Cardiology in the real world and whole world

One Sunday last month, colourful Sydney-based barrister and social commentator Charles Waterstreet began his regular column for the Sydney Morning Herald with the casual revelation, “By the time you read this, with a bit of luck, I will have joined tens of thousands of Australians who have a mesh stent placed in the coronary artery in their heart” (http://www.smh.com.au/comment/we-can-take-heart-for-a-change-is-gonna-come-20130713-2pwhe.html).

That this brush with coronary artery disease rated only a passing mention seems a far cry from the days, just a few decades ago, when men in their middle-aged years were admitted to coronary care with “heart attacks”, and doctors did their best to deliver supportive management while watching as the electrocardiographic changes of dying myocardium evolved to their full and crippling potential. The improvements in our knowledge and skills directed at cardiovascular disease — encompassing public health successes, drug regimens for primary and secondary prevention, and interventional therapy — are among the major medical advances of the 20th and 21st centuries.

Yet in an era when we know so much about how to manage cardiovascular disease, it is vexing that many patients who would benefit from a given therapy miss out. The SNAPSHOT ACS study (doi:
10.5694/mja12.11854), conducted over a 2-week period to examine the management and outcomes of patients with acute coronary syndrome in 286 hospitals in Australia and New Zealand, shows that we are not always good at providing guideline-recommended care and, more importantly, points to potentially remediable reasons. According to editorialists MacDonald and colleagues (doi: 10.5694/mja13.10842), while some variations in care can be explained by access barriers to interventional facilities, others, such as non-prescription of recommended drugs, failure to refer for rehabilitation and a lack of support for changes in diet and exercise, indicate that not everyone is yet onboard the best-practice cardiology train. The third article in our cardiology series (doi: 10.5694/mja12.11224) uses two clinical scenarios to highlight this contemporary challenge in cardiovascular disease management.

To bring doctors’ clinical practice in line with best practice, Australia’s quality use of medicines watchdog, NPS MedicineWise, uses prescriber feedback, academic detailing, case studies, audits and printed educational materials. The results of an interrupted time-series analysis examining prescribing and service use for Department of Veterans’ Affairs patients between 2002 and 2010 (doi: 10.5694/mja12.11779) indicate that four important management strategies (warfarin for atrial fibrillation, aspirin for secondary stroke prevention, echocardiograms to confirm heart failure, and spironolactone for heart failure) are leading to small improvements with potentially big benefits when applied to large numbers of patients.

Parts of Australia present special challenges to sophisticated care provision and — as outlined in Shannon’s rural health care contribution to our pre-election series (doi: 10.5694/mja13.10928) — probably always will. In remote Central Australia, clinicians are acutely aware that when managing patients with coronary artery disease, the nearest angiography facilities are 1500 km away. Here, careful patient selection for investigation of suspected coronary artery disease is vital. Hurune and colleagues (doi: 10.5694/mja13.10364) report that exercise electrocardiography testing is still useful in regional and remote settings — particularly if the result is negative. Another study examines the utility of auscultatory screening for rheumatic heart disease among schoolchildren in the Northern Territory (doi: 10.5694/mja13.10520). This disease of poverty barely exists in most industrialised countries, but Indigenous Australians have among the highest rates in the world. The poor accuracy of the stethoscope for making the vital diagnosis should cause a rethink of current screening programs.

Our own struggles and progress — past and present — with cardiovascular disease are both a burden and an opportunity for Australia, says Leeder (doi: 10.5694/mja13.10911). We should be generous with our success by providing support to less developed countries where cardiovascular disease is taking over as the major killer. Who knows; maybe some of the knowledge gleaned from the real-world Australia can be usefully applied to the rest of the world.

Developing a global agenda for action on cardiovascular diseases

Australian health policy can and should address, as a core aim, cardiovascular health in less economically advanced nations

Cardiovascular diseases have snatched the mantle of top-priority global health problem from infectious diseases including tuberculosis, malaria and HIV/AIDS. This is because of the deaths attributable to cardiovascular diseases, the years of life lost, and the longer-term disability from heart failure and stroke.1 While deaths due to cardiovascular diseases among people younger than 65 years have fallen dramatically in the past 50 years in Australia, in less economically advanced communities one-third of these deaths occur among people younger than 65 years.2

Cardiovascular diseases are potent widow- and orphan-makers. Particularly in developing communities, they can precipitate poverty. The cost of care in communities lacking affordable health insurance and effective primary care can be catastrophic.

The effect on a nation’s lost productivity and growth is no less disastrous. Every 10% rise in chronic non-communicable diseases is estimated to bring a 0.5% decrease in economic growth.3 It has also been estimated that deaths in developing countries attributable to chronic disease will grow from 46% of all deaths in 2002 to 59% of all deaths in 2030, or to more than 37 million lives lost per year.3

Why the delayed recognition? These circumstances have been many decades in the making. Three principal reasons for global inaction over those years stand out.

First, in many countries maternal and infant mortality rates are high, visible, tragic and immediate, and a natural priority for scarce health care resources. Such countries that now also face the cardiovascular crisis are war-weary from fighting infant and maternal mortality, tuberculosis, malaria and HIV/AIDS. But great gains have been made in these conditions, and it is now imperative that we encourage and support those nations to address chronic diseases.

Second, perception of cardiovascular diseases, in relation to human behaviour, differs radically from that of infectious diseases. As with type 2 diabetes, obesity and chronic lung disease, cardiovascular diseases occur principally among older people, in social conditions of fast economic development and generally favourable, poverty-reducing urban development. They depend on human behaviour — smoking tobacco, overeating fats and sugars, abandoning traditional (usually healthier) nutrition, and underexercising. Potential donors who wish to improve international health consider cardiovascular diseases off limits for funding, since these diseases are “the sufferers’ fault” or diseases of old age. It is hard to convince major donors that such adverse individual health behaviour is largely determined by domestic, community, work and economic environments and that older people matter.

Preventive strategies for chronic disease that respond to the individual and the social environment behind these disorders appear soft and diffuse. They are complex compared with, say, an immunisation program with its clean start, jab and finish. Interest groups that profit from an environment that promotes chronic diseases, especially cardiovascular diseases, resist efforts that encourage change.4

But these detached, judgemental and indolent attitudes are changing, stimulated by a 2011 United Nations meeting on the global chronic diseases crisis.5 The UN meeting resulted from years of advocacy by a few governments, including Australia’s, and non-government agencies concerned about cardiovascular diseases, diabetes, cancer and chronic respiratory disease — the NCD Alliance. The Lancet has shown admirable academic leadership in non-communicable diseases research by creating an action group, publishing special issues and providing support for international meetings.

Often the recognition of a crisis jolts us to take the matter seriously, and so it is with cardiovascular diseases. A political declaration from the UN meeting articulated goals and strategies for preventing and controlling non-communicable diseases over the following 5 years. This has pushed international agencies such as the World Health Organization to act. The WHO is responding with global strategies: enhancing tobacco control, addressing dietary salt reduction, nominating essential medicines (including antihypertensives), and advocating for fuller and more stable primary care services everywhere.

In addition, chronic diseases are being reconceptualised, and are now frequently perceived as an impediment to social development, thus adding them to the agenda for discussion concerning the next steps to be taken after the Millennium Development Goals conclude in 2015.6

The third factor behind our relative inaction, despite indisputable progress, has been those massive holes, only now beginning to close, in knowledge about what to do, and how to implement the knowledge we have.

Although we have had the major risk factors for cardiovascular diseases nailed for the past 50 years, and can use them to explain most of the variance in cardiovascular disease frequency, more basic and clinical research is required alongside health services research to translate these insights into effective policy, population interventions and individual behaviour change.

Fruitful fields of inquiry include events in early life capable of setting the later epigenetic, physiological and behavioural trajectories for chronic disease.7

Australia has generally done well with cardiovascular disease control, although onset and mortality occur a decade earlier in our Indigenous communities than in the rest of the population.8 Overall, rates of deaths due to coronary heart disease in Australia fell by 83% between 1968 and 2000, as newer medical and surgical interventions have exerted a spectacular positive influence on individuals, and lifestyle changes have contributed positively at the individual and population levels.9

Tobacco smoking is now less common in Australia than in most other economically advanced nations. Our efforts, although incomplete, in cardiovascular disease prevention and management in urban and rural Indigenous communities might apply to other communities. In a spirit of mutual learning, we should share our experience with these efforts.

We know well the battles over entrenched behaviour, practices and social structures that nourish risk factors. The tobacco war is by no means over, and the food and alcohol wars are just beginning here and elsewhere. In the United Kingdom, the government has recently suspended the push for tobacco plain packaging legislation,10 and the same is likely to happen to a minimum alcohol pricing policy.11

In Africa, rapid modernisation will, by the middle of this century, potentially not only lead to food self-sufficiency but also surplus food to export.12 Although this will alleviate starvation, it will spell disaster for rapidly urbanising populations where, if the previous experience of developed societies is any model, cardiovascular disease rates will increase quickly.

Translating knowledge and science into resource-poor (or even just less-developed) settings is culturally, politically and logistically difficult. But as a good and progressive global citizen, Australia can still advocate for access to essential medications, meaningful aid and public health support. Such strategies have worked to combat infectious diseases globally, but now they must address non-communicable diseases.

Australia has much expertise and experience to share in international efforts to prevent and control cardiovascular and other chronic diseases. If this challenge is embraced by both major parties in the upcoming federal election, it would be pleasing indeed.

The SNAPSHOT ACS study: getting the big picture on acute coronary syndrome

How snapshot methodology identifies factors limiting translation of evidence to practice

Translating evidence-based treatments into clinical practice is fundamental to modern health care delivery. Yet numerous studies demonstrate limited uptake of guideline-endorsed treatment recommendations.1,2 Why is this so? There are many possible explanations. Patient characteristics such as age, comorbidity, socioeconomic status, cultural background and frailty are likely to be important. Most trials of novel drugs or devices are funded by industry. Trials are very expensive, and a trial sponsor is understandably keen to ensure that their product is administered to those patients most likely to benefit. Consequently, patients entered into clinical trials are typically younger and have less comorbidity than the broader population of patients with a particular condition. This was found to be the case in a recent Canadian registry report on patients admitted with acute coronary syndrome (ACS), which compared the baseline characteristics of those who were included in clinical trials with the much larger cohort of patients who were not.3 Other variables also limit the translation of evidence-based treatments. For ACS, which requires acute hospital care, the type of hospital (eg, peripheral versus major teaching hospital) and its location (eg, urban versus rural or remote setting) can determine the level of medical expertise and complexity of treatment offered to a patient.

How best then to identify all the factors that limit the translation of evidence-based medicine into clinical practice? One approach is to take a “snapshot” of all patients with an acute condition admitted to every hospital nationwide and to compare patient characteristics, patterns of investigation, treatment and patient outcomes. This would allow hospitals, states and even countries to be compared, if the snapshot is broad enough. Undertaking such a study is logistically daunting, but in a landmark study published in this issue of the Journal, Chew and colleagues have attempted exactly that.4 The investigators approached 525 hospitals across Australia and New Zealand and obtained ethics approval from 478 to perform a prospective audit of patients admitted with suspected or confirmed ACS during 2 weeks in May 2012. They enrolled 4398 patients in 286 hospitals. Hospitals that did not enrol patients were smaller and did not admit patients with ACS during the snapshot window.4

Three design features of the SNAPSHOT ACS study are worth highlighting. First, use of an opt-out consent process (a consent waiver in New Zealand) no doubt contributed to the high recruitment rate.5 Second, standardised data definitions and real-time data collection ensured consistency between participating hospitals, in contrast to other methods of administrative data extraction where data validity is often questioned.6 Third, including a survey to document the range of cardiac services at the participating hospitals facilitated benchmarking between institutions. Facilities for percutaneous coronary intervention and coronary artery bypass surgery were available in less than 30% and 20% of hospitals, respectively. This expected finding probably explains the high rate of interhospital transfer, involving 26% of enrolled patients. However, surprisingly, only two-thirds of the 286 hospitals in the study contained an acute coronary care ward.

