Guidelines for the management of atrial fibrillation released

Guidelines for the management of atrial fibrillation (AF) have been released by the European Society of Cardiology (ESC).

The 2016 Atrial Fibrillation Guidelines, created around state-of-the-art research and evidence, were released earlier this week at the ESC Congress in Rome.

AF remains one of the major causes of stroke, heart failure, sudden death and cardiovascular morbidity in the world, with emerging evidence offering innovative approaches to its diagnosis and management.

The guidelines list recommendations for diagnosis, general management, stroke prevention, rate control and rhythm control of AF.

Catheter ablation, which has now become a common treatment for recurrent AF, is also discussed as a possible treatment within the guidelines. In general, it should be used as second-line treatment after failure of or intolerance to antiarrhythmic drug therapy. In such patients, when performed in experienced centres by adequately trained teams, catheter ablation is more effective than antiarrhythmic drug therapy.

Other guideline recommendations for the management of AF include:

Opportunistic screening for AF is recommended by pulse taking or ECG rhythm strip in patients over the age of 65
The proposal of lifestyle changes to all suitable AF patients to make their management more effective
The use of the CHA₂DS₂-VAS_c score to predict stroke risk, and initiation of oral anticoagulation when score is 2 or more for males, or 2 or more for females
The avoidance of combinations of oral anticoagulants and platelet inhibitors in AF patients without another indication for platelet inhibition
The selection of antiarrhythmic drugs based on the presence of co-morbidities, cardiovascular risk, potential for proarrhythmia, extracardiac toxic effects, patient preference and symptoms, and consideration of catheter or surgical ablation when antiarrhythmic drugs fail
Moderate regular physical activity is recommended to prevent AF, while athletes should be counselled that long-lasting, more intense sports participation can promote AF

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[Perspectives] Shengshou Hu: leader of cardiac surgery and health reform in China

“Wise man finds pleasure in streams”, says an old Chinese saying. Being at one with water has always been part of Chinese cardiac surgeon Shengshou Hu’s life, from the wide waters of the Yangtze river to the swimming pool close to his professional home today in Beijing, where he is President of Fuwai Hospital, affiliated with the Chinese Academy of Medical Sciences. “As a young man, swimming across the Yangtze river with its strong currents seemed a good metaphor for life, and even today I find swimming a good time for reflection and relaxation, especially after surgery”, he says.

Cardiac machines linked to infection

Health departments around the country are contacting open heart surgery patients who may have been exposed to a rare infection that can be found in some heater-cooler units used in surgery.

According to international reports the design and manufacture of some heart bypass heater-cooler units made by Sorin have made them susceptible to harbouring the rare bacterium mycobacterium chimaera.

M. chimaera infections in cardiac surgery patients overseas have been linked to the heater-cooler units made by medical equipment manufacturer Sorin. It is thought that the units were contaminated during their manufacture.

It’s a common bacterium that occurs naturally in the environment and only causes rare infection. The infections tend to be slow to develop (it can take from several months to over a year for an infection to develop) and often affect people with compromised immune systems.

There has been one reported possible patient infection following an open cardiac surgery in 2015.

According to a statement by the Therapeutic Goods Association: “These infections have been associated with the use of heater-cooler devices which are used within the operating theatre to control the temperature of blood diverted to cardio-pulmonary bypass machines. Heater-cooler devices contain water tanks that provide temperature-controlled water for the operation of the device. This water does not come in contact with the patient.”

The TGA says it’s monitoring the situation and has updated its advice for health facilities regarding how to manage devices that test positive for mycobacterium chimaera.

In NSW, the hospitals that have used the potentially contaminated machines are Prince of Wales, St George, Sydney Children’s Hospital and The Children’s Hospital at Westmead.

All machines have been cleaned or replaced and the risk to patients is low.

Related: Cheap way to cut infection risk

“The risk of infections to an individual patient is very small, but it’s important that we’ve alerted clinicians to the risk and put systems in place to reduce the risk further,” infectious disease specialist Dr Kate Clezy, from the NSW Clinical Excellence Commission, said in a statement.

In Victoria, Fairfax media reports that the bacterium has been detected in heater-cooler units at The Alfred, Austin and Cabrini hospitals in Melbourne.

