Cardiovascular diseases

The association of elevated plasma TMAO with poorer prognosis is only partially mediated by renal dysfunction

Wensheng Li · Anqing Huang · Hailan Zhu · Xinyue Liu · Xiaohui Huang · Yan Huang · Xiaoyan Cai · Jianhua Lu · Yuli Huang

Introduction: Coronavirus disease 2019 (COVID‐19) is a contagious disease that is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Health care workers are at risk of infection from aerosolisation of respiratory secretions, droplet and contact spread. There are a number of procedures that represent a high risk of aerosol generation during cardiothoracic surgery. It is important that adequate training, equipment and procedures are in place to reduce that risk. Recommendations: We provide a number of key recommendations, which reduce the risk of aerosol generation during cardiothoracic surgery and help protect patients and staff. These include general measures such as patient risk stratification, appropriate use of personal protective equipment, consideration to delay surgery in positive patients, and careful attention to theatre planning and preparation. There are also recommended procedural interventions during airway management, transoesophageal echocardiography, cardiopulmonary bypass, chest drain management and specific cardiothoracic surgical procedures. Controversies exist regarding the management of low risk patients undergoing procedures at high risk of aerosol generation, and recommendations for these patients will change depending on the regional prevalence, risk of community transmission and the potential for asymptomatic patients attending for these procedures. Changes in management as a result of this statement: This statement reflects changes in management based on expert opinion, national guidelines and available evidence. Our knowledge with regard to COVID‐19 continues to evolve and with this, guidance may change and develop. Our colleagues are urged to follow national guidelines and institutional recommendations regarding best practices to protect their patients and themselves. Endorsed by: Australian and New Zealand Society of Cardiac and Thoracic Surgeons and the Anaesthetic Continuing Education Cardiac Thoracic Vascular and Perfusion Special Interest Group.

Joanne F Irons · Warren Pavey · Jayme S Bennetts · Emily Granger · Elli Tutungi · Aubrey Almeida

Overcoming patient, GP, and health system barriers to changes in care delivery are critical to progress

Charlotte M Hespe · Anna Campain · Ruth Webster · Anushka Patel · Lucie Rychetnik · Mark F Harris · David P Peiris

To the Editor: Takotsubo syndrome, also known as stress cardiomyopathy, apical ballooning syndrome, or broken heart syndrome, is a reversible cardiomyopathy frequently precipitated by a stressful event. Its clinical presentation is indistinguishable from a myocardial infarction,1 with electrocardiogram (ECG) changes and elevation in cardiac enzymes. The syndrome was first described in 1991 in Japan and named in reference to the left ventricle morphological features that resemble a pot used for trapping octopuses. Takotsubo syndrome has recently been reported in association with coronavirus disease 2019 (COVID‐19),2 but we report a case of takotsubo cardiomyopathy brought on by the stress of isolation as a result of social distancing. A 71‐year‐old woman presented to the emergency department complaining of chest pain. On arrival, an ECG demonstrated diffuse ST elevation (Box) and troponin was elevated (7800 ng/L). Coronary angiography was performed immediately which did not demonstrate any obstructive lesion and she was admitted to the intensive care unit (ICU) for ongoing haemodynamic support. Echocardiography performed in the ICU showed a dilated left ventricle with an akinetic apex and preserved contraction of the basal segments (Box) suggestive of takotsubo cardiomyopathy. On questioning regarding recent stressors, our patient, who lived alone, reported significant anxiety about not being able to visit family due to social distancing, and was particularly saddened by being unable to see her grandchildren. Public health interventions undertaken by governments around the world in an attempt to reduce the rate of transmission of COVID‐19, or to “flatten the curve”, have included measures such as social distancing.3 While being effective in the aim of lowering infections, these measures may have many unintended consequences. Social isolation is detrimental to mental health, associated with increased stress levels and anxiety, especially in older people, who may be less able to use technology to stay in contact with friends and family.4 In our patient, this stress was enough to trigger takotsubo cardiomyopathy. Box – Electrocardiogram (A) showing diffuse ST elevation. Echocardiogram (B) showing a dilated left ventricle with an akinetic apex and preserved contraction of the basal segments (arrows)

Jon Rivers · Joshua F Ihle

To the Editor: The recent article by Akram and Sadashiv1 presents a timely and most welcome opportunity to enhance awareness, in the medical community at large, of the investigation and treatment options for proximal deep vein thrombosis (DVT) of the lower extremity. Diagnosis of lower extremity DVT is generally made or confirmed with duplex ultrasound assessment. Standards in Australia and New Zealand state that duplex ultrasound for DVT should determine the proximal extent of the thrombus, as well as identify structures causing extrinsic compression that may have contributed to the thrombosis.2 This information assists the clinician in determining the need to consider specific treatments, such as venous stenting for May–Thurner syndrome or placement of a caval filter in cases where there is a free‐floating thrombus in the inferior vena cava. Duplex ultrasound can play a key role in the diagnosis of May–Thurner syndrome.3 Technical factors, such as the presence of bowel gas, may inhibit ultrasonographic views of the abdominal and pelvic vasculature, and may therefore prevent attainment of the required information. Further, clinical experience in vascular surgery services in Australia and overseas has shown that, despite the above‐mentioned standards, it is common for there to be no attempt to obtain adequate proximal views during ultrasound DVT scans. Clinicians should therefore be wary of the limitations of ultrasound DVT scans and consider alternate imaging modalities such as computed tomography venography in cases where ultrasound has yielded inadequate information. Clinicians should also be aware of the potential of clot removal therapies such as catheter‐directed thrombolysis to improve long term outcomes for patients with proximal lower extremity DVT, whether or not May–Thurner syndrome is identified as a predisposing factor. Recent studies have reported improvements in the incidence and/or severity of post‐thrombotic syndrome in patients receiving catheter‐directed thrombolysis compared with those treated with anticoagulation alone.4,5 The appropriateness of catheter‐directed thrombolysis for some patients is acknowledged in the relevant guidelines,6 although patient selection remains a topic of debate. Lower extremity DVT is a common condition encountered in both inpatient and community settings. Due to technical considerations and quality variations, ultrasound DVT scans do not always yield adequate information to determine the optimal therapeutic approach. In such situations, consultation with a vascular specialist is strongly encouraged.