The SNAPSHOT ACS study is in every sense a contemporary “real world” audit of the diagnostic evaluation and management of ACS across Australasia. The authors report some noteworthy findings. Although virtually all patients presented to a hospital that was capable of providing acute reperfusion therapy for ST-segment-elevation myocardial infarction, this was administered to only two-thirds of patients with this diagnosis. In addition, patients with higher Global Registry of Acute Coronary Events (GRACE) scores (and higher risk of hospital mortality) were less likely to receive an invasive management strategy. Previous publications from large prospective registries have reported similar findings.7,8 This may be explained by factors such as advanced age and renal failure, which contribute to the GRACE score but also reduce the likelihood of acute intervention.3 Other major comorbidities are also likely to contribute to underuse of evidence-based therapies in these high-risk patients.7 These and other findings deserve further published analysis of this unique dataset.

Most disturbing are the substantial variations found in implementation of evidence-based management and in patient outcomes, not only between hospitals but also between jurisdictions. Differences in the use of invasive diagnostic and therapeutic measures (coronary angiography and percutaneous or surgical revascularisation) are to be expected, as most enrolled hospitals lacked these facilities.4 On the other hand, the significant differences between hospitals in the use of guideline-recommended medications, cardiac rehabilitation, and diet and exercise advice are harder to explain. An important feature of the SNAPSHOT ACS study is the benchmarking of (de-identified) hospital data to enable individual clinicians and institutions to compare their performance against other institutions providing comparable services. But benchmarking needs to be followed by change-management strategies to improve the uptake of evidence-based treatments in underperforming hospitals.

Jurisdictional differences in use of evidence-based therapies for ACS and patient outcomes indicate differences in health service policy, resourcing and delivery. Exploring these differences will be important to identify jurisdictional barriers to implementing evidence-based treatments and will require bringing together national and state government agencies, professional bodies, individual clinicians and researchers across all hospitals. This approach has been applied successfully (albeit on a limited scale) in the management of ACS, acute heart failure and stroke.9,10 However, a clear message from the SNAPSHOT ACS study is that much broader engagement of these stakeholders will be required to improve the outcomes of patients with ACS across the entire health sector.

The impact of trans fat regulation on social inequalities in coronary heart disease in Australia

To the Editor: The evidence that industrially produced trans fatty acids (TFAs) increase the risk of coronary heart disease is compelling, and it is widely agreed that their use in food products should be minimised.1–3 Dietary TFAs are generally found in higher quantities in “unhealthy” food products,4 consumption of which is also found to follow predictable socio-demographic patterns.5 Thus, although the average TFA intake for Australians is relatively low, socioeconomically disadvantaged people are likely to disproportionately represent those with above average intakes.

Mandatory labelling of TFA content on all packaged foods in Australia has recently been advocated,1 so that individuals can make informed decisions about purchasing products with excessive levels of TFA. However, while such an intervention may reduce TFA intake at the population level, it is likely to increase social inequalities in TFA consumption and, therefore, inequalities in deaths from coronary heart disease. The reasons for this are as follows. First, research has shown that people who have healthier diets and who are from higher socioeconomic backgrounds are more likely to seek out and use food labels to make healthier choices,6 while those from more disadvantaged backgrounds who do not understand or act on nutrient labelling are much less likely to benefit. Second, mandatory TFA labelling may prompt food manufacturers to brand their products as “TFA-free”, which may bestow an undeserved “health halo” on energy-dense nutrient-poor foods.3 This “health halo” effect is likely to disproportionately influence the purchasing decisions of lower socioeconomic groups, among whom nutrition knowledge tends to be lower than among higher socioeconomic groups.4,5

The ability to replace industrially produced TFAs with healthier alternatives at minimal expense to consumers has prompted jurisdictions such as Denmark and New York City to introduce mandatory limits on the total amount of TFA permitted in all food products. Recent evaluation of the New York City policy showed a significant reduction of TFA in restaurant products, without a corresponding increase in saturated fat, and this effect was similar across high-income and low-income neighbourhoods.7

It is time that Australia introduced strong regulation to reduce TFA intake for all Australians.

A case of spontaneous renal infarction secondary to an accessory renal artery thrombosis

To the Editor: A 43-year-old woman presented with sudden onset of severe left-sided abdominal pain and hypertension (blood pressure, 180/120 mmHg). She developed flash pulmonary oedema, which was confirmed on chest x-ray. Her urine microscopy results and creatinine levels were normal.

A computed tomography (CT) scan with contrast showed a thrombus in an accessory artery supplying the lower pole of the left kidney and a left renal infarction secondary to the vascular occlusion (Box).

Telemetry did not detect arrhythmia. Transoesophageal echocardiography did not show any evidence of a cardiac thrombus but did confirm normal left ventricular systolic and diastolic function. A screen was negative for autoimmune and inherited causes of thrombophilia.

Renal infarction is a rare cause of abdominal or flank pain. Presentation mimics that of nephrolithiasis or pyelonephritis, but there is no haematuria. Patients present with nausea and vomiting, abdominal or flank pain, hypertension, leukocytosis and a raised lactate dehydrogenase (LDH) level.1–3 Our patient had a white cell count of 13.0 × 109/L (reference interval [RI], 4–11 × 109/L) and
an LDH level of 1227 U/L (RI,
170–230 U/L). CT urography is a common first-line investigation in this setting but may miss renal infarction. Therefore, the absence of haematuria should prompt further imaging.

Reported aetiologies of renal infarctions include vascular abnormalities (atherosclerosis, fibromuscular dysplasia, vasculitis), hypercoagulable states and thromboembolism.1,2 Renal infarction has also been described with cocaine use and as a complication after procedures.4 There was no evidence of any of these causes in this patient.

A review of the literature found limited management suggestions based on small studies.4 Several small case series reported good outcomes with anticoagulation; however, most of the patients in these series had concurrent atrial fibrillation.4

This is the first reported case of an acute thrombosis in an accessory renal artery causing a renal infarction. In light of the known association between renal artery stenosis (RAS) and pulmonary oedema,5 we postulate that the flash oedema occurred as a consequence of the artery occlusion and acute hypertension. We could not exclude RAS without further imaging of the renal arteries; however, there was no evidence of RAS on the CT image.

Coronal computed tomography images of the patient, showing a wedge-shaped renal infarction (A) and a thrombus in the accessory renal artery* supplying the lower pole of the left kidney (B)

* Arrow points to the origin of the artery.

Contemporary themes in acute coronary syndrome management: from acute illness to secondary prevention

Acute coronary syndrome (ACS; myocardial infarction and unstable angina) is the leading cause of mortality in Australia and accounts for more than 300 000 years of life lost due to premature death (aged < 65 years) annually. The cost of repeat ACS events in 2010 exceeded $8 billion.1 About half of the cardiovascular events in Australia occur in people who have had a prior hospital episode for coronary heart disease (CHD).2 Therefore, access to evidence-based and optimal ACS management in both the acute and long-term periods is of great importance.

In recent years, advances in monitoring, revascularisation and pharmacotherapy for acute illness have contributed to a reduction in mortality. However, a quarter of these survivors will be readmitted to hospital within a year of the index event, and a significant number of readmissions will result in death.3,4 Consequently, the demand for effective secondary prevention is intensifying, and ensuring access to structured management strategies that complement standard medical care is now a priority.

The burden of CHD is disproportionately greater for certain patient groups. People living in outer regional and remote areas experience disease rates 20% higher than do those living in major cities, with higher mortality proportionate to increasing distance from major centres.5 Cardiovascular disease is also the largest contributor to the 17-year gap in life expectancy between Indigenous and non-Indigenous Australians.

Here, we provide an overview of key contemporary issues in the provision of ACS care, including the importance of early diagnosis of ischaemia; risk stratification; provision of timely, appropriate and evidence-based management; and prevention of recurrent events. We describe barriers to the equitable provision of immediate and long-term optimal care and suggested strategies to overcome them. These strategies focus on the practice and policy changes needed to implement networked systematic care across all geographical and economic strata serviced by our health care system.

Contemporary considerations for ACS management

Contemporary management of ACS should be rapid and should include reperfusion, medical therapy and ongoing secondary prevention. Management should be comprehensive, coordinated and ongoing. Ideally, patients should seek medical care as early as possible after the onset of symptoms and should be provided with: rapid access to a hospital or a defibrillator; early reperfusion therapy for ST-segment-elevation myocardial infarction (STEMI); early angiography and revascularisation where indicated; appropriate medical therapy; and ongoing secondary prevention that encompasses medication adherence and lifestyle change.6

Rapid reperfusion for STEMI

STEMI accounts for about 25% of ACS presentations and remains a cardiac emergency. As rapid restoration of epicardial blood flow is of initial importance,6 the first goal of therapy is immediate reperfusion, which is best achieved by primary percutaneous coronary intervention (PCI) when appropriately staffed facilities are available.7 If delays are likely because of the need to transfer patients long distances for primary PCI, fibrinolysis is a superior option, particularly for patients receiving medical attention early after the onset of symptoms.6,7 Fibrinolysis can be of substantial value in the rural prehospital setting, where delays to PCI are unavoidable. For patients with large infarcts receiving fibrinolysis in non-PCI-capable centres, early transfer (ideally within 24 hours) to a PCI-capable centre for coronary angiography is now recommended.8 This enables emergency treatment (rescue PCI) for patients who have not reperfused after fibrinolysis. For those who have reperfused, emergency PCI is best performed from 3 to 24 hours after lysis; this minimises both the access-site bleeding consequences of the lytic therapy and the likelihood of culprit vessel reocclusion.

An invasive management strategy for
non-ST-segment-elevation ACS

Patients with a non-ST-segment-elevation ACS and who are at high risk of inhospital and late death or myocardial infarction benefit from coronary angiography, which guides an appropriate revascularisation strategy during their hospital stay.9 The earlier this procedure is performed, the greater the benefit.10 Lower-risk patients may be risk stratified through either angiography or non-invasive testing. Intervention-related bleeding can be reduced by adopting a radial rather than femoral approach to coronary angiography. The radial approach may also be associated with reduced mortality in the STEMI population,11 and this strategy is gaining in popularity.

