CD patients (OR: 1.74, 95% CI: 1.15–2.6).

Results In total, 132 patients (52%) of the patients enrolled in the registry replied to the questionnaire. This included 81 (61%) CD and 51 (39%) UC patients. Patients’ demographic characteristics are shown in Table 1. Non-responders did not differ significantly from the responders in age, gender or disease phenotype, and equal proportion of both CD and UC patients responded (not shown in table).

Sanitation and the hygiene hypothesis Having a pet as a child was protective against UC (OR: 0.3, 95% CI: 0.1–0.7) and insignificant in CD (see Table 3). Poor sanitation, defined as at least two exposures during childhood regarding in-house and hot water, flush toilets and shared bathrooms, showed a trend towards being protective against UC (OR: 0.45, 95% CI: 0.2–1.03) but not CD.

Family history

Smoking

A total of 10% (8 patients) with CD had a first degree relative with a history of IBD. In UC, this was the case in 8%4 of the patients. In the control group, there were no individuals with a first degree relative with IBD.

A past history of smoking was significantly associated with both CD (OR: 1.42, 95% CI: 1.0–2.02) and UC (OR: 1.39, 95% CI: 1.1–1.92), as shown in Table 4. Very few CD and UC patients continued to smoke after diagnosis, so numbers were too small to assess.

Childhood immunity Chicken pox infection as a child was higher amongst CD compared with healthy controls (OR: 1.74, 95% CI: Table 1 Patient characteristics of 132 incident cases from the Barwon cohort who participated in the environmental case control study

Total no. patients (%) Male (%) Female (%) Age at diagnosis (range) Median time to diagnosis in months (range) First degree relative Extra intestinal complications Joint Skin Eye Disease extent Proctitis Left-sided colitis Pancolitis Disease location L1: terminal ileum L2: colonic L3: ileocolonic +L4: upper gastrointestinal Disease behaviour Inflammatory Stricturing Penetrating Perianal CD, Crohn disease; UC, ulcerative colitis.


CD

UC

81 (62%) 36 (44%) 45 (56%) 37 (11–75) 6.4 (0.5–79)

51 (39%) 22 (43%) 29 (57%) 40 (11–76) 3 (0–73)

8 (10%)

4 (8%)

7 (9%) 4 (5%) 1 (1%)

3 (6%) 2 (4%) 3 (6%)

— — —

15 (29%) 21(41%) 15 (29%)

30 (37%) 16 (20%) 35 (43%) 9 (11%)

— — — —

62 (78%) 11 (14%) 7 (9%) 15 (19%)

— — — —

Dietary factors Frequent fast food intake, defined as more than once a week, was significantly associated with a risk of UC (43%, OR: 5.78, 95% CI: 2.38–14.03) and CD (27%, OR: 2.84, 95% CI: 1.21–6.64), as shown in Table 4. Caffeine was protective against UC, with 87% of controls reporting a high intake compared with 61% of UC patients (UC OR: 0.51, 95% CI: 0.30–0.87). There was a trend towards significance in CD (OR: 0.59, 95% CI: 0.34–1.03). Daily fruit intake was protective against UC (OR: 0.26, 95% CI: 0.12–0.57).

Discussion This is the first population-based Australian cohort study to investigate the impact of environmental factors on the development of IBD in an area known to have a very high incidence of disease. Childhood immunological events, such as tonsillectomy, are associated with a higher risk of CD. Childhood pet ownership decreased the risk of UC. An important finding was the influence of diet. High caffeine intake was protective against both CD and UC, while frequent fruit intake was protective against UC. Frequent fast food intake on the other hand increased the risk of both diseases. The findings support emerging theories on IBD aetiology, firstly that early childhood exposures are important and secondly that modulation of the intestinal microbiota through immunological, hygienic and dietary events may increase the risk of IBD in the future. 671