Trevor MY Kwok

Blood pressure is the reflection of the performance of the heart and responsiveness of the vascular system

Syamkumar D Menon · Sanjay Ganapathi

Our approach to estimating risk in some patients should be updated and the role of coronary artery calcium scoring evaluated

Harry Klimis · Clara K Chow

Introduction: The coronavirus 2019 disease (COVID‐19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Pre‐existing cardiovascular disease (CVD) increases the morbidity and mortality of COVID‐19, and COVID‐19 itself causes serious cardiac sequelae. Strategies to minimise the risk of viral transmission to health care workers and uninfected cardiac patients while prioritising high quality cardiac care are urgently needed. We conducted a rapid literature appraisal and review of key documents identified by the Cardiac Society of Australia and New Zealand Board and Council members, the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, and key cardiology, surgical and public health opinion leaders. Main recommendations: Common acute cardiac manifestations of COVID‐19 include left ventricular dysfunction, heart failure, arrhythmias and acute coronary syndromes. The presence of underlying CVD confers a five‐ to tenfold higher case fatality rate with COVID‐19 disease. Special precautions are needed to avoid viral transmission to this population at risk. Adaptive health care delivery models and resource allocation are required throughout the health care system to address this need. Changes in management as a result of this statement: Cardiovascular health services and cardiovascular health care providers need to recognise the increased risk of COVID‐19 among CVD patients, upskill in the management of COVID‐19 cardiac manifestations, and reorganise and innovate in service delivery models to meet demands. This consensus statement, endorsed by the Cardiac Society of Australia and New Zealand, the Australian and New Zealand Society of Cardiac and Thoracic Surgeons, the National Heart Foundation of Australia and the High Blood Pressure Research Council of Australia summarises important issues and proposes practical approaches to cardiovascular health care delivery to patients with and without SARS‐CoV‐2 infection.

Sarah Zaman · Andrew I MacIsaac · Garry LR Jennings · Markus P Schlaich · Sally C Inglis · Ruth Arnold · Saurabh Kumar · Liza Thomas · Sudhir Wahi · Sidney Lo · Carolyn Naismith · Stephen J Duffy · Stephen J Nicholls · Andrew Newcomb · Aubrey A Almeida · Selwyn Wong · Mayanna Lund · Derek P Chew · Leonard Kritharides · Clara K Chow · Ravinay Bhindi

Objectives: To assess the predictive value of the Australian absolute cardiovascular disease risk (ACVDR) calculator and other assessment tools for identifying Australians with family histories of early onset coronary artery disease (CAD) who have coronary artery calcification. Design, setting, participants: People without known CAD were recruited at seven Australian hospitals, October 2016 – January 2019. Participants were aged 40–70 years, had a family history of early onset CAD, and a 5‐year ACVDR of 2–15%. Main outcome measures: CT coronary artery calcium score greater than zero (any coronary calcification) or greater than 100 (calcification warranting lipid therapy). Results: 1059 participants were recruited; 477 (45%) had non‐zero coronary artery calcium scores (median 5‐year ACVDR, 4.8% [IQR, 2.9–7.6%]; median coronary artery calcium score, 41.7 [IQR, 8–124]); 582 (55%) did not (median 5‐year ACVDR, 3.2% [IQR, 2.0–4.6%]). Of 151 participants with calcium scores of 100 or more, 116 (77%) were deemed to be at low cardiovascular risk by Australian guidelines, while 14 of 75 participants at intermediate risk (19%) had zero calcium scores. The sensitivity of the ACVDR calculator for identifying people with non‐zero calcium scores (area under receiver operator curve [AUC], 0.674) was lower than that of the pooled cohort equation (AUC, 0.711; P < 0.001). ACVDR (10‐year)‐ and Multi‐Ethnic Study of Atherosclerosis (MESA)‐predicted risk categories concurred for 511 participants (48%); classifications were concordant for 925 participants (87%) when the ACVDR was supplemented by calcium scores. Conclusions: Coronary artery calcium scoring should be considered as part of the heart health check for patients at intermediate ACVDR risk and with family histories of early onset CAD. Alternative risk calculators may better select such patients for further diagnostic testing and primary prevention therapy. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN 12614001294640; 11 December 2014 (prospective).

Prasanna Venkataraman · Tony Stanton · Danny Liew · Quan Huynh · Stephen J Nicholls · Geoffrey K Mitchell · Gerald F Watts · Andrew Maxwell Tonkin · Thomas H Marwick