Medical therapy

Antithrombotic strategies using heparin or low-molecular-weight heparin remain a cornerstone of therapy to prevent propagation or embolisation of the thrombus responsible for the coronary instability. However, iatrogenic bleeding events, traditionally regarded as a tolerable complication of anti-ischaemic therapy, are themselves associated with increased mortality.12 Newer anticoagulant agents, such as fondaparinux and bivalirudin, can reduce recurrent ischaemic events with comparable efficacy and less bleeding than traditional heparins among medically managed and PCI-managed ACS patients, respectively.13,14 Where increased bleeding risk is anticipated, these newer therapies are recommended.8

In addition to anticoagulants, dual antiplatelet therapy with low-dose aspirin and the ADP receptor antagonist clopidogrel is associated with reduced ischaemia in patients after an ACS when compared with aspirin alone.15 More potent ADP receptor antagonists, such as prasugrel and ticagrelor (Box 1), prescribed as substitutes for clopidogrel, extend this benefit further, but do so at the cost of increased bleeding.16,17 Here, the risk–benefit equation is more complex because these newer agents have improved efficacy with a possible reduction in mortality,17 underscoring the need for a better understanding of the prognostic impact of different types of bleeding (eg, access-related versus gastrointestinal), together with more sophisticated tools to predict bleeding.

Emerging acute treatments

Reperfusion after coronary occlusion is associated with the release of products that are toxic to injured but perfused myocardial cells. Over the past 40 years, many therapeutic strategies have been trialled, unsuccessfully, to prevent reperfusion injury. Strategies for which there is cautious optimism include intracoronary adenosine, hypothermia, and “conditioning” the myocardium by alternating periods of brief ischaemia and reperfusion.18,19 Early studies indicate that infusing a patient’s own stem or progenitor cells in the infarct setting may promote restoration of myocardial function.20,21 Larger trials with standardised methodology are required to establish the role of this therapy.

Secondary prevention

In the transition to primary care after hospital discharge, ongoing participation in a secondary prevention program is recommended for all ACS survivors.22 Attending secondary prevention programs, adhering to risk factor modification and complying with drug regimens may reduce hospital readmissions within 1 year by 45% and increase survival.23 Advances in secondary prevention approaches include clinic-based coordinated care, individualised case management and coaching with regular monitoring and, more recently, e-health strategies that provide flexible ongoing care.4

Secondary prevention ideally requires a lifelong commitment to ongoing behaviour change. The original model for delivery of “cardiac rehabilitation” to patients with CHD focused on supervised exercise to counter deconditioning after bypass graft surgery and to improve exercise capacity after myocardial infarction. However, patients are no longer confined to long periods of bed rest after an ACS event, and their needs are different than when traditional programs were developed. Around 70% of secondary prevention programs offered in Australia continue to follow the traditional cardiac rehabilitation model of structured, group-based exercise and education delivered in a hospital setting.24 However, traditional facility-based cardiac rehabilitation is currently facing substantial challenges in terms of access, appeal and cost. Non-attendees are returning to work commitments early and are less likely to believe that rehabilitation is necessary, despite having higher baseline risk and poorer risk factor knowledge than those who do attend.25 Evidence that hospital-based secondary prevention interventions are effective26 is now supplemented by evidence that programs can be provided in various settings, by different health professionals, and in various ways.4 The development of contemporary flexible models that use existing community services (eg, government “quit smoking” programs, the Enhanced Primary Care Program, National Heart Foundation of Australia physical activity initiatives, and private health insurer programs) are examples of this.

Evidence–practice gaps in Australian ACS management

Deficits in the application of optimal ACS care occur in the prehospital, inhospital and postdischarge periods. The case studies outlined in Box 2 highlight some of these contemporary issues.

Delays in reperfusion for STEMI

In the first case study, Mr T experienced delays in presentation to hospital and in the performance and interpretation of the electrocardiogram (ECG), which significantly delayed time to reperfusion. Australian evidence suggests that patients with STEMI wait a median time of 100 minutes before seeking medical attention, and this delay has not changed since it was first described in the early 1990s. A significant proportion of patients with STEMI do not receive timely reperfusion after presentation to hospital (within 90 minutes of presentation for PCI, and 30 minutes for fibrinolysis).27 Overcrowding of emergency departments and access block can contribute to this delay.28 This means there is a median delay from symptom onset to reperfusion exceeding 190 minutes for patients receiving PCI and 130 minutes for those receiving fibrinolysis — times well beyond the threshold for the development of significant irreversible myocardial necrosis.

Of equal concern is that about 30%–40% of all patients with STEMI receive no reperfusion therapy.3 It has been estimated that increasing the numbers of patients treated with reperfusion therapy would save 270 lives per 10 000 patients with STEMI.6

Access to and appropriate application of invasive management

If Mr T had been transferred to a PCI-capable centre within 24 hours after receipt of fibrinolytic therapy, he could have had early angiography, which would likely have prevented his recurrent myocardial infarction. Similarly, had Mrs D been recognised as being at high risk of a recurrent event, she could have received earlier coronary angiography. There are well validated bedside tools29 that predict the likelihood of inhospital events and guide the application of appropriate management. However, these tools are rarely applied in Australian hospitals. There is also geographical heterogeneity in the provision of coronary angiography for ACS patients in Australia.30 Where access to coronary angiography is available, risk-averse physician behaviour is observed, whereby the highest-risk patients with the most to gain from invasive management are the least likely to receive it.31 Clinicians select therapy on the basis of acute risk factors (ECG changes and troponin level elevation), while patients accumulating chronic risk factors are less likely to receive evidence-based therapies.32

Poor access to and uptake of secondary prevention

Mr T was discharged with suboptimal secondary prevention therapies, some written information and a letter for his general practitioner. At the time of discharge, there was no strategy for ensuring he complied with these instructions.

A 2005–2007 Australian audit showed that only a minority of patients with ACS received all five guideline-recommended secondary prevention treatments at hospital discharge.33 Although there have been some improvements, gaps remain3 and there is a lack of recognition of this problem by clinicians. Australian general practice surveys show that only half of patients with established CHD take recommended treatments.34 Only about a third of patients adhere to recommendations on diet, exercise and smoking, and participation rates in cardiac rehabilitation programs are as low as 10%–30%.35

Failure to follow guidelines can result in errors of commission, as well as errors of omission. Mrs D continued taking “triple therapy” (warfarin and two antiplatelet agents) for 18 months after coronary stenting. Current recommendations minimise the duration of this combination therapy to reduce the risk of bleeding.36 The fact that this did not occur further illustrates the lack of fluidity between tertiary and primary care.

Overcoming the deficits

An integrated and multifaceted strategy that targets both the public and our systems of health care delivery is needed. Some strategies implemented in the Australian context have been shown to be effective. For example, educating the public to recognise symptoms of a heart attack has been a major focus of the National Heart Foundation of Australia’s “warning signs” campaign, which has run since 2008.37 Empowering ambulance service personnel to perform and interpret 12-lead ECGs at first patient contact allows for the immediate identification of STEMI. Reports from clinical cardiac networks in both New South Wales and Victoria have shown the benefit of prehospital diagnosis and triage.38,39 The introduction of the National Emergency Access Target to overcome issues of access block and emergency department overcrowding is an important organisational strategy that facilitates timely ACS management in busier centres. Furthermore, the creation of local hospital networks has provided a substrate for optimising interhospital transfers. If STEMI is identified in a patient self-presenting to a non-PCI-capable centre, it is possible to facilitate near-immediate transfer to a notified nearby PCI-capable hospital. Strategies to minimise transfer (door-in–door-out) time include ambulance prioritisation of these patients, and standardised protocols for STEMI reperfusion at both referring and receiving hospitals.40 Using combined geographical, road transport time and census data, researchers have estimated that implementing improved efficiencies, such as prehospital ECG diagnosis and triage and facilitated interhospital transfers, can improve access to timely reperfusion for more than five million Australians.41

One of the greatest challenges facing hospital clinicians is identifying high-risk patients and stratifying treatment accordingly. Several clinical networks are now providing systematic rural ECG reading services, with the provision of clinical advice to support rural clinicians. Additional strategies include using telemedicine to empower rural GPs to read ECGs. Beyond this, studies investigating the prognostic benefit of routine application of risk stratification tools are planned locally. Interhospital transfer for identified high-risk patients can be facilitated by real-time, web-based interhospital catheter laboratory triage systems. In Queensland, this has been associated with a dramatic improvement in timely appropriate transfer of patients from non-PCI-capable to PCI-capable hospitals.

Universal prescription of evidence-based secondary prevention therapies remains challenging and can only partly be addressed by medication reconciliation at discharge. In one Australia-wide study, the introduction of clinical tools, together with academic detailing of selected clinical staff, had a modest effect on the prescription of evidence-based therapies.42 It appears that hospital culture is the most important determinant of whether improvements in care processes are successful. An effective culture is one that values quality improvement and has clinical leadership, senior management involvement, and good communication between the various clinical groups responsible for providing care.43

Transitioning from the acute to the postdischarge phase can be facilitated by automatic referrals and availability of a range of innovative secondary prevention programs (Box 3).26 These programs frequently involve (in isolation or combination) in-person visitations, community services, and home manuals with telephone or electronic support for flexible and individualised management of CHD. They include clinic nurse-coordinated care,44 individualised case management and monitoring with periodic follow-up,45,46 and community-based groups with ongoing health practitioner support provided across a range of settings.

To achieve optimal and sustainable benefits for the majority of patients, secondary prevention strategies must be flexible; tailored to the individual’s preferences, needs and values; lifelong; and integrated with primary care.6,47 All contemporary secondary prevention programs should include individual patient assessments and structured follow-up, as well as ongoing support and monitoring. Programs should target medication adherence, coupled with biomedical and lifestyle risk factors, while also attending to psychosocial wellbeing. Further, they should recognise the role of patients in self-management and the importance of family and caregiver engagement and support.4

Future innovations

While the dominant pharmaceutical-derived research funding streams will continue to be directed towards newer therapies, the real impact of these is becoming limited as absolute event rates fall. Greater practical gains will be achieved through more widespread application of existing therapies. Improving information technology infrastructure has the potential for great impact on geographical inequities through the availability of clinical support systems (remote ECG interpretation and efficient web-based triage for interhospital transfer).

Many of the available data regarding the quality of patient care have been derived from clinician-driven clinical registries that are restricted by small patient numbers and hospital selection biases.3,30,33 Only through a national ACS registry will we be able to truly understand the patterns and gaps in treatment around the country. In the short term, these data can be acquired through manual data extraction performed at a “snapshot” in time. However, this is resource- and labour-intensive, and as the electronic medical record environment matures, there will be opportunities to collect and audit performance measures and outcomes using clinically collected data. There are ethical, governance and data quality issues that require careful attention; however, principles for the conduct of these registries have been established.48 More mature electronic medical record technology will also help bridge the divide between hospitals and primary care.

Resources need to be allocated to permit the application of a national approach to secondary prevention, encompassing the variety of services outlined here, but unified by a patient-centred focus. Ultimately, a cohesive approach that is accessible, standardised and evidence-based is needed to improve widespread effectiveness.

1 Indications and precautions for the newer orally active ADP receptor antagonist antiplatelet agents*

Agent

Indications

Precautions

Prasugrel

ST-segment-elevation myocardial infarction with planned percutaneous coronary intervention (PCI)

Non-ST-segment-elevation acute coronary syndrome undergoing PCI

Contraindicated in patients with previous stroke or transient ischaemic attack

Caution in patients aged over 75 years or weighing under 60 kg (increased bleeding; consider reduced maintenance dose)

Ticagrelor

All acute coronary syndromes

Caution in patients with second- or third-degree heart block

Caution in patients at increased risk of bleeding (although these patients are often also at high risk of recurrent ischaemic events)

* This list of precautions is not exhaustive; consult a full list before prescribing.