“All the units were decommissioned and replaced once the test results were known,” a department spokesman said.

It’s believed doctors are checking patient records to see whether anyone has been harmed by the bacterium.

According to director of infectious diseases and microbiology at the Austin Hospital Professor Lindsay Grayson, there is about a 1 in 10 000 chance of the bacterium causing an infection.

“If you think about this, the chances of having a car accident are one in 4000, so it is very rare.”

He said the infection could be cured with surgery and use of specific antibiotics.

According to NSW Health, the signs of possible M. chimaera infection include:
fatigue
difficulty breathing
persistent cough or cough with blood
fever
night sweats
redness, heat, or pus at the surgical site
muscle pain
joint pain
abdominal pain
weight loss
nausea
vomiting

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Progress in the care of familial hypercholesterolaemia: 2016

Familial hypercholesterolaemia (FH) is the most common autosomal dominant condition.1 FH reduces the catabolism of low-density lipoprotein cholesterol (LDL-c) and increases rates of premature atherosclerotic cardiovascular disease (CVD). This review focuses on recent advances in the management of FH, and the implications for both primary and secondary care, noting that the majority of individuals with FH remain undiagnosed.2

FH was previously considered to have a prevalence of one in 500 in the general community, including in Australia.3 Recent evidence, however, suggests the prevalence is between one in 200 and one in 350, which equates to over 30 million people estimated to have FH worldwide.4,5 These prevalence figures relate to the general population, and while FH is present in all ethnic groups, communities with gene founder effects and high rates of consanguinity, such as the Afrikaans, Christian Lebanese and Québécois populations, have a higher prevalence of the condition.

Further, the prevalence of homozygous or compound heterozygous FH has been demonstrated to be at least three times more common than previously reported, with a prevalence of about one in 300 000 people in the Netherlands.4 The detection and management of individuals with homozygous FH has been described in a consensus report from the European Atherosclerosis Society.6 Homozygous FH is a very severe disorder, with untreated people often developing severe atherosclerotic CVD before 20 years of age. Such individuals often have LDL-c concentrations > 13 mmol/L and severe cutaneous and tendon xanthomata. While diet and statins are the mainstays of therapy, early intervention (before 8 years of age) with LDL apheresis or novel lipid-lowering medication, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors or microsomal triglyceride transfer protein inhibitors, is indicated. Patients with suspected homozygous FH should be referred to a specialist centre.6

Several recent international guidelines on the care of FH have been published.3,7–10 These have focused on early detection and treatment of individuals with FH. However, there is still no international consensus on the diagnostic criteria for FH, or on the utility of genetic testing. The Dutch Lipid Clinic Network criteria (DLCNC) are preferred for diagnosing FH in index cases in Australia (Box 1).2 The International FH Foundation guidance acknowledges geographical differences in care, and recognises the need for countries to individualise service delivery. CVD risk in FH is dependent on classic CVD risk factors. However, FH is appropriately excluded from general absolute CVD algorithms, since these underestimate the absolute risk in FH.

FH guidelines provide therapeutic goals, which vary depending on the specific absolute CVD risk for patients with FH. In adults, the general LDL-c goal is a least a 50% reduction in pre-therapy LDL-c levels, followed by a target of LDL-c < 2.5 mmol/L, or < 1.8 mmol/L in individuals with CVD or other major CVD risk factors; these international targets update those of previously published Australian FH recommendations.2,3,10 Currently only about 20% of individuals with FH attain an LDL-c level < 2.5 mmol/L.11

Detecting FH in children

The European Atherosclerosis Society published a guideline focusing on paediatric aspects of the diagnosis and treatment of children with FH in 2015.8 This guideline outlined the benefit of early treatment of children with FH using statins. There is a significant difference in the carotid intima medial thickness (a measure of subclinical atherosclerosis) in children with FH and their unaffected siblings by 7 years of age, with implications for the value of early treatment. Lifestyle modifications and statins from 8 years of age can reduce the progression of atherosclerosis to the same rate as unaffected siblings over a 10-year period.8 Early treatment of children improves CVD-free survival by 30 years of age (100%) compared with their untreated parents (93%; P = 0.002).8 While further long term data on statin use in children are required, there are 10-year follow up data for children who were initiated on pravastatin between the ages of 8 and 18 years, which demonstrate that statin therapy is safe and effective.12 Hence, the balance of risk and benefit suggests that use of statins in children with FH is safe and efficacious, at least in the short to intermediate term, with all recommendations appropriately requiring that potential toxicity and adverse events be closely monitored.