The major impediments to control are lack of commitment, funding and coordination, not lack of knowledge It has been a long time coming, but Australia is starting to understand the tragedy and injustice of rheumatic heart disease (RHD) in Aboriginal and Torres Strait Islander people. No condition is more emblematic of “the gap”: in Australia, the burden of RHD is borne almost exclusively by Indigenous people, with rates among the highest in the world. It is a disease with social determinants, including poverty and overcrowded housing, it starts in childhood but stretches into adulthood, it kills people prematurely, and, most devastatingly, it is preventable. The major impediments to its being controlled or even eliminated are lack of commitment, funding and coordination, not lack of knowledge. Over the past five years, a network of researchers and service providers has come together in the National Health and Medical Research Council‐funded End Rheumatic Heart Disease Centre of Research Excellence. The Centre is about to publish The RHD Endgame Strategy: The blueprint to eliminate rheumatic heart disease in Australia by 2031. It has already modelled what will happen if we fail to alter course in RHD control: more than 10 000 Indigenous Australians will develop RHD over the next 11 years, of whom 563 will die and 1370 will require heart surgery as a direct consequence of RHD. More than $317 million would be needed for their medical care alone.1 Hearteningly, END RHD, a coalition of organisations led by the Aboriginal Community Controlled Health Organisation (ACCHO) sector, has formed to support communities at greatest risk of RHD, to advocate implementation of the Endgame Strategy, and to educate Australians about the role they can play in ending RHD. END RHD is co‐chaired by the chief executive officer of the National Aboriginal Community Controlled Health Organisation, Ms Pat Turner AM, and includes representatives from ACCHO peak bodies in each of the jurisdictions in which RHD is a major problem. END RHD embodies the essential elements of what is needed to rid Australia of this devastating disease: Indigenous leadership, community empowerment, and a primary focus on the social determinants of disease, in addition to strategies targeting streptococcal A skin and throat infections and care for people with established RHD. A study in this issue of the MJA2 highlights RHD care, other elements needed to implement the Endgame Strategy, and some of the challenges in doing so. Francis and colleagues report a cross‐sectional echocardiographic screening survey of children and young people in the remote Northern Territory community of Maningrida. They found an extraordinarily high prevalence of definite RHD (5.2% of screened people aged 5–20 years), of whom 62% had previously been undiagnosed and 25% had severe disease. This project had many admirable elements that could inform activities in other communities. The focus on education and health promotion in local languages, intense community engagement, and local leadership were exemplary, to which the very high participation rate is testament. However, a range of questions remain unanswered. Why, for instance, are the reported results so different from the findings of the gECHO study,3 conducted a decade earlier? In this study, in which almost 4000 Indigenous children aged 5–15 years in remote communities across northern and central Australia were screened, the prevalence of definite RHD was 0.86%; 53% of cases were previously undiagnosed, and only one in 18 new cases was severe. While the prevalence of definite RHD was highest in the Top End of the NT (1.5%), where Maningrida is located, the threefold difference in prevalence between the two studies is remarkable. A single community may not be representative of an entire region, but if the Maningrida findings are to stimulate consideration of more widespread screening, how one identifies communities in which it is warranted is critical. The difference in prevalence found by the two studies is difficult to explain. There is no evidence that socio‐economic determinants of group A streptococcal infections and RHD had dramatically worsened in this region over the past 10 years to a degree that would explain such discordance. However, four years prior to the study by Francis and colleagues, a large cluster of acute rheumatic fever (ARF) cases was identified in Maningrida: more than 1.5% of 5–14‐year‐old children developed ARF over a 6‐month period.4 As most people with RHD in the NT do not have known histories of ARF, and ARF can be very mild or even asymptomatic, it is likely that a substantially greater proportion of Maningrida residents had ARF at this time.5 Such a significant outbreak has rarely, if ever, been reported for an Indigenous community, and the study of Francis and colleagues may have included a number of RHD cases related the ARF outbreak four years earlier. Francis and his co‐authors also point out that auscultation is still used in child health checks in NT Indigenous communities. This approach, however, is less accurate than flipping a coin for diagnosing RHD, and should therefore be abandoned for this purpose.6 We commend the authors for the careful wording of their recommendations. They recognise that echocardiographic screening may have obvious benefits; besides detecting new cases of RHD and facilitating life‐saving treatment and secondary prevention, it is an excellent tool for motivating a community to focus on RHD, which, together with education about prevention and related activities, can enhance engagement. But it is also intensive and costly: hence the need to focus on more practical methods for implementation, as the authors point out, but also to ensure that communities are advised about a threshold for screening in accordance with established criteria. They must also be provided with adequate technical support and advice before embarking on such screening programs. Australia has a rare opportunity to eliminate RHD by implementing the Endgame Strategy. In so doing, we will make an important step towards closing the health gap between Indigenous and non‐Indigenous Australians, not only by reducing the burden of RHD but also the burdens of other diseases that share similar social determinants. But success depends on communities being supported to direct local strategies that comprehensively address streptococcal A infections, ARF and RHD at many levels. Maningrida is a perfect example.

Jonathan R Carapetis · Alex Brown

A 52-year-old man presented with fever and progressive dyspnoea

Jeet Ram Kashyap · Suraj Kumar

Objectives: Using echocardiographic screening, to estimate the prevalence of rheumatic heart disease (RHD) in a remote Northern Territory town. Design: Prospective, cross‐sectional echocardiographic screening study; results compared with data from the NT rheumatic heart disease register. Setting, participants: People aged 5–20 years living in Maningrida, West Arnhem Land (population, 2610, including 2366 Indigenous Australians), March 2018 and November 2018. Intervention: Echocardiographic screening for RHD by an expert cardiologist or cardiac sonographer. Main outcome measures: Definite or borderline RHD, based on World Heart Federation criteria; history of acute rheumatic fever (ARF), based on Australian guidelines for diagnosing ARF. Results: The screening participation rate was 72%. The median age of the 613 participants was 11 years (interquartile range, 8–14 years); 298 (49%) were girls or women, and 592 (97%) were Aboriginal Australians. Definite RHD was detected in 32 screened participants (5.2%), including 20 not previously diagnosed with RHD; in five new cases, RHD was classified as severe, and three of the participants involved required cardiac surgery. Borderline RHD was diagnosed in 17 participants (2.8%). According to NT RHD register data at the end of the study period, 88 of 849 people in Maningrida and the surrounding homelands aged 5–20 years (10%) were receiving secondary prophylaxis following diagnoses of definite RHD or definite or probable ARF. Conclusion: Passive case finding for ARF and RHD is inadequate in some remote Australian communities with a very high burden of RHD, placing children and young people with undetected RHD at great risk of poor health outcomes. Active case finding by regular echocardiographic screening is required in such areas.

Joshua R Francis · Helen Fairhurst · Hilary Hardefeldt · Shannon Brown · Chelsea Ryan · Kurt Brown · Greg Smith · Roz Baartz · Ari Horton · Gillian Whalley · James Marangou · Alex Kaethner · Anthony DK Draper · Christian L James · Alice G Mitchell · Jennifer Yan · Anna Ralph · Bo Remenyi

Objective: To assess the cost‐effectiveness of a computer‐guided quality improvement intervention for primary health care management of cardiovascular disease (CVD) in people at high risk. Design: Modelled cost‐effectiveness analysis of the HealthTracker intervention and usual care for people with high CVD risk, based on TORPEDO trial data on prescribing patterns, changes in intermediate risk factors (low‐density lipoprotein cholesterol, systolic blood pressure), and Framingham risk scores. Participants: Hypothetical population of people with high CVD risk attending primary health care services in a New South Wales primary health network (PHN) of mean size. Intervention: HealthTracker, integrated into health care provider electronic health record systems, provides real time decision support, risk communication, a clinical audit tool, and a web portal for performance feedback. Main outcome measures: Incremental cost‐effectiveness ratios (ICERs): difference in costs of the intervention and usual care divided by number of CVD events averted with HealthTracker. Results: The estimated numbers of major CVD events over five years per 1000 patients at high CVD risk were lower in PHNs using HealthTracker, both for patients with prior CVD events (secondary prevention; 259 v 267 with usual care) and for those without prior events (primary prevention; 168 v 176). Medication costs were higher and hospitalisation costs lower with HealthTracker than with usual care for both primary and secondary prevention. The estimated ICER for one averted CVD event was $7406 for primary prevention and $17 988 for secondary prevention. Conclusion: Modelled cost‐effectiveness analyses provide information that can assist decisions about investing in health care quality improvement interventions. We estimate that HealthTracker could prevent major CVD events for less than $20 000 per event averted. Trial registration (TORPEDO): Australian New Zealand Clinical Trials Registry, ACTRN 12611000478910.