2 Australian case studies of acute coronary syndrome (ACS) management

Case study 1: ST-segment-elevation myocardial infarction

A 64-year-old man (Mr T) was driven by his wife to the emergency department (ED) of a rural hospital 2 hours after onset of retrosternal chest discomfort. He had a 12-month history of exertional angina, was a retired office worker and did not participate in regular exercise. His local general practitioner, whom he generally saw “as little as possible”, had recommended smoking cessation and medical treatment with aspirin, a statin and long-acting nitrates. Mr T had managed to reduce his smoking to five cigarettes/day, had not liked the statin (it gave him muscle pain), took aspirin intermittently and had stopped taking the nitrates (they gave him a headache).

Within 20 minutes of arrival at the ED, an electrocardiogram (ECG) showed ST-segment elevation in the anterior leads. The resident faxed the ECG to the coronary care unit at the nearest base hospital, where it was reviewed by a medical registrar, who discussed it with the on-call physician. The resident was instructed to administer thrombolysis with tenecteplase (TNK), which was delivered 90 minutes after Mr T’s presentation to the hospital. Within 30 minutes, his chest pain settled, and the ECG results improved. Staff at the rural hospital phoned the nearest tertiary hospital (with cardiac catheterisation facilities) to arrange a transfer. This hospital was a 4-hour drive away and had no available coronary care beds.

Forty-eight hours after initial presentation, Mr T experienced recurrent pain accompanied by further ST-segment elevation. A second dose of TNK was given, and he was transferred to the tertiary hospital. Coronary angiography showed a 90% lesion with reduced flow in the proximal left anterior descending coronary artery, a 70% lesion in the left circumflex artery and a 60% lesion in the right coronary artery. Mr T was referred for coronary artery bypass grafting, which was performed during the same admission. He was discharged 5 days later with a medication regimen of aspirin, frusemide and an angiotensin-converting enzyme (ACE) inhibitor. While in hospital, he was seen by a cardiac rehabilitation nurse, who provided some written information about heart disease and a letter for his GP. The hospital did not arrange an appointment with the GP.

Case study 2: Non-ST-segment-elevation ACS

A 75-year-old woman of Italian origin (Mrs D), who had been in Australia for 15 years but had poor command of English, called an ambulance 3 hours after developing intermittent nausea and diaphoresis. She had experienced similar symptoms before undergoing a coronary artery bypass graft 10 years earlier and had noticed recurrence of these symptoms on exertion for the past 2 weeks. Mrs D had been diagnosed with atrial fibrillation 5 years earlier when she presented with heart failure. She had been taking warfarin since then, and was also taking frusemide and an ACE inhibitor, but no statin.

The ambulance took Mrs D to the nearest hospital, which did not have percutaneous coronary intervention (PCI) facilities. Her symptoms had settled by the time of arrival. Examination showed mild left ventricular failure (crepitations in the lower third of the lung fields), an ECG showed a non-specific intraventricular conduction delay, and her troponin level was normal. Measurement of the troponin level was not repeated. Her creatinine level was elevated (165 μmol/L [reference interval, 60–115 μmol/L]). She was diagnosed with possible unstable angina and commenced taking aspirin and a nitrate, with a plan for 48 hours of observation followed by discharge for outpatient functional study. On her second day in hospital, Mrs D developed recurrent symptoms with pulmonary oedema, which responded to continuous positive airways pressure and diuretic therapy. Arrangements were made for coronary angiography at the nearest PCI-capable hospital. She was transferred 4 days later (once her international normalised ratio [INR] had fallen to < 1.5). Coronary angiography showed a stenosed vein graft to a circumflex vessel, which was treated with a 3.5 mm drug-eluting stent.

Mrs D was discharged 5 days later (once her INR had reached 2) with a medication regimen of aspirin, clopidogrel, warfarin, frusemide, an ACE inhibitor and a statin. The hospital arranged an appointment with her GP. Eighteen months later, she re-presented to the hospital with a massive gastrointestinal bleed. At this time, she was still taking aspirin, clopidogrel and warfarin.

3 Strategies aimed at increasing access to secondary prevention

Automatic referral of all eligible patients
Availability of different program types, including home, primary care, hospital and community-based strategies
Use of e-health, including communication by telephone, email, the internet or videoconferencing
Provision of programs that involve family-based strategies
Coordinated care comprising medical visits with general practitioners and specialists in combination with participation in a structured secondary prevention program

Improving cardiovascular disease management in Australia: NPS MedicineWise

Cardiovascular disease (CVD) is the largest cause of premature death in Australia; it accounted for over a third of all deaths in 2007.1 Over the past decade, NPS MedicineWise (previously known as the National Prescribing Service) implemented a number of educational programs on cardiovascular management in primary care, including two programs on the use of antithrombotics in atrial fibrillation (AF) and secondary stroke prevention,2,3 as well as programs for improving management of heart failure.4–6 NPS MedicineWise used a mix of interventions, both passive (eg, written education materials) and active (eg, one-on-one educational visits, general practitioner clinical audits, case studies), to deliver these programs, to maximise reach among GPs and to reinforce program key messages. Educational visits have been shown to be effective in changing health professional practice.7

The veteran community in Australia is further supported to achieve optimal use of medicines through the Veterans’ Medicines Advice and Therapeutics Education Services (Veterans’ MATES) program.8 In addition to the NPS MedicineWise programs, one of the Veterans’ MATES interventions also targeted warfarin use.9

The aim of this research was to evaluate the effect of these NPS MedicineWise interventions on the use of medicine and medical tests. The research focused on evaluating the effect of the key educational messages targeted in the interventions, which were to:

consider warfarin in all patients with atrial fibrillation and who are at moderate-to-high risk of stroke, and aspirin in those at low risk (delivered as part of the 2003 and 2009 therapeutic programs on antithrombotic use in atrial fibrillation and secondary stroke prevention2,3);
consider aspirin as the drug of choice for secondary stroke prevention (delivered as part of the 2003 and 2009 therapeutic programs on antithrombotic use in atrial fibrillation and secondary stroke prevention2,3);
confirm heart failure with an echocardiogram (delivered as part of the therapeutic program on heart failure management from 20086); and
use low-dose spironolactone in moderate-to-severe heart failure as it confers additional mortality benefit for patients (part of the 2004 and 2008 programs on heart failure management5,6).

Methods

Data source

We conducted time-series analyses using the Department of Veterans’ Affairs (DVA) health claims database. It provides details on all subsidised prescription medicines, medical and allied health services and hospitalisations for veterans. Overall, 60% of the DVA population are men and the mean age is 80 years (SD, 9.8 years).10

Study design

Monthly time series were established between 1 January 2002 and 31 August 2010 to evaluate the effect of the key educational messages. The selection criteria for the populations of interest, contribution of person-time, and the monthly prevalence are described in Box 1.

The monthly prevalence of medicine and medical test use was calculated as the proportion of the population receiving a specific medicine or test in a given month in the population of interest. In calculating the population using a specific medicine each month, a prescription duration estimate was applied, which was calculated from the data and reflected the period within which 75% of prescriptions for that medicine were refilled, as sensitivity analysis has shown that the 75th percentile is most likely to represent the period of actual consumption of a medicine. To account for the ageing population, rates were age-standardised using the veteran population in January 2002.

Statistical analyses

Interrupted time-series modelling with change points at the time of the interventions was used to determine the impact of the NPS MedicineWise interventions. Analyses controlled for the baseline trend, seasonality and any autocorrelation evident in the time series. Change-in-trend and change-in-level terms were included to determine the impact of interventions. Additional terms were modelled to account for other events that could have influenced the time series, including changes in copayments in January 2005, and the impact of the Veterans’ MATES program aiming to improve medication use for Australian war veterans.8 Stepwise backward elimination was used to select the most parsimonious model, the one that included only statistically significant predictors. The intervention effect from the most recent NPS MedicineWise intervention was reported as:11

absolute effect, expressed as the absolute difference between the model-estimated values of the outcome after the intervention and values estimated as if the intervention had not occurred (ie, without any postintervention effects in the model);
relative change in the outcome associated with the intervention, expressed as a percentage increase or decrease; and
average month-to-month change (%) for the period since the most recent intervention calculated as ratio of the model-estimated values in each month to the values from the previous month, for the trend line with and without the intervention.

Data extraction and analysis were performed using SAS version 9.3 (SAS Institute Inc).

Ethics approval

An ethics protocol for the study was approved by the University of South Australia Human Research Ethics Committee (ethics protocol P218/09) and the Department of Veterans’ Affairs Human Research Ethics Committee (E009/0190).

Results

Of the four areas evaluated, all were associated with improvement in practice at 6 to 12 months after the most recent intervention, with relative effect sizes ranging from 1.27% to 4.31% (Box 2 and Box 3). Three of the trend lines showed a sustained constant month-to-month increase (Box 2 and Box 3). Further, the monthly increase in the rate with the intervention effects was 3–10 times higher than the increase shown by the trend line without the intervention. For example, the rate of aspirin use in secondary stroke prevention, when accounting for the effect of the February 2009 program, increased by 0.29% each month (compared with the previous month), compared with 0.03% monthly increase in the rate without the intervention.

There was an abrupt increase in the use of aspirin and warfarin in AF around the time of the interventions, followed by a slow decrease in the trend over time towards the estimated rate without intervention (Box 3).

Discussion

Our results showed that over half of the population with a prior hospitalisation for AF received warfarin or aspirin treatment. The results are comparable with an American study that reported use of warfarin by 42% of patients with AF at high risk of stroke, and by 44% of patients with moderate stroke risk.12

Aspirin significantly reduces the risk of stroke in patients who experienced a transient ischaemic attack (TIA) or stroke,13 and should be given as soon as possible after onset and continued as long-term antiplatelet therapy.14 Our analysis showed that an increasing number of patients were receiving aspirin as a monotherapy after a TIA or ischaemic stroke event, reaching around one-quarter of the at-risk group in March 2010.

Symptoms of heart failure can be non-specific, and many at-risk patients remain undiagnosed in the early stages.15 If heart failure is suspected, further investigations are required, including an echocardiogram, as it provides information about the type of heart failure and thus treatment implications.16,17 We found that echocardiography was requested before diagnosis of incident heart failure for one in five at-risk people.

Low-dose spironolactone (25 mg), when added to loop diuretic and angiotensin-converting enzyme inhibitor therapy, can improve prognosis in patients with moderate-to-severe heart failure.18 Around 11% of our patients with heart failure were given low-dose spironolactone. This rate is similar to the 11% rate of spironolactone use in patients with chronic heart failure reported by a Dutch study in 2000.19

This evaluation has shown that the NPS MedicineWise programs delivered in primary care were effective in improving prescribing and service use in cardiovascular management, with relative effects ranging from 0.63% to 4.31% 12 months after the intervention. The NPS MedicineWise used a combination of passive and active interventions to reinforce their key messages. Active components such as one-to-one educational visits have been shown to be effective in improving health professional practice, providing small but consistent changes in prescribing (median, 4.8%), and small-to-moderate effects on other professional performance (eg, screening tests).7,20 Although small to moderate, such changes might be potentially important when hundreds of patients are affected.7

There are several limitations to our study. There is no way to ascertain whether the GPs who are responsible for changes in prescribing and medical test requests are also the ones who received the information through the NPS MedicineWise program or other sources. The data does not provide direct diagnostic information; thus our analyses rely on previous hospitalisation records, including documentation of a medication regimen to define the presence of a condition, and therefore there are likely to be a number of people with the conditions of interest who are omitted from the study population.