Childhood is the optimal period for detecting FH, as LDL-c concentration is a better discriminator between affected and unaffected individuals in this age group. After excluding secondary causes and optimising lifestyle and repeating fasting LDL-c on two occasions, a child is considered likely to have FH if they have:

an LDL-c level ≥ 5.0 mmol/L;
a family history of premature CVD and an LDL-c level ≥ 4.0 mmol/L; or
a first-degree relative with genetically confirmed FH and an LDL-c level ≥ 3.5 mmol/L.

Universal screening for FH in children has been demonstrated to be effective in Slovenia, but experience is limited elsewhere.13 The therapeutic targets for children are less aggressive than for adults: a reduction in LDL-c of over 50% in children aged 8–10 years and an LDL-c level < 3.5 mmol/L from the age of 10 years.8

Cascade screening

Recent reports from Western Australia confirm that cascade screening is efficacious and cost-effective.11,14 The genetic cascade screening and risk notification process followed in Western Australia is shown in Box 2.11 Cascade screening involves testing close relatives of individuals diagnosed with FH. The autosomal dominant inheritance suggests 50% of first-degree relatives would be expected to have FH. Two new cases of FH were found by cascade screening for each index case in WA.11 These individuals were younger and had less atherosclerotic CVD than index cases. Interestingly, about 50% were already on lipid-lowering therapy, but they were not treated to the recommended goals and further lipid reductions were achieved overall. Over 90% of patients were satisfied with the cascade screening process and care provided by this service .11 However, for individuals who have not had genetic testing performed, or for individuals with clinical FH in whom a mutation has not been identified, cascade screening should also be undertaken using LDL-c alone.

Although we have recently shown that genetic testing is cost-effective in the cascade screening setting ($4155 per life year saved),14 only a few centres in Australia have this facility and testing is currently not Medicare rebatable. However, combining increased awareness of the benefits of identifying people with FH with the reducing analytical costs may increase the use of genetic testing. This in turn could guide advocacy and lobbying Medicare to support genetic testing for FH.

Detecting FH in the community

A novel approach that utilises the community laboratory to augment the detection of FH has recently been tested in Australia. The community laboratory is well placed to perform opportunistic screening, since they perform large numbers of lipid profiles, the majority (> 90%) of which are requested by general practitioners.15 Clinical biochemists can append an interpretive comment to the lipid profile reports of individuals at high risk of FH based on their LDL-c results. These interpretive comments on high risk individuals (LDL-c ≥ 6.5 mmol/L) led to a significant additional reduction in LDL-c and increased referral to a specialist clinic.16 A phone call from the clinical biochemist to the requesting GP improved both the referral rate of high risk (LDL-c ≥ 6.5 mmol/L) individuals to a lipid specialist and the subsequent confirmation of phenotypic FH in 70% of those referred, with genetic testing identifying a mutation in 30% of individuals.17 There is a list of specialists with an interest in lipids on the Australian Atherosclerosis Society website (http://www.athero.org.au/fh/health-professionals/fh-specialists).

In Australia, GPs consider they are the best placed health professionals to detect and treat individuals with FH in the community.18 A large primary care FH detection program in a rural community demonstrated that using pathology and GP practice databases was the most successful method to systematically detect people with FH in the community.19 However, a survey of GPs uncovered some key knowledge deficits in the prevalence, inheritance and clinical features of FH, which would need to be addressed before GPs can effectively detect and treat individuals with FH in the community.18 A primary care-centred FH model of care for Australia has recently been proposed to assist GPs with FH detection and management, but this requires validation.20 The model of care includes an algorithm that is initiated when an individual is found to have an LDL-c level ≥ 5.0 mmol/L, which could be highlighted as at risk of FH by either a laboratory or the GP practice software.20,21 The doctor is then directed to calculate the likelihood of FH using the DLCNC. Patients found to have probable or definite FH are assessed for clinical complexity and considered for cascade testing. See the Appendix at mja.com.au for the algorithm and definition of complexity categories. FH-possible patients should be treated according to general cardiovascular disease prevention guidelines.