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Table 2 Comparison of childhood immunological exposures and infections in Crohn and ulcerative colitis compared with controls Exposure Tonsillectomy† Appendicectomy Vaccinations BCG Measles Rubella Diphtheria Tetanus Polio Childhood disease Measles Pertussis Rubella Chicken pox† Mumps Scarlet fever

Control

CD

UC

CD versus controls (P-value)

Odds ratio (95% CI)

UC versus controls (P-value)

16 (21.9%) 9 (12.3%)

27 (45.8%) 12 (21.1%)

9 (22.5%) 4 (10.5%)

0.003 0.170

1.74 (1.15–2.6)

0.943 0.780

32 (76.2%) 42 (79.2%) 48 (85.7%) 46 (100%) 56 (98.2%) 50 (90.9%)

16 (72.7%) 42 (89.4%) 37 (84.1%) 45 (93.8%) 50 (96.2%) 47 (95.9%)

10 (58.8%) 31 (88.6%) 26 (81.3%) 29 (90.6%) 35 (100%) 32 (94.1%)

0.683 0.189 0.784 0.999 0.505 0.333

0.187 0.261 0.583 0.999 0.999 0.588

5 (38.5%) 0 (0%) 0 (0%) 6 (46.2%) 5 (35.7%) 1 (7.7%)

20 (50%) 1 (3.3%) 8 (23.5%) 35 (87.5%) 10 (27%) 3 (8.8%)

14 (46.7%) 2 (7.7%) 1 (3.7%) 23 (74.2%) 7 (24.1%) 2 (7.1%)

0.425 0.999 0.999 0.005 0.583 0.880

0.619 0.999 0.999 0.080 0.430 0.950

3.89 (1.61–9.4)

Odds ratio (95% CI)

Number refers to those who replied yes to the question. Percentage refers to those with positive reply over the total number that answered the question (not every participant replied to each question). Bold values are statistically significant. CD, Crohn disease; CI, confidence interval; UC, ulcerative colitis. †Significant difference in that exposure between the groups. Table 3 Comparison of childhood sanitation exposure in Crohn and ulcerative colitis patients compared to controls Exposure Pet(s)† Swimming pool Other‡ Both Poor sanitation§

Control

CD

UC


67 (93.1%) 19 (28.8%) 16 (24.2%) 31 (47%) 4 (5.9%)

54 (84.4%) 19 (32.2%) 17 (28.8%) 23 (39%) 7 (11.7%)

36 (69.2%) 11 (29.7%) 8 (21.6%) 18 (48.6%) 9 (23.1%)

Odds ratio (95% CI)


Odds ratio (95% CI)

0.201 0.594

0.001 0.953

0.36 (0.2–0.79)

0.252

0.014

0.45 (0.2–1.03)

Number refers to those who replied yes to the question. Percentage refers to those with positive reply over the total number that answered the question (not every participant replied to each question). Bold values are statistically significant. CD, Crohn disease; CI, confidence interval; UC, ulcerative colitis. †Significant difference in that exposure between the groups. ‡Swimming in the lake, river and beach during childhood. §Refers to exposure to poor sanitation, which was defined arbitrarily as answering no to two of the five sanitation questions.

There is considerable evidence that environmental factors play a role in the aetiology of IBD. Firstly, there has been a rapid global rise in incidence in the last few decades,1 with a recent rise in incidence among regions where IBD was previously uncommon, such as Asia and Eastern Europe.13 This has coincided with a transition to a more ‘westernised’ lifestyle in these regions.21 Another clue is the ratio of CD and UC as it has considerable geographical variation. Nordic and Eastern European countries show a predominance of UC over CD,6,8,9 but this is the reverse in Northern Europe, Australia and New Zealand.16,22,23 Finally, it has also been shown that migrants will adopt the risk of IBD of their new country in the first generation of migrating over.24,25 These rapid changes over a few decades are unlikely to be explained by genetic susceptibility and suggest an environmental impact. 672