Bindu Patel · David P Peiris · Anushka Patel · Stephen Jan · Mark F Harris · Tim Usherwood · Kathryn Panaretto · Thomas Lung

During the COVID‐19 pandemic, people with heart disease are likely abandoning usual medical advice As the world watches the spread of the coronavirus disease 2019 (COVID‐19) pandemic, affecting the health of millions of people and the lives of everyone, common health conditions including heart disease, stroke, cancer and other chronic diseases continue. While there is no doubt that there are direct consequences for morbidity and mortality of COVID‐19, including its direct cardiovascular effects, it will be important to ensure that these are not matched by the indirect consequences. Countries are at different stages in the natural history of the pandemic, but there is a clear pattern. Overloaded health systems necessitate the hasty development of new protocols and pathways for common conditions that deviate from established guidelines and that may be caused by changes in community behaviour, either imposed or arising from fear. Unproven therapies are being tested in the field and, in the absence of evidence, there is the potential for theory to drive practice to an extent that is generally not seen in conditions with an established evidence base. During the COVID‐19 pandemic, emergency department (ED) attendances fell dramatically in England, with 89 584 attendances in the week after the lockdown (23–29 March 2020), down 25% compared with the 120 356 attendances during the previous week and almost 50% down on attendances in February 2020.1 This decrease in ED attendances has also been reported in Europe, Canada and Australia.2 ST elevated myocardial infarction (STEMI) rates fell by about 40% in reports from Austria3 and the United States.4 It is possible that COVID‐19 is associated with plaque stabilisation and lower rates of STEMI, but it seems more likely that people with heart disease are abandoning usual medical advice at a time when they may need it the most. In New York, US, a 50% decrease in ED visits for acute coronary syndromes has been reported at the same time as an eightfold increase in out‐of‐hospital cardiac arrest calls in the first week of April 2020.5 It is not clear how many of these calls are COVID‐19‐related, but there seems to be no doubt that people have a reluctance to attend hospital during the peak of the epidemic, which is having a significant cost in mortality. The angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers controversy In the midst of all this, a controversy has emerged about the safety and value of angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) — commonly used for the treatment of hypertension and heart failure — in the context of the COVID‐19 pandemic. In ordinary times, these are considered to be among the safest, best tolerated and most effective drugs for the management of both hypertension and heart failure, with a strong evidence base showing a reduction in morbidity and mortality from these conditions.6,7 To date, there is insufficient clinical evidence that ACEIs, ARBs or other inhibitors of the renin angiotensin system are either harmful or beneficial in the acquisition of COVID‐19 or its subsequent clinical course in individual patients. A number of clinical trials of losartan and recombinant angiotensin‐converting enzyme 2 (ACE2) are underway, such as the Losartan for Patients with COVID‐19 Requiring Hospitalization trial (ClinicalTrials.gov, NCT04312009). The debate has arisen because of circumstantial arguments based on COVID‐19 pathophysiology and renin angiotensin system physiology.8,9 It is argued that ACEIs and ARBs may be harmful because: hypertension is overrepresented among people who develop the most severe complications of COVID‐19;10 severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) gains entry to a cell using ACE2 and type II transmembrane serine proteases;11 ACE2 is highly expressed in the cardiovascular system, gut, kidneys and lungs (in the cardiovascular system, ACE2 is expressed in cardiomyocytes, epicardial adipose tissue, cardiac fibroblasts, vascular smooth muscle and endothelial cells);11 ACEIs or ARBs upregulate ACE2 in heart cells in some experimental models;12 these factors in theory may lead to a greater viral load and more serious infection. Several important links in this logic chain are contested. Early reports of high rates of hypertension in people dying of COVID‐19 or presenting with severe COVID‐19 were not adjusted for age. However, it is clear that most of these patients have comorbidities, including hypertension, heart failure and diabetes, all of which are more common in an older population. The mortality rate in the intensive care unit in 72 regional hospitals in Lombardy, Italy, was 26%. Most patients were male (82%) and had extensive comorbidities, especially hypertension (49% overall and 62% of deaths).10 ACE2 and COVID‐19 pathophysiology The relationship between COVID‐19 and the renin angiotensin system has been reviewed extensively.11 Although there is no doubt that ACE2 is a receptor for COVID‐19 and that the gene is widely expressed in the body, there is mixed evidence on whether it is upregulated by ACEIs or ARBs in animal models, and there is no evidence that it is increased de novo in tissues that have low expression.13 COVID‐19 suppresses ACE2.11 If ACE2 expression is increased by ACEIs or ARBs, it does not necessarily imply that this enhances the ability of SARS‐CoV‐2 to infect cells. The affinity of the virus for ACE2 is very high, and it is not clear that a small increase in expression due to renin angiotensin inhibition would increase intracellular viral load. Another counterargument to this hypothesis is that an increase in ACE2 expression would provide a counter to the suppression due to SARS‐CoV‐2 and allow the beneficial effects of ACE2, including anti‐inflammatory activity, to manifest; that is, ACEIs or ARBs may be beneficial. Trial design to resolve the matter In considering the possibility of interactions between COVID‐19 and medications, it is important to take into account the different stages in the evolution of the disease in an individual. The earliest stages are characterised by mild or absent upper respiratory symptoms and lymphopenia. A minority of people infected with SARS‐CoV‐2 subsequently develop pneumonitis and pulmonary complications. Even fewer people develop the most severe complications with hyperinflammation — also called “cytokine storm” — often with myocarditis and other major organ failures. It is quite likely that the renin angiotensin system and, by implication, drugs that interact with it, such as ACEIs or ARBs, have different actions at various stages of the condition according to the tissues affected. For example, ACE2 is protective in acute lung injury, suggesting that, although it facilitates viral entry through the epithelium, the ACE2 and its product, the angiotensin (1‐7) axis, could be used to reduce tissue injury caused by SARS‐Cov‐2, a potential target for therapy.11 This will be an important consideration in the design and setting of clinical trials. What clinicians can do in the meantime There are highly circumstantial arguments for and against the use of ACEIs and ARBs in patients with COVID‐19 and there are many more in the literature — as preprints and on social media. In the absence of good epidemiological and clinical trial data, there is no immediate and definitive resolution to the debate. What is clear is that people with hypertension and heart failure benefit from ACEIs and ARBs where indicated, and withdrawing treatment is likely to have serious consequences in some people. We are thus left with a situation where stopping ACEIs or ARBs in some people has known and potentially serious sequelae, whereas continuing them in people with or vulnerable to COVID‐19 has unknown consequences that, depending on how the experimental evidence is interpreted, may be negative, neutral or even positive. International and national authorities on cardiovascular disease, including the High Blood Pressure Research Council of Australia, the World Health Organization, the American Heart Association and the European Society of Cardiology, have been united in their recommendation that treatments with ACEIs or ARBs should be continued during the present pandemic pending evidence from clinical studies to the contrary.14,15 In a number of patient groups, ACEIs or ARBs are first line choices; for example, in patients with hypertension and proteinuria or in people with heart failure. Given the clear benefits they have provided over several decades, a decision to withdraw first line therapies should only be based on reasons supported by a strong evidence base. In other groups, such as in patients with uncomplicated essential hypertension, there are alternatives, including calcium channel blockers or diuretics. However, changing medications in patients with well controlled blood pressure requires careful monitoring and there is a risk in the short term that blood pressure will fall outside the optimal range. This may prove challenging during a period when telemedicine is the norm and given that not all households have home blood pressure monitoring equipment and training. As the ACEIs and ARBs controversy has been wisely canvassed in the media, health professionals will need to have a conversation with patients about the benefits or otherwise of continuing their present therapies. It is important that people understand that no concerns have been raised about other medications they may be taking, such as statins, antithrombotic agents, or treatment for diabetes. In recommending continuation of ACEIs or ARBs, physicians can draw comfort that they are backed by almost every cardiovascular health authority in the world. Nevertheless, the clinical trial results of both administration or withdrawal of ACEIs or ARBs cannot come quickly enough, and in the best case, they will allow us to turn practice into the right theory.