Molecular aspects

There have also been advances in molecular aspects of FH. A recent community-based study in the United States confirmed that among patients with hypercholesterolaemia, the presence of a mutation was independently predictive of CVD, underscoring the value of genetic testing.22 The mutation spectrum of FH was described in an Australian population and was found to be similar to that in Europe and the United Kingdom.23 Mutation detection yields in Australia are comparable with the international literature; for example, 70% of individuals identified with clinically definite FH (DLCNC score > 8) had an identifiable mutation, whereas only 30% of those with clinically probable FH had a mutation.23

Polygenic hypercholesterolaemia (multiple genetic variants that each cause a small increase in LDL-c but collectively have a major effect in elevating LDL-c levels) is one explanation for not identifying an FH mutation. An LDL-c gene score has been described to differentiate individuals with FH (lower score) from those with polygenic hypercholesterolaemia (higher score), but this requires validation.24 About 30% of individuals with clinical FH are likely to have polygenic hypercholesterolaemia, and cascade screening their family members may not be justified.25

A further possible explanation for failure to detect a mutation causative of FH in an individual with clinically definite FH may lie in the limitations of current analytical methods such as restricting analysis to panels of known mutations. Further, FH is genetically heterogeneous and there may be unknown alleles and loci that cause FH. Next generation sequencing is capable of sequencing the whole genome or targeted exomes rapidly at a relatively low cost, and may improve mutation detection and identify novel genes causing FH, but further experience with its precise value in a clinical setting is required. Whole exome sequencing was able to identify a mutation causing FH in 20% of a cohort of “mutation negative” but clinically definite FH patients.25 However, when applied to patients with hypercholesterolaemia in a primary care setting, pathogenic mutations were only detected in 2% of individuals, with uncertain or non-pathogenic variants detected in a further 1.4%.26

Cardiovascular risk assessment

Absolute CVD risk assessment, employing risk factor counting, should be performed as atherosclerotic CVD risk is variable in FH.10,27 This involves appraisal of classic CVD risk factors including, age, sex, hypertension, diabetes, chronic kidney disease and smoking. The prevalence of classic CVD risk factors among Western Australians with recently identified FH was 13% for hypertension, 3% for diabetes and 16% for smokers, all of which were amenable to clinical intervention.11

Other non-classic CVD risk factors are also important for individuals with FH, especially chronic kidney disease and elevated levels of lipoprotein(a).28 Lipoprotein(a) is a circulating lipoprotein consisting of an LDL particle with a covalently linked apolipoprotein A. Its plasma concentration is genetically determined and it is a causal risk factor for CVD in both the general population and FH patients.29,30 Lipoprotein(a) concentrations are not affected by diet or lowered by statins.31

Management and new therapies

The past 2 years have also seen the development of new treatments for FH, but lifestyle modifications and statins remain the cornerstones of therapy for FH. Ezetimibe has been demonstrated to reduce coronary events against a background of simvastatin in non-FH patients with established CVD.32 PCSK9 inhibitors have recently been approved to treat individuals with FH or atherosclerotic CVD not meeting current LDL-c targets in Europe and America. PCSK9 is a hepatic convertase that controls the degradation and hence the lifespan of the LDL receptor. PSCK9 is secreted by the hepatocyte and binds to the LDL receptor on the surface of the hepatocyte. The LDL receptor–PCSK9–LDL-c complex is then internalised via clathrin-dependent endocytosis, but the PSCK9 directs the LDL receptor towards lysosomal degradation instead of recycling it back to the hepatocyte surface.33 A recent meta-analysis of early PCSK9 inhibition trials involving over 10 000 patients demonstrated a 50% reduction in LDL-c, a 25% reduction in lipoprotein(a), and significant reductions in all-cause and cardiovascular mortality.34