It has been postulated that environmental exposures such as food antigens, antibiotics and infections contribute to the dysbiosis of the gut flora, resulting in the dysregulation of the immune system in a genetically predisposed individual. The westernised lifestyle has been implicated in bringing about changes in these exposures through improved sanitation, dietary changes and widespread medical intervention in the form of medications, vaccinations and surgery (such as appendicectomy and tonsillectomy). Diet is difficult to study as an aetiological factor in IBD. This is due to methodological limitations inherent in studies relying on retrospective assessment of diet. Nonetheless, diet has a significant impact on the composition and metabolic behaviour of gut microbiota.26 We have shown that daily fruit intake is protective against UC, irrespective of fibre intake. Citrus fruit intake has © 2016 Royal Australasian College of Physicians

Risks of developing inflammatory bowel disease

Table 4 Comparison of pre-illness exposure to smoking, contraceptive use and diet habits in Crohn disease and ulcerative colitis to healthy controls Exposure Past smoker† Ongoing smoker† Fruit daily† Vegetables daily Eggs daily Fast food† High fibre High sugar High caffeine† Breastfed Contraceptive

Control

CD

UC


Odds ratio (95% CI)


Odds ratio (95% CI)

24 (33.3%) 10 (15.2%)

33 (50.8%) 2 (3.3%)

24 (53.3%) 1 (2.4%)

0.029 0.023

1.42 (1.0–2.02) 0.58 (0.4–0.80)

0.026 0.029

1.39 (1.1–1.92) 0.63 (0.5–0.81)

77 (78.6%) 65 (92.9%)

43 (68.3%) 57 (90.5%)

20 (48.8%) 33 (80.5%)

0.313 0.600

0.003 0.059

0.59 (0.4–0.88)

3 (4.3%) 7 (10.1%) 5 (23.8%) 17 (23.3%) 61 (87.1%) 54 (78.3%) 31 (79.5%)

5 (8.2%) 16 (26.7%) 23 (39%) 24 (29.6%) 43 (70.5%) 40 (74.1%) 24 (52.2%)

3 (7.3%) 20 (50%) 12 (26.7%) 13 (22.8%) 25 (61%) 21 (65.6%) 20 (83.3%)

0.359 0.003 0.247 0.350 0.031 0.548 0.381

2.26 (1.76–4.33)

0.59 (0.34–1.03)

0.500 2 cm) early stage breast cancer. Patients who receive NAST followed by optimal locoregional therapy have equivalent disease-free and overall survival outcomes to those who receive systemic therapy after surgery.1 NAST has some advantages over a surgery-first approach, including downstaging to breast conserving surgery for some women who would otherwise have required a mastectomy; reducing the volume of surgically resected breast and axillary tissue and providing prognostic information depending on the degree of tumour response.2–4 Maximal response, referred to as pathological complete response (pCR), refers to a lack of identifiable invasive tumour on histopathologic examination of the breast and lymph nodes.5 A pCR is achieved in 50% of hormone receptor negative, human epidermal growth factor receptor 2 (HER2) positive breast cancer (15% of the breast cancer population) and in 33% of hormone 677

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receptor negative, HER2 negative breast cancer (triplenegative, 15% the breast cancer population).4 Lesser responses can be quantified using a score, such as the residual cancer burden, which has prognostic value in hormone receptor positive disease, where approximately 15% patients achieve a pCR.3 Novel treatment strategies for early breast cancer may receive fast-track provisional regulatory approval based on pCR as an early endpoint, particularly in triple-negative and HER2 positive disease where pCR is more likely to act as a surrogate of survival outcomes. However, meta-analyses have not yet shown a correlation between pCR and disease-free or overall survival endpoints2,4, and confirmatory results from trials powered for these survival outcomes are required for full approval.6 Given equivalent survival outcomes, NAST is an option that may be preferred by some patients with operable breast cancer; however, the rate of use in Australia and New Zealand appears low, at fewer than 3% of all operable breast cancer patients.7 According to one report, approximately 3.8% of women with operable breast cancer in the United States receive NAST; however, benchmarking is difficult as the optimal rate is not known.8 International guidelines support the use of NAST as an option for operable breast cancer,9–11 patient advocates support the use of neoadjuvant clinical trials,12 and patients with a past diagnosis of breast cancer endorse the option of NAST being discussed with patients as part of routine clinical care.13 As such, NAST is expected to remain an important treatment option for women with early breast cancer and their treating clinicians. Data are limited on routine clinical practice, facilitators and barriers to the use of NAST both internationally and in Australia/New Zealand. We sought to understand how NAST is currently used in Australia and New Zealand, in order to inform strategies to optimise its appropriate use in routine practice and in clinical trials.