Nevertheless, the results of this study are likely to be generalisable to the overall Australian population, as there are only slightly more general practice visits (rate ratio, 1.17; P < 0.05) and hospitalisations (rate ratio, 1.21; P < 0.05) in the veteran population per year than in other Australians aged 40 years and over.21 Veterans receive slightly more prescriptions annually than other Australians aged 40 years and over (rate ratio, 1.13; P < 0.05).21 This suggests that our study results are likely to reflect the general Australian population, but may slightly overestimate the utilisation rates.

In conclusion, NPS MedicineWise programs delivered in primary care are associated with significant changes in drug use patterns and service use in cardiovascular management. The quality use of medicines programs implemented as an initiative of the National Medicines Policy have the potential to improve Australia’s medicines and health environment.

1 Study design: key messages of four NPS MedicineWise programs, selection criteria and key definitions

Key message

Selection criteria for the population of interest

Person-time

Monthly prevalence

Consider aspirin
or warfarin in AF

At least one hospital admission between 2002 and 2010 with primary diagnosis for AF (ICD codes I48.0
to I48.9)

All months from the first hospitalisation to death
or end of study

Proportion of patients
given aspirin or warfarin

Consider aspirin as
a monotherapy in secondary stroke prevention

At least one hospitalisation between 2002 and 2010 with primary diagnosis for transient ischaemic attack (ICD code G45.0 to G45.9) or ischaemic stroke (ICD code I63.0 to I63.9)

All months from the first hospitalisation to death
or end of study

Proportion of patients given
aspirin as a monotherapy

Confirm an incident HF event with an echocardiogram

First ever hospitalisation for HF (ICD codes I50.0
to I50.9, I11.0, I13.0, I13.2) or first ever dispensing
of medications indicative of HF* between 2002
and 2010

Just for the month of
the incident HF event

Proportion of patients who had
an echocardiogram (MBS item numbers 55113, 55118) in the
3 months before the incident
HF event

Use low-dose spironolactone (25 mg) in patients with HF

Hospitalisation for HF or dispensing of medications indicative of HF*

All months with a hospitalisation for HF or dispensing of medications indicative of HF*

Proportion of patients given
low-dose spironolactone (25 mg)

AF = atrial fibrillation. HF = heart failure. ICD = International Classification of Diseases (10th revision). MBS = Medicare Benefits Schedule. * Medications indicative of HF included rennin–angiotensin system medications concurrent with loop diuretics or the heart failure-specific beta-blockers bisoprolol, metoprolol succinate or carvedilol.

2 Results: summary of impact of programs targeting quality use of medicines in cardiovascular management in primary care

Month-to-month change (%) in the trends after most recent intervention

Absolute and relative effect (95% CI) after most recent intervention

Key message (population of interest in January 2002)

Monthly prevalence
in January 2002

Trend with
intervention

Trend without intervention

Absolute increase

Relative increase

Consider aspirin or warfarin
in AF (2863 patients
with AF)

1642/2863 patients (57.35%) were given warfarin or aspirin

Initial increase of 1.32% (P = 0.03), then monthly change of
(− 0.06%)

0.04%

0.80%
(0.19%–1.41%) at 6 months and 0.39% (0.13%–1.00%)
at 12 months

1.27% (1.26%–1.28%)
at 6 months and 0.63% (0.62%–0.64%)
at 12 months

Consider aspirin as a monotherapy in secondary stroke prevention (2015 patients with TIA or ischaemic stroke)

333/2015 patients (16.53%) were
given aspirin as a monotherapy

0.29%

0.03%

0.36%
(0.04%–0.68%)
at 12 months

1.51%
(1.49%–1.53%)
at 12 months

Confirm an incident HF event with an echocardiogram
(959 patients with
incident HF)

139/959 patients (14.49%) had an echocardiogram in the past 3 months

0.45%

0.15%

0.77%
(0.07%–1.47%)
at 12 months

4.31%
(4.27%–4.35%)
at 12 months

Use low-dose spironolactone (25 mg) in patients with
HF (22 176 patients
with HF)

2362/22176 patients (10.65%) were
given low-dose spironolactone

0.18%

0.05%

0.41%
(0.14%–0.69%)
at 12 months

3.69%
(3.67%–3.71%)
at 12 months

AF = atrial fibrillation. HF = heart failure. TIA = transient ischaemic attack.

3 Monthly time series showing effects of NPS MedicineWise educational programs targeting quality use of medicines in cardiovascular management

* The changes in Safety Net copayments in January 2005 contributed to the decrease in the rate around that time.

Utility of auscultatory screening for detecting rheumatic heart disease in high-risk children in Australia’s Northern Territory

Rheumatic heart disease (RHD), the long-term sequel of acute rheumatic fever, is a leading cause of heart disease in children in low- and middle-income countries.1 Poverty and overcrowding are known risk factors for RHD,2 and with improvements in socioeconomic conditions, the disease has essentially disappeared from industrialised countries, with the exceptions of the Indigenous populations of Australia and New Zealand.3 Indigenous Australians continue to experience among the highest rates in the world, with an acute rheumatic fever incidence of up to 380 per 100 000 children aged 5–14 years, and an estimated RHD prevalence of 8.5 per 1000 children in this age group.4 A recent government report shows that young Indigenous Australians (< 35 years) in the Northern Territory have a 122-fold greater prevalence of RHD than non-Indigenous Australians.5

In populations with high prevalence, RHD satisfies many of the criteria for a disease to be deemed suitable for screening,6 and RHD has long been a target of public health screening internationally. Cardiac auscultation was the traditional approach,7 but with the evolution of portable echocardiography there has been increasing interest in echocardiographic screening for RHD.8–15 In the echocardiographic era, a new category of RHD has been recognised: “subclinical RHD”, defined as structural or functional changes consistent with RHD evident on an echocardiogram in the absence of a pathological cardiac murmur.6 By definition, it is not possible to identify children who have subclinical RHD using auscultatory screening alone, and published data consistently show that auscultation is considerably less sensitive than echocardiography, missing up to 90% of cases of RHD in some studies.8 Also of concern is the high false-positive rate associated with auscultation, resulting in many children undergoing further unnecessary diagnostic evaluation.9,16

Auscultatory screening for RHD commenced in the NT in 1997 and is still used today. Cardiac auscultation is performed by primary care doctors on schoolchildren aged 10 and 15 years who live in remote Indigenous communities; those with a cardiac murmur are referred for echocardiography.17 The NT is the only jurisdiction in Australia with a formal RHD screening program.

As part of a large echocardiographic screening study undertaken in northern Australia, we performed cardiac auscultation on a subset of schoolchildren in remote Indigenous communities in the NT and compared clinical findings with echocardiographic findings. We aimed to establish whether cardiac auscultation is an appropriate tool for RHD screening to identify children who should be referred for echocardiography.

Methods

Setting and participants

Our study was conducted in 12 rural and remote communities in Central Australia and the Top End of the NT between September 2008 and June 2010. Children aged 5–15 years, identified by school enrolment records, were eligible to participate. These children were a subset of a larger group of children, from 17 communities in Northern Australia, who had echocardiography performed for a larger study. Nurse and doctor auscultators were present during visits to the 12 communities, and all the children in these communities who were participating in the larger study were eligible to participate in the auscultation component.

Written informed consent was obtained from parents and guardians, and written assent was obtained from children aged ≥ 13 years before they took part. Ethics approval was obtained from the Human Research Ethics Committee of the Northern Territory Department of Health and Community Services, and the Central Australian Human Research Ethics Committee.

Echocardiography

All children had a screening echocardiogram performed by an experienced cardiac sonographer using a Vivid e (GE Healthcare) portable cardiovascular ultrasound machine. Sonographers were blinded to the auscultators’ findings and to the clinical history of the children. Screening echocardiograms were performed according to an abbreviated protocol, previously used in Tonga and Fiji,9,16 that focused on the mitral and aortic valves, but would also enable detection of significant congenital lesions. If a potential abnormality was detected, a complete echocardiogram was performed.

Echocardiograms were recorded to DVD and reported offsite by a pool of 14 cardiologists who were blinded to the clinical findings. Detailed data about the mitral and aortic valves were entered into an electronic database.

Children were classified as having definite or borderline RHD according to the 2012 World Heart Federation (WHF) criteria for the echocardiographic diagnosis of RHD.18 This was done by extracting each individual echocardiographic feature, as objectively measured and recorded by reporting cardiologists, and combining features to determine whether WHF definitions were met. Children were also classified as having pathological mitral regurgitation or pathological aortic regurgitation according to these criteria.

Cardiac auscultation

Children underwent auscultation performed by a nurse and a doctor who were blinded to the sonographers’ findings, each others’ findings and to the clinical history of the children. Auscultation was performed by nurses with varying levels of experience and doctors of different specialties (including general practitioners, paediatricians and cardiologists). It was completed with children supine and sitting, in a quiet room where possible. The diaphragm and bell of the stethoscope were used at the apex and axilla, lower left sternal edge, upper left sternal edge and upper right sternal edge. The nurses and doctors who performed auscultation were asked to comment on the presence or absence of a murmur. The doctors were further asked to specify whether a murmur was “innocent”, “suspicious” or “pathological”. Suspicious and pathological murmurs were classified as “significant” murmurs. This enabled assessment of three screening approaches: one-stage auscultation by a nurse to detect any murmur; one-stage auscultation by a doctor to detect any significant murmur; and two-stage auscultation, with the first stage to detect any murmur by a nurse and the second stage to detect which of these was significant by a doctor.

Analysis

Statistical analysis was performed using Stata statistical package version 12.1 (StataCorp). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each screening approach.

Results

A total of 1986 NT children had a screening echocardiogram as part of the larger study, of whom 1015 had auscultation performed by a doctor and a nurse; 960 (94.6%) were Indigenous and 498 were girls (49.1%). The mean age was 9.3 years (SD, 2.5 years), and the median body mass index was 15.6 kg/m2 (interquartile range, 14.4–17.8 kg/m2). Children who had an echocardiogram but did not undergo auscultation were slightly older (mean age, 9.7 years), but were otherwise comparable based on sex and body mass index.

Echocardiographic findings

Thirty-four children (3.3%) had abnormalities identified on their echocardiogram. Fifteen (1.5%) of them had definite RHD, 9 (0.9%) had borderline RHD (including two who also had small atrial septal defects), and 10 (1.0%) had isolated congenital anomalies: ventricular septal defect (two), atrial septal defect (one), mitral valve prolapse (two), patent ductus arteriosus (two), dilated aortic root (two) and complex congenital heart disease (one). Of the 24 children with RHD, 14 had pathological mitral regurgitation, six had pathological aortic regurgitation, and one child had both.

Clinical findings

One-stage auscultation

A cardiac murmur (significant or not) was heard by nurses in 263 children (25.9%), by doctors in 257 children (25.3%), and by a doctor and a nurse in 137 children (13.5%). Compared with echocardiogram, one-stage auscultation to detect any murmur by a doctor or a nurse had a sensitivity of less than 50%, a specificity of about 75%, and a positive predictive value (PPV) of less than 10% (Box 1). Asking doctors to decide which murmurs were pathological or suspicious increased the specificity from 75.1% to 92.2%, but further dropped the sensitivity to 20.6%. The breakdown of medical specialists and their auscultation findings are presented in Box 2.