The PCSK9 inhibitors alirocumab and evolocumab were approved by the European Medicines Agency in 2016 for homozygous and heterozygous FH and non-FH individuals unable to reach LDL-c targets, and for individuals with hypercholesterolemia who are statin intolerant. In the US, the Food and Drug Administration has approved alirocumab for heterozygous FH and individuals with atherosclerotic CVD who require additional reduction of LDL-c levels. Evolocumab and alirocumab have recently been approved by the Therapeutic Goods Administration in Australia for people with FH. Adverse events are generally similar to placebo, but reported side effects include influenza-like reaction, nasopharyngitis, myalgia and raised creatine kinase levels, and there have been reports of neurocognitive side effects (confusion, perception, memory and attention disturbances).34 The cost of these agents is likely to be the major limitation to their clinical use. The indications and use of lipoprotein apheresis and other novel therapies, including lomitapide, a microsomal triglyceride transfer protein inhibitor, and mipomersen (an antisense oligonucleotide that targets apolipoprotein B), have been recently reviewed.35

Despite the advances reviewed, the implementation and optimisation of models of care for FH remain a major challenge for preventive medicine. Areas of future research should focus on better approaches for detecting FH in the young and on enhancing the integration of care between GPs and specialists. The value of genetic testing and imaging of pre-clinical atherosclerosis in stratifying risk and personalising therapy merits particular attention. Further, with families now living in a global community, more efficient methods of communication and data sharing are required. This may be enabled by international Web-based registries.36 Care for people with FH needs to be incorporated into health policy and planning in all countries.10

Conclusion

There have been significant advances in the care of individuals with FH over the past 3 years. An integrated model of care has been proposed for primary care in Australia. Progress has also been made in the treatment of FH with the emergence of PCSK9 inhibitors capable of allowing more patients already on statins to attain therapeutic LDL-c targets and hence redressing the residual risk of atherosclerotic CVD. Future research is required in the areas of models of care, population science and epidemiology, basic science (including genetics), clinical trials, and patient-centric studies.37 Finally, the onus rests on all health care professionals to improve the care of families with FH, in order to save lives, relieve suffering and reduce health care expenditure.

Box 1 –
Dutch Lipid Clinic Network Criteria score for the diagnosis of familial hypercholesterolaemia (FH)2

Criteria

Score

Family history

First-degree relative with known premature coronary and/or vascular disease (men aged < 55 years, women aged < 60 years); or

First-degree relative with known LDL-c > 95th percentile for age and sex

First-degree relative with tendon xanthomas and/or arcus cornealis; or

Children aged < 18 years with LDL-c > 95th percentile for age and sex

Clinical history

Patient with premature coronary artery disease (ages as above)

Patient with premature cerebral or peripheral vascular disease (ages as above)

Physical examination

Tendon xanthomata

Arcus cornealis at age < 45 years

LDL-c

≥ 8.5 mmol/L

6.5–8.4 mmol/L

5.0–6.4 mmol/L

4.0–4.9 mmol/L

DNA analysis: functional mutation in the LDL receptor, apolipoprotein B or PCSK9 gene

Stratification

Definite FH

> 8

Probable FH

6–8

Possible FH

3–5

Unlikely FH

< 3

LDL-c = low-density lipoprotein cholesterol. PCSK9 = proprotein convertase subtilisin/kexin type 9.

Box 2 –
Protocol for genetic cascade screening in Western Australia*

* Family cascade screening process performed according to national guidelines2 after obtaining written consent from the index case.11 This was undertaken by a trained nurse who contacted the family members and obtained verbal consent to contact further family members, after providing counselling and offering specialist review as indicated.

[Editorial] Atrial fibrillation and stroke: unrecognised and undertreated

When did you or your primary care physician last palpate your wrist to check for a regular heart rate? This simple action, followed by an electrocardiogram if the heart rate is irregular, might be crucial in preventing death and disability from ischaemic stroke, heart failure, or myocardial infarction. In this week’s issue, we publish a clinical Series of three papers on atrial fibrillation ahead of the annual European Society of Cardiology (ESC) meeting held in Rome, Italy, Aug 27–31. Atrial fibrillation is estimated to affect 33 million people worldwide.

Remote Australians more likely to be hospitalised with heart-related issues

Patients from very remote Australia are nearly twice as likely to need a hospital for a heart-related event.