Garry LR Jennings

A 48-year-old Chinese woman with obesity and no significant past medical history presented to the emergency department with acute onset pain and swelling in the entire left leg

Farooq Akram · Roshni G Sadashiv

The use of defibrillators for ventricular arrhythmias may significantly reduce mortality when sudden cardiac death is the major contributor The 2018 guidelines from the National Heart Foundation and the Cardiac Society of Australia and New Zealand provide evidence‐based direction for the management of heart failure in Australia.1 A Perspective article published in the Journal in 20192 challenged the weak recommendation for the implantation of a defibrillator in the primary prevention of mortality in dilated cardiomyopathy (DCM) with a left ventricular ejection fraction (LVEF) of 35% or below.1 The authors of the MJA article2 questioned the differences between this recommendation1 and recent Canadian and American guidelines.3,4 We welcome this opportunity to clarify the basis for the Australian guidelines recommendation. To understand the heart failure disease process, it is fundamental to recognise the differences in mechanisms of death and prognosis in ischaemic cardiomyopathy (ICM) versus DCM. Sudden cardiac death is more frequently responsible for mortality in ICM compared with pump failure and death from non‐cardiac causes in DCM. As such, defibrillators that provide shocks for ventricular arrhythmias are expected to significantly reduce mortality when sudden cardiac death is the major contributor. Combined with recent clinical trial data, this is the foundation for the current guidelines in primary prevention, making a strong recommendation for a defibrillator in reducing mortality in ICM compared with a weak recommendation for DCM.1 The GRADE methodology (www.gradeworkinggroup.org) used in these guidelines ensures that the strength of a recommendation not only takes into account the quality of evidence but also the benefits and harms of an intervention, improvements in quality of life, longevity, patient preferences, and resource considerations. The contrasting prognoses of the two major underlying causes for systolic heart failure is demonstrated in the outcomes of clinical trials exploring the role of primary prevention defibrillators. The MADIT‐II trial found a significant reduction in mortality in ICM with an ejection fraction of 30% or below (P = 0.016).5 In contrast, there have been no randomised controlled trials demonstrating a significant reduction in total mortality with implantable cardioverter defibrillators (ICDs) in DCM. On the basis of the SCD‐HeFT trial,6 ICDs were recommended in patients with heart failure with reduced ejection fraction with an LVEF below 35% regardless of underlying coronary artery disease, despite the absence of statistical significance in DCM. The 2016 DANISH study randomly allocated 1116 patients with DCM and a LVEF below 35% to ICDs versus medical therapy, with no significant difference in total mortality.7 Importantly, there were higher rates of optimised medical therapy compared with earlier randomised ICD studies, and cardiac resynchronisation therapy was included in 58% of patients. The limitations of the DANISH trials suggested in the MJA article,2 such as the optimised medical treatment and low mortality, are strengths and more accurately reflect the expected outcomes in a contemporary DCM population who receive guideline‐directed medical therapy. Nonetheless, despite the absence of positive randomised controlled trials, recent meta‐analyses, with the inclusion of DANISH, continue to demonstrate a significant mortality reduction for primary prevention defibrillators in DCM.8 While meta‐analyses provide an analytical technique to pool results and inflate sample sizes to improve statistical power, there are important limitations. Biases related to study selection, publication bias, heterogeneity of study populations in relation to treatment, follow‐up, and study time points have an impact on the findings of meta‐analyses, despite attempts at statistical corrections. Early primary prevention ICD studies were stopped prematurely due to futility and, as such, contribute little to meta‐analyses.9 The inclusion of older studies in undertreated medical patients with the variable inclusion of cardiac resynchronisation therapy is an important limitation in the interpretation of meta‐analyses investigating primary prevention ICDs in DCM. Implanting physicians are cognisant of potential harm, with Australian data reporting ICD‐related complications requiring rehospitalisation or re‐operation in 10% of patients.10 Battery longevity and defibrillator lead durability are additional considerations. Careful patient selection is required to identify patients with DCM likely to benefit from ICD therapy. The 2018 Australian guidelines draw attention to the increased efficacy of ICD therapy in patients younger than 70 years identified as a pre‐specified endpoint in the DANISH study.11 Although the incidence of sudden cardiac death did not differ between age groups, the incidence of non‐sudden cardiac death becomes significantly higher in the older population. Our recommendation is supported by a recent clinical practice update from the Heart Failure Association of the European Society of Cardiology. Providing specific recommendations regarding subpopulations, such as patients with infiltrative or hypertrophic cardiomyopathy, was beyond the scope of the 2018 national guidelines. As we await better tools for risk stratification of patients with DCM, supportive data from randomised controlled trials and improvements in pharmacological and device‐based heart failure therapy, the weak recommendation for ICDs for the primary prevention of mortality1 provides the support for a considered decision between patient and physician, balancing the absence of randomised controlled trial data with the morbidity of an ICD implant. “It is precisely where evidence is lacking or is controversial that clinicians need the most guidance.”12