Material and methods Population and design A cross-sectional cohort study of Australian and New Zealand breast cancer specialists was undertaken. Eligible participants were clinicians who treat patients with breast cancer, including medical oncologists, surgeons, radiation oncologists and breast physicians. An email invitation was sent to clinician members of the Australia and New Zealand Breast Cancer Trials Group (ANZBCTG), the Medical Oncology Group of Australia, Breast Surgeons of Australia and New Zealand (BreastSurgANZ) and the New Zealand Breast Special 678

Interest Group, the major professional bodies representing breast cancer specialists in the region. Some clinicians are members of multiple organisations; however, to maintain members’ confidentiality, only duplicates between the ANZBCTG distribution list and the BreastSurgANZ members on their publicly available website could be removed. A total of 930 invitation emails were sent, excluding known duplicates. The invitation email contained brief description of the study and a hyperlink to participate in an online survey, hosted by the ANZBCTG. Two reminder emails were sent.

Questionnaire The questionnaire was developed by a multidisciplinary group, including medical oncologists, a surgeon, a psychologist and a consumer, then pre-tested and modified based on feedback from a small group of clinicians who had not previously seen it. Three levels of participation were possible. Surgeons and medical oncologists, as the target audience, were offered (i) a core questionnaire and (ii) an optional supplementary questionnaire (Supporting Information, Appendix S1). Other specialists were offered (iii) an abbreviated questionnaire about demographics and barriers only. This design aimed to optimise the completion rate by allowing clinicians to minimise their time commitment by completing the core questionnaire only, and to add value if they were willing to spend additional time on the supplementary questionnaire. The core questionnaire included: demographics, neoadjuvant referral patterns, patient and tumour characteristics for which NAST was considered appropriate, barriers to the use of NAST and interest in offering NAST as a treatment option for routine care and clinical trials. The supplementary questionnaire included questions on clinical workup and management of NAST patients, decision making, perceived patient experiences and patient selection for clinical trials compared with routine care. Data from this survey about clinical decision-making control preferences about neoadjuvant therapy have been published previously and will not be reported here.14

Analysis Descriptive statistics were used to describe responses. Demographics were reported as frequencies, medians and proportions. Pearson Chi-squared tests were used for categorical data, and t-tests for continuous data. Statistical significance was set at a P-value of 0.05 for all tests. A logistic regression model was fitted, including potential predictors for offering NAST. © 2016 Royal Australasian College of Physicians

Neoadjuvant clinician survey

This study was designed and conducted according to principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. All participants provided informed, voluntary consent prior to participation. The study was prospectively approved by the Hunter New England Human Research Ethics Committee and was prospectively registered on the Australia and New Zealand Clinical Trials Registry (www.anzctr.org. au, ACTRN12613000658718).