The Heart Foundation has released heart-related hospital admissions data maps, revealing huge gaps between city dwellers and those living in remote Australia.

Heart Foundation National Chief Executive Officer Adjunct Professor John Kelly said the maps bring together a national picture of hospital admission rates for the first time.

“Those regions that rate in the top hotspot areas are regions where a large proportion of residents are of significant disadvantage. This disadvantage includes a person’s access to education, employment, housing, transport, affordable healthy food and social support,” he said.

“This contrasts to areas with the lowest rates – particularly the northern suburbs of Sydney, where there is little disadvantage of the community.

“There is a five-fold difference of hospital admissions between Northern Territory Outback and the region with the lowest admission rates North Sydney & Hornsby, which highlights the association between remoteness, disadvantage and our heart health.”

The heart maps reinforce the knowledge that heart admissions are correlated with obesity, smoking and physical activity.

However Professor Kelly points out that the differences are not because people from disadvantaged areas make unhealthy choices.

“They are the result of a combination of social, economic and physical conditions, like a person’s access to education, employment, housing, transport, affordable healthy food, and social support,” he explained.

“These conditions shape matters such as people’s eating habits, participation in physical activity and their likelihood to see a doctor.

He said governments and health services need to work together to provide access and opportunities for people in more remote locations.

“Prevention programs work, simple early detection and heart health checks by doctors can help early identification of the risk factors and reduce hospital admissions.

“Health is a basic human right. It should not matter who you are, how much you earn or where you live,” he said.

Top 5 Regions for Heart-Related Hospital Admissions

Top 5 Regions with the lowest heart-related hospital admission rates

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Pitting and non-pitting oedema

The distinction is essential to determine aetiology and treatment

Oedema can be divided into two types: pitting and non-pitting. These types are relatively easy to distinguish clinically and the distinction is essential to determine aetiology and treatment.

Oedema is the swelling of soft tissue due to fluid accumulation. Pitting is demonstrated when pressure is applied to the oedematous area and an indentation remains in the soft tissue after the pressure is removed (Box 1 and Box 2). Moreover, mild pitting oedema is best identified by applying pressure over an area of bony prominence. Non-pitting oedema refers to the lack of persistent indentation in the oedematous soft tissue when pressure is removed.1

In addition to the differentiation of pitting and non-pitting oedema, the pattern of distribution is reflective of the underlying aetiology. With pitting oedema, there may be bilateral dependent oedema of the lower limbs, generalised oedema or localised oedema. Non-pitting oedema generally affects an isolated area, such as a limb. There are two ways of describing the severity of pitting oedema. Most commonly, in the setting of peripheral oedema, severity is graded by its proximal extent, so that oedema located above the knee is more severe than oedema presenting below the knee. The alternative approach is based on depth and duration of pitting after the release of pressure (Box 3).2

A number of factors3 can be considered to be major contributors to the development of oedema:

increased intravascular hydrostatic pressure;
reduced intravascular oncotic pressure;
increased blood vessel wall permeability;
obstructed fluid clearance in the lymphatic system; and
increased tissue oncotic pressure.

The underlying pathophysiology for oedema explains the reason for pitting and non-pitting. Oedema is the accumulation of fluid in the interstitium. In normal circumstances, there is a balance between fluid leaking from capillaries and drainage by the lymphatics.3 In the setting of increased intravascular hydrostatic pressure, reduced oncotic pressure or where there is increased vessel wall permeability, fluid leaks out of vessels into the interstitial space. When external pressure is applied, extracellular fluid is displaced with increased drainage through the lymphatic system, creating an indentation that is visible in the skin and is described as pitting. When pressure is removed, the fluid slowly returns and the indentation disappears (see the video at mja.com.au). Lymphoedema, which is the most common form of non-pitting oedema, occurs when fluid accumulates in the interstitial space as a result of a reduction in lymphatic drainage. The application of pressure does not result in an indentation as there is an inability to drain fluid through the damaged lymphatic system.4 An uncommon form of non-pitting oedema, myxoedema, can occur as a result of accumulation of hydrophilic molecules in the subcutaneous tissue.5