Peter M Kistler · John J Atherton · Garry Jennings

Weather conditions conducive to extreme bushfires are becoming more frequent as a consequence of climate change.1 Such fires have substantial social, ecological, and economic effects, including the effects on public health associated with smoke, such as premature mortality and exacerbation of cardio‐respiratory conditions.2,3 During the final quarter of 2019 and the first of 2020, bushfires burned in many forested regions of Australia, and smoke affected large numbers of people in New South Wales, Queensland, the Australian Capital Territory and Victoria. The scale and duration of these bushfires was unprecedented in Australia. We undertook a preliminary evaluation of the health burden attributable to air pollution generated by bushfires during this period. Using standard methods for assessing the health impact of air pollution,4 we estimated the numbers of excess deaths, hospitalisations for cardiovascular and respiratory problems, and emergency department presentations with asthma in NSW, Queensland, the ACT and Victoria between 1 October 2019 and 10 February 2020 that could be attributed to bushfire smoke exposure. We estimated population exposure to particulate matter less than 2.5 μm in diameter (PM2.5) for the regions of NSW, Queensland, the ACT and Victoria for which publicly available air quality monitoring data were available (for about 90% of the total population of these states). Data were obtained from the NSW Department of Planning, Industry and Environment,5 the Queensland Department of Science,6 ACT Health,7 and the Environmental Protection Agency Victoria.8 We defined bushfire smoke‐affected days as days on which the 24‐hour mean PM2.5 concentration exceeded the 95th percentile of historical daily mean values for individual air quality stations. We estimated daily mean PM2.5 levels by Statistical Area Level 2 (SA2), using station level data whenever at least one monitoring station was within 100 km of the SA2 centroid, and applying inverse distance weighting.9 Published population and health data from the Australian Bureau of Statistics,10,11 the Australian Institute of Health and Welfare,12,13,14,15 and the NSW Ministry of Health were used.16 We quantified health outcomes by combining baseline incidence rates12,13,14,15 for each health outcome with daily exposure data and applying the relevant exposure–response risk coefficients for each outcome.17,18 We also conducted sensitivity analyses with different PM2.5 thresholds for defining bushfire smoke‐affected days. Further methodological details, including underlying assumptions and limitations, are included in the online Supporting Information. Our analysis of publicly available aggregated data did not require ethics approval. During the study period, PM2.5 concentrations exceeding the 95th percentile of historical daily mean values were recorded by at least one monitoring station in the study area on 125 of 133 days (Box 1). We estimated that bushfire smoke was responsible for 417 (95% CI, 153–680) excess deaths, 1124 (95% CI, 211–2047) hospitalisations for cardiovascular problems and 2027 (95% CI, 0–4252) for respiratory problems, and 1305 (95% CI, 705–1908) presentations to emergency departments with asthma (Box 2). Applying lower thresholds for defining bushfire smoke‐affected days (no threshold, 90th percentile of historical values) did not markedly alter our findings; a higher threshold (99th percentile) reduced the estimates by about 20%. The highest population‐weighted PM2.5 exposure level, 98.5 μg/m3 on 14 January 2020 (Box 1), exceeded the national air quality 24‐hour standard (25 μg/m3)19 and was more than fourteen times the historical population‐weighted mean 24‐hour PM2.5 value of 6.8 μg/m3. We have estimated the excess health burden during 19 weeks’ continuous fire activity in the states most severely affected by smoke. Our estimates are based on air quality data from monitoring stations in the four eastern states — that is, we did not include data for smoke from all extreme fires in Australia during the study period — and we did not attempt to estimate health effects for which exposure–response relationships are less well characterised, such as primary health care attendances and ambulance calls. Detailed epidemiological analysis of more comprehensive exposure estimation and empirical health data will provide more complete information about the harms attributable to the severe air pollution associated with these unprecedented fires, but our findings indicate that the smoke‐related health impact was substantial. Smoke is just one of many problems that will intensify with the increasing frequency and severity of major bushfires associated with climate change. Expanded and diversified approaches to bushfire mitigation and adaptation to living in an increasingly hot and fire‐prone country are urgently needed.20 Box 1 – Population‐weighted PM2.5 levels, New South Wales, Queensland, the Australian Capital Territory and Victoria, 1 October 2019 – 10 February 2020* * Data by state are included in the online Supporting Information. Box 2 – Estimated health burden attributable to bushfire smoke, Queensland, New South Wales, the Australian Capital Territory and Victoria, 1 October 2019 – 10 February 2020 Outcome Estimated number of cases (95% confidence intervals) Queensland New South Wales Australian Capital Territory Victoria Total Excess deaths (any cause) 47 (17–77) 219 (81–357) 31 (12–51) 120 (44–195) 417 (153–680) Hospital admissions, cardiovascular 135 (25–246) 577 (108–1050) 82 (15–149) 331 (62–602) 1124 (211–2047) Hospital admissions, respiratory 245 (0–513) 1050 (0–2204) 147 (0–308) 585 (0–1227) 2027 (0–4252) Emergency department attendances, asthma 113 (61–165) 702 (379–1026) 89 (48–131) 401 (217–586) 1305 (705–1908)