Results Core questionnaire Between April and July 2014, 225 responses were received. After excluding 13 who reported not treating breast cancer patients and 5 who did treat breast cancer but indicated that they did not want to complete the survey, 207 responses were analysed, representing a conservative response rate of 23% (207 out of 917). Eighty clinicians answered the supplementary questionnaire. Responses were received from Australia (n = 155) and New Zealand (n = 52): 112 surgeons (54%), 87 medical oncologists (42%), 6 radiation oncologists (3%) and 2 breast physicians (1%). This included 120 metropolitan, 81 regional and 6 rural practitioners. Fifty-two were primarily academic, 111 public hospital and 44 private practitioners. There were equal numbers of males and females. Forty-five respondents (22%) reported not offering NAST, and 162 (78%) reported routinely offering NAST to selected women with operable breast cancer. Respondents saw a median of 80 newly diagnosed breast cancer patients per year, of whom a median of 80% (interquartile range (IQR) 70–80%) were considered to have operable disease at the time of diagnosis. Clinicians reported offering NAST to a median of 9% (IQR 5–15%) of their patients with operable disease, of whom a median of 90% (IQR 70–90%) agreed to see a medical oncologist; a median of 85% (IQR 70–90%) of those who saw a medical oncologist started NAST. Reasons for recommending or offering NAST, by the 162 respondents who use this treatment strategy, are shown in Figure 1. NAST was offered as a treatment option for selected patients with all breast cancer subtypes, shown in Table 1, but more frequently to women with HER2 positive and triple-negative cancers. Comparison of subtypes, by hormone receptor and HER2 status, did not reach statistical significance. The HER2 positive and triple-negative subtypes were numerically more likely to be offered NAST for a smaller primary tumour size. In univariate analysis, >10 years of experience as a © 2016 Royal Australasian College of Physicians

specialist predicted for offering NAST (P = 0.048), but specialty, location, practice type and gender were not significant predictors. In a multivariate model, including specialty, location, practice type, gender or years of experience, there were no significant predictors for offering NAST (data not shown).

Barriers Table 2 lists patient, system, clinician and clinical trialrelated barriers to the use of NAST. Of the 165 responses to this part of the questionnaire, more non-surgeons than surgeons reported clinician or system-related barriers (37 vs 73%, P < 0.001). The most commonly reported barriers overall were patient related: desire for immediate surgery, lack of awareness of NAST, fear of progression on NAST and lack of interest in downstaging. Compared with surgeons, more non-surgeons indicated that patients’ lack of awareness of NAST (60 vs 41%, P = 0.016), other clinicians’ disinterest in NAST (43 vs 13%, P < 0.001) and lack of NAST clinical trials (41 vs 7%, P < 0.001) to be important barriers.

Interest in offering NAST in routine care and in clinical trials Of 165 responses to this question, 74 (45%) and 96 (58%) indicated a preference to increase the number of patients who receive NAST as part of routine care and as part of a clinical trial respectively. Ninety-one (55%) felt that the number of their patients given NAST in routine care was appropriate, and 69 (42%) felt that the right number of patients is accessing NAST clinical trials. Importantly, there were no respondents who believed that NAST is being given too often, as routine care or in clinical trials. Fifty-eight (35%) had enrolled one or more patients on a NAST clinical trial. Considering only the 45 respondents who did not routinely offer NAST for operable breast cancer, 20 (44%) were interested in offering more of their patients NAST in routine care, and 29 (64%) were interested in offering more patients NAST in a clinical trial. In sum, 193 out of 207 (93%) respondents demonstrated interest in offering NAST to at least some of their patients with operable breast cancer.

Supplementary questionnaire NAST patient workup and treatment In the supplementary questionnaire, 77 out of 80 (96%) respondents indicated that a core biopsy was required to make treatment decisions, and for 64 (80%), a core biopsy was carried out as the first diagnostic biopsy for 679

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Plan for immediate reconstruction Downstage locally advanced disease Neoadjuvant clinical trial Downstage to breast conserving surgery Await genetic testing results Any adjuvant chemotherapy candidate Plan for definitive surgery Test systemic therapy effectiveness 0%

20%

40%

60%

80%

100%

Figure 1 Clinicians’ reasons for offering/ recommending neoadjuvant systemic therapy. ( ), Recommend; ( ), offer; ( ), do not offer.

Table 1 Patient’s characteristics for whom clinicians would consider NAST

NAST offered to this subtype Smallest breast tumour size for routine NAST (cm)

Axillary lymph node status Inoperable disease only If downstaging from mastectomy to BCS desired Any mastectomy candidate Clinical trial participants only