The differentiation between pitting and non-pitting oedema, in addition to the pattern of distribution, reflects different pathophysiology and may therefore be helpful in identifying the underlying aetiology. Pitting peripheral lower limb oedema resulting from raised hydrostatic pressure can occur in congestive cardiac failure, venous insufficiency and as a result of the use of a calcium channel blocker. Generalised oedema may be seen in kidney disease, where reduced intravascular oncotic pressure occurs through protein loss or where increased vascular volume occurs through sodium and fluid retention. Localised pitting oedema is likely related to a local inflammatory process resulting in increased vessel wall permeability. Non-pitting oedema of an isolated area is consistent with failure of lymphatic drainage, which may rarely have a primary (hypoplastic) aetiology or, more commonly, a secondary (obstructive) aetiology. Secondary causes include external compression from a tumour, involvement of lymph nodes in metastatic disease, and lymph vessel damage following radiotherapy or following lymph node resection. Myxoedema is associated with thyroid disease.5

The underlying aetiology will guide treatment options. In the setting of congestive cardiac failure, treatment would generally include fluid restriction and diuretics (including spironolactone). Compression bandaging and leg elevation are useful for oedema related to venous insufficiency. In the setting of oedema related to inflammation, a general approach would include applying ice and elevation in addition to treating the underlying cause of the inflammatory process. Lymphoedema may be detected using a perometer and managed with compression garments and manual lymph drainage. Myxoedema may resolve with treatment of the underlying thyroid condition.

Box 1 –
Pressure applied to an oedematous area to demonstrate pitting

Box 2 –
Indentation remaining in soft tissue after pressure to an oedematus area is removed

Box 3 –
Alternative approach for grading the severity of pitting oedema based on depth and duration of pitting after release of pressure

Severity

Description

Grade 1+

A pit of up to 2 mm that disappears immediately

Grade 2+

A pit of 2–4 mm that disappears in 10–15 seconds

Grade 3+

A pit of 4–6 mm that may last more than 1 minute

Grade 4+

A deep pit greater than 6 mm that may last as long as 2–5 minutes

Adapted from Guelph General Hospital Congestive Heart Failure Pathway.2

The clinical utility of new cardiac imaging modalities in Australasian clinical practice

Cardiac imaging is a rapidly evolving field, with improvements in the diagnostic capabilities of non-invasive cardiac assessment. In this article, we seek to introduce family physicians to the two main emerging technologies in cardiac imaging: computed tomography coronary angiography (CTCA) to evaluate chest symptoms consistent with ischaemia and exclude coronary artery disease; and cardiovascular magnetic resonance (CMR) imaging for evaluating cardiac morphology, function and presence of scar. These modalities are now in routine clinical practice for cardiologists in Australia and New Zealand. We provide a practical summary of the indications, clinical utility and limitations of these modern techniques to help familiarise clinicians with the use of these modalities in day-to-day practice. The clinical vignettes presented are cases that may be encountered in clinical practice. We searched the PubMed database to identify original papers and review articles from 2008 to 2016, as well as specialist society publications and guidelines (Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, Cardiac Society of Australia and New Zealand, and Australian and New Zealand Working Group for Cardiovascular Magnetic Resonance), to formulate an evidence-based overview of new cardiac imaging techniques, as applied to clinical practice.

Part 1: Computed tomography coronary angiography for clinicians

CTCA is a non-invasive coronary angiogram, using electrocardiogram (ECG)-gated CT. The accuracy of CTCA has been well established in three large multicentre studies, with a negative predictive value approaching 100%, making it an excellent “rule out” test.1 This means that a normal CTCA showing no coronary plaque or stenosis accurately correlates to absence of disease on invasive angiography. Prognostic data have shown that a negative CTCA has very low event rate (< 1%), whereas increasing levels of disease seen on CTCA are associated with increasing risk of myocardial infarction and death over 5 years for both men and women.2

CTCA has been formally tested in randomised trials of chest pain in the emergency department, showing more rapid discharge and decreased health care costs, including in the Australian health system.3,4

The radiation dose for CTCA has decreased dramatically in recent years, with current generation scanners able to image the entire heart and coronary arteries for 2–3 mSv (equivalent to annual background radiation), and < 1 mSv in appropriate patients (similar to a mammogram). Thus, CTCA is gaining traction in clinical practice to rule out coronary artery disease (CAD) in a variety of clinical situations.