Nicolas Borchers Arriagada · Andrew J Palmer · David MJS Bowman · Geoffrey G Morgan · Bin B Jalaludin · Fay H Johnston

Screening guidelines specific to the needs of Australia’s Indigenous population are needed

Nicole Lowres · Ben Freedman

Cardiovascular disease (CVD) is a leading cause of preventable morbidity and mortality in Aboriginal and Torres Strait Islander peoples. This statement from the Australian Chronic Disease Prevention Alliance, the Royal Australian College of General Practitioners, the National Aboriginal Community Controlled Health Organisation and the Editorial Committee for Remote Primary Health Care Manuals communicates the latest consensus advice of guideline developers, aligning recommendations on the age to commence Aboriginal and Torres Strait Islander CVD risk assessment across three guidelines. Main recommendations: In Aboriginal and Torres Strait Islander peoples without existing CVD: CVD risk factor screening should commence from the age of 18 years at the latest, including for blood glucose level or glycated haemoglobin, estimated glomerular filtration rate, serum lipids, urine albumin to creatinine ratio, and other risk factors such as blood pressure, history of familial hypercholesterolaemia, and smoking status. Individuals aged 18–29 years with the following clinical conditions are automatically conferred high CVD risk: ▶type 2 diabetes and microalbuminuria; ▶moderate to severe chronic kidney disease; ▶systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg; ▶familial hypercholesterolaemia; or ▶serum total cholesterol > 7.5 mmol/L. Assessment using the National Vascular Disease Prevention Alliance absolute CVD risk algorithm should commence from the age of 30 years at the latest — consider upward adjustment of calculated CVD risk score, accounting for local guideline use, risk factor and CVD epidemiology, and clinical discretion. Assessment should occur as part of an annual health check or opportunistically. Subsequent review should be conducted according to level of risk. Changes in management as a result of this statement: From age 18 years (at the latest), Aboriginal and Torres Strait Islander adults should undergo CVD risk factor screening, and from age 30 years (at the latest), they should undergo absolute CVD risk assessment using the NVDPA risk algorithm.

Jason W Agostino · Deborah Wong · Ellie Paige · Vicki Wade · Cia Connell · Maureen E Davey · David P Peiris · Dana Fitzsimmons · C Paul Burgess · Ray Mahoney · Emma Lonsdale · Peter Fernando · Leone Malamoo · Sandra Eades · Alex Brown · Garry Jennings · Raymond W Lovett · Emily Banks

Percutaneous coronary intervention with stent implantation (PCI‐S) has revolutionised the management of patients with coronary artery disease at high risk of myocardial infarction and stroke.1 Dual antiplatelet therapy (aspirin with clopidogrel, prasugrel or ticagrelor) is superior to aspirin alone for preventing atherothrombotic events, including stent thrombosis, in patients undergoing PCI‐S,2 and is recommended by Australian guidelines.3 We analysed de‐identified, linked Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Schedule (MBS) data for a 10% random sample of Medicare beneficiaries provided by the Australian Department of Health, to quantify rates of antiplatelet drug dispensing within 30 days of PCI‐S. We included all patients with MBS claims for PCI‐S (items 38306, 38312, 38318) between 1 January 2013 and 30 September 2014. MBS data on PCI‐S procedures are available only for private patients, who account for about 45% of PCI‐S procedures in Australia.4 The medicines of interest for our analysis were clopidogrel and clopidogrel/aspirin (Anatomical Therapeutic Chemical [ATC] codes B01AC04 and B01AC30), ticagrelor (ATC code B01AC24), and prasugrel (ATC code B01AC22). Aspirin alone was not examined because over‐the‐counter use is not captured in PBS claims data. We assessed the association of several factors with antiplatelet medication dispensing within 30 days of PCI‐S, expressed as odds ratios, by logistic regression modelling. The New South Wales Population and Health Services Research Ethics Committee approved the study (Cancer Institute NSW reference, 2013/11/494). Of 2869 patients who underwent PCI‐S during the study period, 2592 (90%) were dispensed antiplatelet drugs within 30 days of the procedure. Dispensing was more frequent for concessional PBS beneficiaries, patients who had not undergone PCI‐S in the preceding year, patients not dispensed antiplatelet drugs during the preceding six months, and patients dispensed proton pump inhibitors within 30 days of the procedure. Antiplatelet therapy was also more frequent among patients from Victoria or Tasmania, Queensland, and Western Australia than for those from NSW or the Australian Capital Territory (Box). Our findings indicate that 10% of patients undergoing PCI‐S did not receive guideline‐recommended dual antiplatelet therapy within 30 days of their procedure. Cost may have been a barrier, as antiplatelet therapy was less frequent among general than concessional PBS beneficiaries; the maximum out‐of‐pocket cost for any single PBS item in 2013 was $5.90 for concessional beneficiaries, but $36.10 for general beneficiaries, and general beneficiaries may have already experienced significant out‐of‐pocket costs for both health insurance and their procedure. In most states, the Public Hospitals Pharmaceutical Reform Agreement6 ensures that PBS‐subsidised medications can be dispensed to patients when they are discharged from hospital. NSW and the ACT, however, do not participate in this agreement; patients are discharged from public hospitals with unsubsidised medicines sufficient for only 2–7 days, after which they must visit a community doctor for prescribing of PBS‐subsidised medications. This inconvenience may contribute to the lower 30‐day dispensing rate in these jurisdictions. We were unable to evaluate the long term clinical effect of antiplatelet therapy as the analysed datasets do not include information about hospital admissions. The number of PCI‐S procedures in Australia increased from 24 500 MBS claims in 2013 to 29 000 in 2018 (http://medicarestatistics.humanservices.gov.au/statistics/mbs_item.jsp), and the number of patients at risk of early stent thrombosis may also have grown. Why some patients undergoing PCI‐S are not receiving dual antiplatelet therapy directly after their procedure should be further investigated. Box – Characteristics of patients undergoing percutaneous coronary intervention with stent implantation (PCI‐S) in Australia, and their association with dual antiplatelet therapy within 30 days of PCI‐S Number of patients Odds ratio (95% confidence interval) Underwent PCI‐S Antiplatelet therapy within 30 days Univariate models Multivariate model Total number of patients undergoing PCI‐S 2869 2592 (90%) Age (years) 18–54 351 (12%) 307 (87%) 1 1 55–64 711 (25%) 640 (90%) 1.29 (0.87–1.93) 1.26 (0.83–1.91) 65–74 965 (34%) 879 (91%) 1.47 (0.99–2.16) 1.17 (0.76–1.81) 75–84 660 (23%) 605 (92%) 1.58 (1.04–2.40) 1.09 (0.66–1.81) 85 or more 182 (6%) 161 (88%) 1.10 (0.63–1.91) 0.83 (0.66–1.60) Sex Women 670 (23%) 604 (90%) 1 1 Men 2199 (77%) 1988 (90%) 0.97 (0.73–1.30) 0.86 (0.63–1.18) State where PCI‐S was undertaken New South Wales/Australian Capital Territory 1121 (39%) 986 (88%) 1 1 Victoria/Tasmania 752 (26%) 694 (92%) 1.64 (1.19–2.26) 1.56 (1.12–2.17) South Australia/Northern Territory 147 (5%) 129 (88%) 0.98 (0.58–1.66) 0.94 (0.55–1.60) Queensland 549 (19%) 504 (92%) 1.53 (1.08–2.19) 1.47 (1.02–2.13) Western Australia 300 (10%) 279 (93%) 1.82 (1.13–2.94) 2.14 (1.28–3.59) PBS patient category General 1453 (51%) 1293 (89%) 1 1 Concessional 1404 (49%) 1299 (93%) 1.53 (1.18–1.98) 1.63 (1.18–2.26) Previous PCI‐S Preceding 12 months 234 (8%) 199 (85%) 1 1 None 2635 (92%) 2393 (91%) 1.74 (1.19–2.55) 1.41 (0.93–2.13) Previous antiplatelet therapy Preceding 6 months 1135 (40%) 995 (88%) 1 1 None 1734 (60%) 1597 (92%) 1.64 (1.28–2.10) 1.96 (1.45–2.64) Anticoagulant therapy within 30 days of PCI‐S No 84 (3%) 77 (92%) 1 1 Yes 2785 (97%) 2515 (90%) 1.18 (0.54–2.59) 1.04 (0.47–2.33) Proton pump inhibitor therapy within 30 days of PCI‐S No 1002 (35%) 931 (93%) 1 1 Yes 1867 (65%) 1661 (89%) 1.63 (1.23–2.16) 1.42 (1.05–1.92) Comorbid conditions (six months before PCI‐S) None 196 (7%) 169 (86%) 1 1 1 180 (6%) 165 (92%) 1.76 (0.90–3.42) 1.47 (0.72–3.01) 2 259 (9%) 234 (90%) 1.50 (0.84–2.67) 1.34 (0.71–2.56) 3 389 (14%) 356 (92%) 1.72 (1.00–2.96) 1.54 (0.84–2.82) 4 452 (16%) 395 (87%) 1.11 (0.68–1.81) 1.01 (0.57–1.79) 5 or more 1393 (49%) 1273 (91%) 1.70 (1.08–2.65) 1.56 (0.88–2.75) PBS = Pharmaceutical Benefits Scheme. *Patients were classified as concessional beneficiaries if all PBS dispensing was concessional during year preceding and the three months following the PCI‐S procedure. †Based on RxRisk comorbidity indices.5