Two-stage auscultation

Only 52% (137/263) of the murmurs heard by nurses were also heard by doctors. Of these, 57 were considered pathological or suspicious. Using two-stage auscultation, 28 children with abnormalities were missed (sensitivity, 17.6%), and six children with abnormalities were correctly identified (PPV, 10.5%). This approach had a specificity of 94.8%.

Discussion

Our study confirms that cardiac auscultation has poor sensitivity, despite moderately high specificity, for detecting RHD and other cardiac abnormalities evident on echocardiograms, regardless of the experience of the examiner. More than 50% of children with abnormal echocardiography results did not have a murmur detected, and more than 90% of murmurs heard were false positives. The observed high NPVs and low PPVs are expected in a low-prevalence disease such as RHD, and are consistent with the results of previous studies (Box 3). Our findings highlight the paramount importance of sensitivity in determining the utility of auscultation as a screening test for RHD.

The current approach to screening for RHD in the NT is one-stage doctor auscultation by a GP, with referral of any child with a murmur for an echocardiogram.17 Program reports suggest that cardiac murmurs are heard in about 10% of those screened,19 but few data regarding follow-up and clinical outcomes for these children are available. In a detailed report on RHD screening in Central Australia during 2009, 67 of 1095 children who were screened (6.1%) had a murmur and were referred for echocardiography. One year later, only 38 of them had had their echocardiogram, of whom four had abnormalities (two RHD, two non-RHD abnormalities).19 This prevalence of RHD (2 per 1000 children) is considerably lower than expected in the Central Australian population and suggests that some disease went undetected. In addition, the fact that nearly half of referred children had not had their echocardiogram 12 months later also highlights difficulties with the current approach.

According to the current NT screening model (one-stage doctor auscultation), 257 children in our study would have been referred for echocardiogram, with only 13 of them having abnormalities (eight with RHD, five with congenital heart disease). A high false-positive rate has important implications for screening programs, to both the individual and the health system. In the NT, limited paediatric cardiology services exist, and waiting times for echocardiography can be long. Such high false-positive rates would result in a substantial increase in referral of children to tertiary services for further evaluation, and would risk overburdening already-stretched paediatric cardiology services with children who do not have heart disease.

Of greatest concern, however, is that using the current approach to RHD screening, 16 of 24 children with RHD (10 with definite RHD, six with borderline RHD) would have been missed. While there is uncertainty about the significance of the borderline RHD category, the WHF recommends that all children meeting echocardiographic criteria for definite RHD be started on secondary prophylaxis.18 In our study, the 10 children who met these criteria but did not have murmur detected by one-stage doctor auscultation would not have had further evaluation and would not have commenced secondary antibiotic prophylaxis, leaving them at high risk of acute rheumatic fever recurrences and further valve damage.

The prognosis of RHD is best if secondary prophylaxis with long-acting intramuscular penicillin is commenced when the disease is mild; continuous adherence to treatment with penicillin can result in valve damage being halted or reversed.20–22 It is therefore imperative that the test used to screen for RHD is highly sensitive, so that children with the earliest stage of disease, who stand to gain the most from the only currently available preventive treatment, are identified.

It is widely accepted that echocardiography is more sensitive than auscultation. While there has been much discussion about echocardiographic definitions of RHD, including concerns about specificity, it is hoped that the publication of the WHF diagnostic criteria will minimise false-positive results. Whether echocardiographic screening for RHD is appropriate, feasible and cost-effective will vary between settings, and remains a topic of vigorous debate.6,23–25 A cost-effectiveness analysis of our data is underway and will contribute to our ultimate recommendations about the future of echocardiographic screening in Indigenous Australian children who are at high risk of RHD.

A limitation of this study is that auscultation was carried out by several different doctors and nurses, potentially leading to high interobserver variation. Similarly, the screening environment varied between communities, and the conditions under which auscultation was performed (eg, in a quiet room) were not the same for all participants. However, we believe that these limitations reflect the day-to-day reality of health care service provision in the participating communities, allowing valid extrapolation of our results to the current school screening procedure in the NT and many other settings.

We conclude that cardiac auscultation is not an effective method of RHD screening, regardless of the expertise of the auscultator. The risk of missing more than 50% of children with RHD, and the risk of overburdening cardiology services with false positives, preclude recommendation of one-stage or two-stage auscultation as a rational approach to RHD screening. We recommend that cardiac auscultation no longer be used to screen for RHD in high-risk schoolchildren in Australia.

1 Comparison of auscultation findings with echocardiographic findings for 1015 children from rural and remote parts of the Northern Territory,
2008–2010

Auscultation approach

No. of children
with abnormalities* (n = 34)

No. of children
without abnormalities
(n = 981)

Sensitivity
(95% CI)

Specificity
(95% CI)

PPV
(95% CI)

NPV
(95% CI)

AUC†
(95% CI)

One stage, by nurse

Any murmur

247

47.1%
(29.8%–64.9%)

74.8%
(72.0%–77.5%)

6.1%
(3.5%–9.7%)

97.6%
(96.2%–98.6%)

0.61
(0.52–0.70)

No murmur

734

One stage, by doctor

Any murmur

13‡

244

38.2%
(22.2%–56.4%)

75.1%
(72.3%–77.8%)

5.1%
(2.7%–8.5%)

97.2%
(95.8%–98.3%)

0.57
(0.48–0.65)

No murmur

21§

737

One stage, by doctor

Significant murmur¶

20.6%
(8.7%–37.9%)

92.2%
(90.3%–93.8%)

8.3%
(3.4%–16.4%)

97.1%
(95.8%–98.1%)

0.56
(0.49–0.63)

No significant murmur

904

Two stage**

Significant murmur

17.6%
(6.8%–34.5%)

94.8%
(93.2%–96.1%)

10.5%
(4.0%–21.5%)

97.1%
(95.8%–98.1%)

0.56
(0.50–0.63)

No significant murmur

930

PPV = positive predictive value. NPV = negative predictive value. AUC = area under the receiver operating characteristic curve. * Definite or borderline rheumatic heart disease and congenital abnormalities detected on echocardiogram; there was no difference in the findings when only definite rheumatic heart disease and congenital abnormalities were considered true cases (data not shown). † AUC is a measure of overall test accuracy; 0.5 indicates zero discrimination, and values approaching 1.0 indicate high sensitivity and specificity. ‡ Includes 8 children with rheumatic heart disease (5 definite, 3 borderline) and 5 with congenital heart disease. § Includes 16 children with rheumatic heart disease (10 definite, 6 borderline) and 5 with congenital heart disease. ¶ Includes 20 pathological and 64 suspicious cardiac murmurs. ** By a nurse to identify any murmur, then by a doctor to identify significant murmur.

2 Comparison of one-stage doctor auscultation findings with echocardiographic findings, by specialty of doctors who performed auscultation, for children from rural and remote parts of the Northern Territory, 2008–2010

	No. of children who underwent auscultation	No. of children with abnormalities*	No. (%) of children with any murmur	No. (%) of children with significant murmur	Sensitivity†	Specificity†

General practitioner	157	8	33 (21.0%)	14 (8.9%)	12.5%	91.3%
Paediatrician	637	17	159 (25.0%)	48 (7.5%)	17.7%	92.7%
Cardiologist	106	4	37 (34.9%)	2 (1.9%)	0	98.0%
Physician	45	2	14 (31.1%)	7 (15.6%)	100.0%	88.4%
Resident medical officer	70	3	14 (20.0%)	13 (18.6%)	33.3%	82.1%
Any doctor	1015	34	257 (25.3%)	84 (8.3%)	20.6%	92.2%

* Definite or borderline rheumatic heart disease and congenital abnormalities detected on echocardiogram. † Comparison of doctor identification of significant cardiac murmur with any abnormality detected on echocardiogram.

3 Comparison of auscultation findings with echocardiographic findings in three large rheumatic heart disease screening studies

	Country (auscultator)
	Mozambique (physician)8	Tonga (medical student)9	Tonga (paediatrician)9	Fiji (paediatrician)16

No. of children who underwent auscultation	2170	980	980	3462
No. of children who underwent echocardiography	2170	980	980	331
No. of children with abnormalities detected on echocardiogram	71	140	140	41
No. (%) of children with any murmur	456 (21%)	964 (98%)	779 (79%)	889 (26%)
No. (%) of children with significant murmur	91 (4%)	NA	358 (37%)	359 (10%)
Sensitivity*	14%	96%	46%	NA
Specificity*	96%	1%	65%	NA
Positive predictive value*	11%	14%	18%	14%
Negative predictive value*	97%	69%	88%	NA

NA = not applicable. * Comparison of significant murmurs (where reported) with any abnormality (rheumatic heart disease and congenital heart disease) detected on echocardiogram; echocardiographic definitions of rheumatic heart disease varied slightly between studies.

Utility of exercise electrocardiography testing for the diagnosis of coronary artery disease in a remote Australian setting

Coronary artery disease (CAD) remains the leading cause of death in Australia, both in the general population and also among Aboriginal and Torres Strait Islander peoples (referred to henceforth as Indigenous Australians).1 Indigenous Australians are three times as likely to suffer a major coronary event than are non-Indigenous Australians,2 and cardiovascular disease remains the leading cause of Indigenous mortality and the main contributor to the mortality gap between Indigenous and non-Indigenous Australians.3 Furthermore, the burden and severity of other diseases that predispose to CAD are higher among Indigenous Australians.4

Patients with an acute coronary syndrome (ACS), as defined by electrocardiography results and biochemical markers, proceed to coronary angiography, which is considered the gold standard diagnostic tool for CAD; however, its use is limited due to its invasive nature, cost and accessibility.5 In the absence of a definite ACS, less invasive, and often more accessible, exercise stress testing is used. Stress testing determines the significance of a patient’s symptoms by indicating whether functional myocardial ischaemia occurs and therefore whether further investigations, including coronary angiography, are needed.

Alice Springs Hospital (ASH), in the Northern Territory, services a dispersed population of 45 000 people spread over 1 million square kilometres, of whom 44% are Indigenous Australians.6 ASH is about 1500 kilometres from the nearest angiography facilities and relies on exercise electrocardiography testing (EET) to prioritise patients for further investigation of possible CAD. Patients with a “positive” test are typically referred for coronary angiography, and patients with a “negative” test are usually reassured and assumed to be at low risk of significant CAD.7 Inconclusive test results typically lead to referral for stress echocardiography — the timing of which is reliant on the frequency of visiting cardiologists. Consequently, the results of EET are heavily relied upon to inform a diagnosis and management plan. In non-Indigenous populations, the usefulness of EET has been reflected in its reported high negative predictive value of 99%.8–11 We chose to retrospectively audit the performance of EET in our local population, as its diagnostic utility in a setting with a significant proportion of Indigenous Australians has not been studied. In addition, we assessed the significance of inconclusive EET results with regard to subsequent clinical outcomes, as patients with inconclusive results may be at increased risk of CAD-related events while waiting for further diagnostic testing.

Methods

We undertook a retrospective audit of data for patients with suspected CAD who underwent EET between 1 June 2009 and 31 May 2010. We excluded patients with a pre-existing diagnosis of CAD and those not permanently residing in the NT. Data collected included patient demographics, CAD risk factors, results of the EET, and clinical outcomes for the following 2 years as documented in the patients’ medical records.