Benjumin Hsu · Michael O Falster · Andrea L Schaffer · Sallie Pearson · Louisa Jorm · David B Brieger

Objectives: To assess the risks of stroke and cardiovascular mortality for Aboriginal and non‐Aboriginal Australians with atrial fibrillation. Design: Retrospective data linkage cohort study. Setting, participants: All people aged 20–84 years hospitalised with atrial fibrillation in Western Australia during 2000–2012. Main outcome measures: Stroke incidence rates and mortality after hospitalisation for atrial fibrillation, and 10‐year risks of stroke and of cardiovascular and all‐cause mortality. Results: Among 55 482 index admissions with atrial fibrillation, 7.7% of 20–59‐year‐old patients and 1.3% of 60–84‐year‐old patients were Aboriginal Australians. A larger proportion of Aboriginal patients aged 20–59 years had CHA2DS2‐VASc scores of 2 or more (59.8% v 21.8%). In 20–59‐year‐old Aboriginal patients, the incidence during follow‐up (maximum, 10 years; median, 7.1 years) of stroke (incidence rate ratio [IRR], 3.2; 95% CI, 2.5–4.1) and fatal stroke (IRR, 5.7; 95% CI, 3.9–8.9) were markedly higher than for non‐Aboriginal patients. Stroke incidence was higher for 60–84‐year‐old patients, but the difference between Aboriginal and non‐Aboriginal patients was smaller (IRR, 1.6; 95% CI, 1.3–2.0). Cardiovascular mortality during follow‐up was also higher for 20–59‐year‐old Aboriginal patients (IRR, 4.4; 95% CI, 4.3–5.9). The hazards of stroke (adjusted HR [aHR], 1.67; 95% CI, 1.22–2.28) and cardiovascular mortality (aHR, 1.47; 95% CI, 1.18–1.83) in younger Aboriginal patients remained significantly higher after multivariable adjustment; age/sex, principal diagnosis of atrial fibrillation, and CHA2DS2‐VASc score were the most influential factors. Conclusion: Stroke risk and cardiovascular mortality are markedly higher for Aboriginal than non‐Aboriginal patients with atrial fibrillation, particularly for patients under 60. Strategies for providing evidence‐based therapies and cardiovascular prevention to Aboriginal people with atrial fibrillation must be improved.

Lee Nedkoff · Erin A Kelty · Joseph Hung · Sandra C Thompson · Judith M Katzenellenbogen

The treatment options for type 2 diabetes have expanded significantly in the past decade, with new classes of agents demonstrating superiority for cardiovascular outcomes

Renata Libianto · Timothy ME Davis · Elif I Ekinci

The global expansion of wearable technology combined with smartphone access creates new questions and opportunities in the diagnosis and management of cardiac conditions

David Jin · Heath Adams · Anthony M Cocco · William G Martin · Sonny Palmer