ASH uses the Bruce protocol for conducting EET, aiming to achieve a target age- and sex-based heart rate, exercise duration and workload (based on metabolic equivalents [METS]).9 A positive result was one or more of: angina during exercise; ST-segment depression that was > 1 mm and/or downsloping; reduction in blood pressure of > 10 mmHg from baseline and/or multiple ventricular premature complexes or runs of ventricular tachycardia. A negative test result was recorded if the patient was asymptomatic with a normal electrocardiogram and blood pressure response on completion of maximal testing. A patient who failed to complete the test for reasons other than those that would classify the test as being positive was reported as having an inconclusive test result.10

Clinical outcomes were reviewed for 2 years after EET for details of subsequent coronary angiography results consistent with CAD, readmission to ASH for investigation of chest pain and readmission to ASH with a separation diagnosis of an ACS. Our assessment of the overall utility of EET was based on the risk of having a coronary angiogram suggestive of either CAD or an ACS within 24 months of testing.

Statistical analysis was undertaken using Stata12 (StataCorp). Continuous variables were compared using the Wilcoxon rank-sum test; categorical variables were compared using the χ2 test. Continuous non-parametric data are presented as medians with interquartile range, and categorical variables are presented as percentages with binomial confidence intervals. Logistic regression models were created using a backwards stepwise approach, including in the first model all variables shown in univariable models to be related to test outcome, as well as variables that differed between Indigenous and non-Indigenous subjects at baseline. All statistical tests were two-sided and P less than 0.05 was taken to indicate statistical significance. Ethics approval for the study was provided by the Central Australian Human Research Ethics Committee.

Results

We reviewed the medical records and EET results of 268 patients who met our inclusion criteria. Descriptive data related to these patients are presented in Box 1. Indigenous identity was not reported for 10/268 patients (3.7%). Indigenous patients were significantly younger than non-Indigenous patients and were more likely to be women. They were also twice as likely to have been diagnosed with one or more chronic diseases (OR, 2.0; 95% CI, 1.1–3.7), particularly diabetes mellitus (OR, 5.9; 95% CI, 3.3–10.7) and chronic kidney disease (OR, 12.2; 95% CI, 4.1–36.1), compared with non-Indigenous patients.

The results of EET and outcomes over the subsequent 24 months are outlined in Box 2. Indigenous patients were less likely to reach a maximum heart rate or adequate workload (> 10 METS) (OR, 10.3; 95% CI, 5.3–20.3). In turn, this translated to a higher proportion of Indigenous patients having inconclusive test results compared with non-Indigenous patients (57/108 v 32/150; P < 0.001) and a lower proportion having positive (6/108 v 21/150; P = 0.03) and negative (45/108 v 97/150; P < 0.001) test results (Box 2). In logistic regression modelling, the major factors independently associated with an inconclusive result were a diagnosis of one or more chronic diseases (OR, 6.0; 95% CI, 2.5–14.1) and identifying as Indigenous (OR, 3.7; 95% CI, 2.1–6.6).

Compared with patients with an inconclusive or negative EET result, patients with a positive result were more likely to proceed to coronary angiography (21/34; P < 0.001) and were significantly more likely to present to hospital with chest pain in the following 2 years (11/28; P = 0.001). Indigenous patients were less likely than non-Indigenous patients to proceed to coronary angiography (10/34 v 24/34, respectively; P = 0.114), and more likely to present with an ACS in the following 2 years (4/108 v 2/139, respectively; P = 0.25); however, neither of these differences were statistically significant. Overall, the risk of presenting with an ACS within 24 months significantly increased as the result of EET moved from negative to inconclusive to positive (OR, 4.4; 95% CI, 1.4–14.0). A similar relationship to EET results was seen for re-presentation with chest pain within 12 months (OR, 2.0; 95% CI, 1.3–3.1) and re-presentation with chest pain within 24 months (OR, 2.0; 95% CI, 1.3–2.9).

The sensitivity, specificity and positive and negative predictive values of EET in our sample are summarised in Box 3.

Discussion

EET clearly represents a cheap, non-invasive diagnostic modality for screening patients presenting with suspected CAD. Our findings provide reassurance that, when maximal testing can be completed, EET has performance characteristics that are at least equivalent to those reported in the literature.8 Even when inconclusive results were included, the lack of a positive EET continued to confer a low risk of a subsequent presentation with an ACS. While the presence of chronic disease was the main predictor of an inconclusive EET there was also an independently elevated risk associated with being Indigenous. This may be related to physical and social factors, including familiarity with treadmill exercise, and fitness.

A focus should be to reduce the proportion of inconclusive tests. In general, an image-based myocardial stress study, typically echocardiography with dobutamine, is performed when the EET result is inconclusive. These tests are conducted by visiting cardiologists, but waiting periods are variable and may extend to months. In the interim, a person with possible CAD may go without treatment and be at risk of a preventable adverse outcome — demonstrated in our study by the high rates of loss to follow-up and re-presentation with an ACS. Possible solutions include enhanced orientation and education of patients before they undergo EET, and greater use of Indigenous language translators.

Our study was limited by its reliance on retrospective collection of data that were non-standardised. The information gathered was limited to data documented at the time of the EET. Similarly, follow-up of patients re-presenting with ACS or chest pain was restricted to those who presented to ASH. Nonetheless, as the only referral hospital servicing the Central Australian region, most clinically significant events in remote clinics would have been captured. This limitation could be overcome by repeating the audit prospectively.

In summary, EET is likely to remain a useful and important tool in determining the risk of CAD among patients in regional and remote Australian locations where onsite specialist cardiology services are limited. Further attention should be given to how inconclusive test results could be reduced. Positive initiatives may include greater involvement of Indigenous people in the health care workforce associated with EET, exploring patients’ understanding of the concepts of CAD and exercise, and educating patients and health care providers. Greater use of myocardial stress testing modalities that do not require specialist cardiologists, such as cardiac computed tomography angiography, or training local staff to perform stress echocardiography could also be considered as means of enhancing the care of patients with inconclusive results.

1 Descriptive details of 268 patients who underwent exercise electrocardiography testing 1 June 2009 – 31 May 2010

All patients

Indigenous patients

Non-Indigenous patients

No.

Proportion (95% CI)*

No.

Proportion (95% CI)*

No.

Proportion (95% CI)*

P†

Age in years, median (IQR)

–

49.0 (41.6–57.5)

–

45.7 (39.1–55.3)

–

51.0 (44.9–58.6)

0.004‡

Total number

268

100%

108

40.3%

150

56.0%

–

Women

118

44.0% (38.0%–50.2%)

59.3% (50.0%–68.7%)

34.7% (27.0%–42.4%)

< 0.001

History of smoking

103/245

42.0% (35.8%–48.5%)

48/100

48.0% (37.9%–58.2%)

55/145

37.9% (30.0%–46.4%)

0.12

Family history of CAD

67/155

43.2% (35.3%–51.4%)

24/45

53.3% (37.9%–68.3%)

43/110

39.1% (29.9%–48.9%)

0.10

Any chronic disease

189/262

72.1% (66.3%–77.5%)

88/108

81.5% (72.9%–88.3%)

101/148

68.2% (60.1%–75.6%)

0.02

Diabetes mellitus

80/250

32.0% (26.3%–38.2%)

57/107

53.3% (43.7%–62.9%)

23/143

16.1% (10.0%–22.2%)

< 0.001

Hypertension

132/252

52.4% (46.0%–58.7%)

71/107

66.4% (56.6%–75.2%)

61/145

42.1% (33.9%–50.5%)

< 0.001

Dyslipidaemia

139/237

58.6% (52.1%–65.0%)

71/98

72.4% (62.5%–81.0%)

68/139

48.9% (40.4%–57.5%)

< 0.001

Renal impairment (eGFR < 60 mL/min/1.73 m2)

18/215

8.4% (5.0%–12.9%)

14/98

14.3% (8.0%–22.8%)

4/111

3.6% (1.0%–9.0%)

0.02

Albuminuria (ACR > 3.4 mg/mmol)

26/48

54.2% (39.2%–68.6%)

25/38

65.8% (48.6%–80.4%)

1/8

12.5% (0.3%–52.7%)

0.02

Renal impairment or albuminuria

35/216

16.2% (11.6%–21.8%)

31/99

31.3% (22.4%–41.4%)

4/111

3.6% (1.0%–9.0%)

< 0.001

* Unless otherwise indicated. † χ2 unless otherwise indicated. ‡ Wilcoxon rank-sum test. ACR = albumin : creatinine ratio. CAD = coronary artery disease.
eGFR = estimated glomerular filtration rate. IQR = interquartile range.

2 Exercise electrocardiography testing results and patient outcomes

All patients

Indigenous patients

Non-Indigenous patients

No.

Proportion (95% CI)*

No.

Proportion (95% CI)*

No.

Proportion (95% CI)*

Exercise electrocardiography test result

Positive

31/268

11.6% (8.0%–16.0%)

6/108

5.6% (2.1%–11.7%)

21/150

14.0% (8.9%–20.6%)

0.03

Inconclusive

90/268

33.6% (28.0%–39.6%)

57/108

52.8% (42.9%–62.5%)

32/150

21.3% (15.1%–28.8%)

< 0.001

Negative

147/268

54.9% (48.7%–60.9%)

45/108

41.7% (32.3%–51.5%)

97/150

64.7% (56.5%–72.3%)

< 0.001

Coronary angiography performed

34/268

12.7% (8.9%–17.3%)

10/108

9.3% (4.5%–16.4%)

24/150

16.0% (10.5%–22.9%)

0.11

Proportion of coronary angiograms that were positive

18/34

52.9% (35.1%–70.2%)

5/10

50.0% (18.7%–81.3%)

13/24

54.2% (32.8%–74.4%)

0.82

Acute coronary syndrome

Within 1 year

4/263

1.5% (0.4%–3.8%)

3/108

2.8% (0.6%–7.9%)

1/145

0.7% (0–3.8%)

0.12

Within 2 years

6/255

2.4% (0.9%–5.1%)

4/108

3.7% (1.0%–9.2%)

2/139

1.4% (0.2%–5.1%)

0.25

Acute coronary syndrome and/or positive angiogram

Within 1 year

20/263

7.6% (4.7%–11.5%)

7/108

6.5% (2.6%–12.9%)

13/145

9.0% (4.9%–14.8%)

0.47

Within 2 years

21/255

8.2% (5.2%–12.3%)

8/108

7.4% (3.3%–14.1%)

13/139

9.4% (5.1%–15.5%)

0.59

Readmission with chest pain

Within 1 year

55/264

20.8% (16.1%–26.2%)

28/108

25.9% (18.0%–35.2%)

25/146

17.1% (11.4%–24.2%)

0.09

Within 2 years

67/256

26.2% (20.9%–32.0%)

35/108

32.4% (23.7%–42.1%)

30/140

21.4% (14.9%–29.2%)

0.05

* Unless otherwise indicated.

3 Diagnostic utility of exercise electrocardiography testing*

Prevalence of outcome†

Sensitivity

Specificity

Positive predictive value

Negative predictive value

All patients

All test results (n = 268)

8.5% (5.2%–12.3%)

61.9% (38.4%–81.9%)

94.0% (90.2%–96.7%)

48.1% (28.7%–68.1%)

96.5% (93.2%–98.5%)

Inconclusive results excluded (n = 178)

9.0% (5.1%–14.4%)

86.7% (59.5%–98.3%)

90.8% (85.0%–94.9%)

48.1% (28.7%–68.1%)

98.6% (94.9%–99.8%)

Indigenous patients

All test results (n = 108)

7.4% (3.3%–14.1%)

37.5% (8.5%–75.5%)

97.0% (91.5%–99.4%)

50.0% (11.8%–88.2%)

95.1% (88.9%–98.4%)

Inconclusive results excluded (n = 51)

9.8% (3.3%–21.4%)

60.0% (14.7%–94.7%)

93.5% (82.1%–98.6%)

50.0% (11.8%–88.2%)

95.6% (84.9%–99.5%)

Non-Indigenous patients

All test results (n = 150)

9.4% (5.1%–15.5%)

76.9% (46.2%–95%)

93.7% (87.9%–97.2%)

55.6% (30.8%–78.5%)

97.5% (92.9%–99.5%)

Inconclusive results excluded (n = 118)

9.2% (4.5%–16.2%)

100% (69.2%–100%)

91.9% (84.7%–96.4%)

55.6% (30.8%–78.5%)

100% (96.0%–100%)

* All values are % (95% CI). † Defined as coronary angiogram suggestive of coronary heart disease or an acute coronary syndrome within 24 months of testing.

Phenytoin: an old but effective antiarrhythmic agent for the suppression of ventricular tachycardia

Clinical record

A 73-year-old man presented with recurrent ventricular tachycardia (VT) on a background of severe, non-ischaemic dilated cardiomyopathy (ejection fraction, 20%) and cardiac resynchronisation therapy with an implantable cardioverter defibrillator (ICD). Over the previous 6 months, he had frequent appropriate ICD shocks for VT after unsuccessful antitachycardia pacing. A coronary angiogram was normal. Amiodarone had been successful in reducing VT burden and ICD shocks, but was ceased because of amiodarone-induced thyrotoxicosis. Shortly after discontinuing amiodarone, there was a significant increase in VT burden and appropriate ICD shocks. An endocardial mapping and VT ablation procedure had been performed, but this was unsuccessful and suggested an epicardial source of VT. The patient also underwent subsequent epicardial mapping and VT ablation using a CARTO 3 (Biosense Webster) electroanatomical mapping system, which localised the source of VT to a diffuse area of the basal anterolateral segment of the left ventricle. A total of 17 ablations were performed. However, VT was still inducible after these ablations, and the procedure was terminated after 6.75 hours. Repeat epicardial VT ablation was performed 3 months later, although this was also unsuccessful. Since the frequency of VT had increased after resynchronisation therapy, the pacing mode was converted to dual-chamber atrioventricular pacing with right ventricular pacing only (right ventricular pacing, 85%; atrial pacing, 49%), in case left ventricular pacing was proarrhythmic. To allow reintroduction of amiodarone for VT suppression, the patient then underwent total thyroidectomy and, after an uneventful postoperative recovery, he was discharged, having been restarted on regular oral amiodarone. His medications included amiodarone 200 mg three times daily, carvedilol 50 mg twice daily, spironolactone 25 mg daily, frusemide 40 mg daily, irbesartan 150 mg daily, atorvastatin 40 mg daily, magnesium supplementation, and warfarin.

The next day, he returned to his local district hospital after experiencing another ICD shock. He was found to be in his usual paced rhythm (Box 1, A), with frequent runs of non-sustained monomorphic VT (Box 1, B). Given that he was already
on amiodarone, a lignocaine infusion (maintenance rate,
2 mg/min) was added. This resulted in suppression of VT, but was complicated by confusion and perioral paraesthesia, which persisted despite reduction of infusion rate. Lignocaine was stopped after 24 hours, but this was followed soon afterwards by a VT storm.

Due to the previous success of lignocaine (a class IB antiarrhythmic drug) in controlling VT, trial of another agent
in this class was warranted. Mexiletine or tocainide were not readily available; however, we noted that phenytoin had class IB activity and was readily available on the ward. Phenytoin was initially administered as a loading dose (15 mg/kg, 1 g/h) and was immediately successful in suppressing the VT storm. However, at the end of the infusion, the patient developed nystagmus, drowsiness and hypotension. QRS duration lengthened (Box 1, C). Bradycardia (heart rate, 35–45 beats/min) resulting from intermittent loss of capture of right ventricular pacing was also noted on continuous telemetry (Box 2, A). This was confirmed on pacemaker–ICD interrogation. The right ventricular pacing threshold had increased from 1.4 V at 0.4 ms before phenytoin to 3.0 V at 0.4 ms after phenytoin (Box 3). Previous right ventricular pacing output had been set at 2.8 V at 0.4 ms, below the new threshold, which explained the frequent loss of capture. The pacing amplitude was increased to accommodate the effects of phenytoin loading and ongoing maintenance therapy (Box 2, B). The defibrillation threshold (21 J at time of implantation) was not initially rechecked, but due to the concern that this may also have been increased by phenytoin, the shock setting was increased to the maximum (41 J). Regular oral phenytoin (100 mg three times daily) was commenced, with trough levels confirming that the patient
was in the therapeutic range (Day 7 after commencement, 52 µmol/L; Day 14 after commencement, 70 µmol/L; reference interval, 40–100 µmol/L).

Repeat pacemaker–ICD interrogation performed 9 days after phenytoin commencement demonstrated sustained suppression of ventricular ectopy, with only one further episode of VT, which was successfully terminated by antitachycardia pacing. The pacing thresholds stabilised at a higher level 12 days after phenytoin commencement (Box 3) and remained stable thereafter. A defibrillation threshold test performed 46 days after phenytoin commencement showed no change to the threshold.

Phenytoin, a widely used anticonvulsant, has class IB antiarrhythmic drug (AAD) properties, and is a potential option for patients with refractory ventricular arrhythmia when other agents are contraindicated or unavailable. In patients with frequent ventricular arrhythmia, AADs are often used to reduce the frequency of arrhythmia and implantable cardioverter defibrillator (ICD) shocks. Amiodarone is often used as first-line therapy. Although class I AADs are generally not prescribed for patients with ischaemic heart disease or cardiomyopathy, they are occasionally used in combination with amiodarone in patients who are refractory to amiodarone monotherapy, especially those with ICDs, as this provides some protection against potential proarrhythmic side effects.1

Phenytoin has class IB antiarrhythmic properties due to its effects on sodium channels in cardiac myocyte and Purkinje fibre cell membranes.2 It reduces the maximum rate of depolarisation of the cardiac action potential and increases the effective refractory period. Therefore, it is particularly effective in inhibiting ventricular ectopy, especially in an ischaemic or damaged myocardium.3 Although used as an AAD from the 1950s to the 1970s,4–6 phenytoin has become obsolete in recent decades due to the arrival of newer and less toxic agents. Recent case reports have documented its successful use in controlling idiopathic ventricular fibrillation in a young man7 and refractory idiopathic ventricular tachycardia (VT) in a newborn,8 but these reports have not documented the potential dangers associated with its use.

Although phenytoin was successful in suppressing VT in our patient, this case report highlights several important learning points. Class I AADs, including phenytoin, can increase pacing threshold through use-dependent inhibition of sodium channel function.9 Most pacemakers have algorithms that allow for potential variations in pacing thresholds.10 However, AAD-induced elevation of pacing threshold may become problematic in circumstances where the pacing threshold is already elevated, such as following ICD shock or, as in our patient, the recent use of other class I AADs. AADs can also increase the defibrillation threshold, increase VT cycle length (potentially resulting in VT undersensing) and reduce antitachycardia pacing efficacy.2 The effect of AADs on pacing threshold can be temporarily ameliorated by increasing the settings to levels that guarantee capture but may require readjustment to conserve battery life in the long term. Phenytoin exhibits zero-order pharmacokinetics, is susceptible to multiple drug interactions and has a narrow therapeutic window. Vertigo, ataxia, headache and nystagmus are common early side effects. At higher plasma concentrations, marked confusion and sedation may result. All of these changes occur acutely and are rapidly reversible. Cardiovascular side effects include bradycardia, hypotension and, occasionally, exacerbation of VT. Our patient developed side effects despite a conventional loading protocol used in treating status epilepticus. Factors that may have contributed to toxicity were the presence of severe cardiomyopathy — which may have altered tissue distribution properties and resulted in a higher availability of unbound drug — and recent lignocaine administration, although this had been ceased 6 hours earlier. Rapid loading of phenytoin for VT has been associated with fatal arrhythmogenic complications3 and should therefore be cautiously performed.

Phenytoin, a commonly used drug in the treatment of status epilepticus, is an old but effective treatment option in patients with malignant VT or electrical storm. Although it is readily available and is successful in terminating and suppressing malignant VT, appropriate caution must be taken with its use, especially with regard to the increased likelihood of drug toxicity in patients with cardiomyopathy and its important effects on pacemaker and ICD function. These reported effects of phenytoin on pacemaker function are not only of interest to cardiologists caring for patients with ventricular arrhythmia, but also to neurologists, and emergency and general physicians who use phenytoin to terminate seizures. Owing to the effects of phenytoin on pacemaker threshold and the attendant risks of loss of pacemaker capture, care should be taken with loading doses of phenytoin in patients who are pacemaker-dependent.

1 Electrocardiograms

Twelve-lead electrocardiograms showing left bundle branch block morphology of the patient’s right ventricular paced rhythm (70 beats/min) (A); ventricular tachycardia originating from the left ventricle (B); and, following phenytoin loading, suppression of VT and return to right ventricular paced rhythm, but with widening of the QRS complex, secondary to the effect of phenytoin (C).

2 Telemetry

Telemetry showing intermittent loss of capture of right ventricular pacing (*) (A); and restoration of normal ventricular capture after an increase in right ventricular pacing output (B).

3 Effect of phenytoin on pacing threshold

Lead

Before loading*

Immediately after loading†

After 9 days‡

After 12 days§

Right ventricular

Pacing impedance

1043 O

1067 O

1074 O

1098 O

Pacing threshold

1.4 V at 0.4 ms

3.0 V at 0.4 ms

4.0 V at 0.4 ms or
2.8 V at 1.0 ms

3.3 V at 0.4 ms or
2.2 V at 1.0 ms

Atrial

Pacing impedance

695 O

710 O

671 O

657 O

Pacing threshold

0.8 V at 0.4 ms

1.2 V at 0.4 ms

1.1 V at 0.4 ms

* Right ventricular pacing output set at 2.8 V at 0.4 ms and atrial pacing output at 1.3 V at 0.4 ms. † After loss of capture and pacemaker interrogation, right ventricular pacing output was increased to 7.5 V at 1.0 ms and atrial pacing output to 2.5 V at 0.4 ms to guarantee capture. ‡ After an increase in right ventricular threshold values, pacing output was temporarily increased to 7.5 V at 2.0 ms for 3 days, with repeat follow-up after 3 days. § After stabilisation of pacemaker threshold values, right ventricular pacing output was reduced to 5.0 V at 1.0 ms, with an estimated battery life of 6.5 years.

Lessons from practice

Phenytoin has class IB antiarrhythmic drug properties and is a potential treatment option for patients with refractory ventricular arrhythmia when other agents have failed or are unavailable.
However, phenytoin has a narrow therapeutic range and the potential for multiple drug interactions.
Phenytoin administration may also result in elevation of pacemaker threshold. Care should be taken with loading doses in patients with cardiomyopathy or who are pacemaker-dependent, because of the potential for loss of pacemaker capture.