The primary use for CTCA is to exclude significant coronary artery stenosis in patients with symptoms consistent with coronary ischaemia due to potential stenotic CAD (harnessing the near 100% negative predictive value of CTCA). Application of the test in this manner is appropriate for patients with chest pain syndromes, with angina equivalent symptoms (eg, dyspnoea), to exclude graft stenosis in symptomatic patients after coronary artery bypass surgery, and also for patients with ongoing symptoms despite negative results from functional tests such as nuclear or echocardiography stress tests (as functional tests may return false-negative results). The Society of Cardiovascular Computed Tomography has published Appropriate Use Criteria,5 and the Cardiac Society of Australia and New Zealand has produced guidelines on non-invasive coronary imaging (Box 1).6

Clinical vignette 1: A 55-year-old woman presents to her general practitioner with dyspnoea on exertion, and risk factors of obesity and hypertension. A nuclear single-photon emission computed tomography myocardial perfusion scan is reported as positive for “mild apical ischaemia”. Computed tomography coronary angiography (CTCA) is performed to exclude significant coronary artery disease, demonstrating no significant stenosis in the major epicardial coronaries (left anterior descending, left circumflex or right coronary artery), but mild diffuse coronary atherosclerosis is present (with a calcium score of 370 Agatston units). She is commenced on medical therapy of aspirin and a statin, and is reassured that she does not have a stenosis requiring stent or bypass surgery, and that her chest symptoms are not due to coronary artery disease.

CTCA showing “clean” coronary arteries with no plaque or stenosis.

In Australia, Medicare reimbursement is available via specialist referral for three indications:

chest symptoms consistent with coronary ischaemia in low to intermediate risk patients;
evaluation of suspected coronary anomaly or fistula; or;
exclusion of CAD before heart transplant or valve surgery (non-coronary cardiac surgery).

Medicare-reimbursed indications do not cover asymptomatic patients with a strong family history of coronary artery disease (in which case, a coronary calcium score may suffice).7 When used appropriately, CTCA reduces the need for invasive coronary angiography, which is about five times more expensive, as a consequence of the reduced need for hospital admissions and different Medicare Benefits Schedule charges. Data suggest that use of CTCA is cost-effective and reduces downstream testing.8

Importantly, CTCA is not appropriate in patients with typical angina (defined as “constricting discomfort in the chest, which is precipitated by physical exertion, and relieved by rest or GTN”9) who have a high pre-test probability of obstructive disease and should proceed directly to invasive coronary angiography.

Evaluation after coronary artery stenting is limited to large diameter stents (> 3 mm) in proximal arteries and, in general, functional testing remains the clinical standard for reassessment of patients with known CAD.5 Conversely, assessment of graft patency following coronary artery bypass surgery can be well assessed by CTCA, without the risks of stroke or graft dissection from invasive engagement of the grafts during catheter angiography.5

The main weakness of CTCA is its modest positive predictive value, which varies from 60% to 90% depending on the prevalence of disease and the study. In clinical practice, this generally means that although coronary disease seen on CTCA is real, the percentage of stenosis generally appears more severe on CTCA compared with invasive coronary angiography. On the other hand, CTCA can visualise eccentric coronary plaques with positive vessel wall remodelling, which may be missed on invasive angiography (which only images the coronary lumen, and not the vessel wall itself).

An important factor in CTCA is heart rate control, which remains essential for good quality CTCA imaging. Ideal heart rates are in the 50–60 beats per minute range for optimal imaging, requiring pre-medication with β-blockers and/or ivabradine. Heart rate control is proportional to radiation dose, therefore low dose studies require a slow and steady heart rate. This improves the diagnostic accuracy of CTCA, but negative chronotropic medications may not be suitable for all patient groups, and atrial fibrillation remains a challenge. Newer high resolution and dual source scanners are able to image at higher heart rates, with algorithms to reconstruct cardiac motion, and are becoming more widely available.

Clinical vignette 2: A 38-year-old man presents to an emergency department with atypical central chest pain. Serial troponins are negative, and a 12-lead electrocardiogram shows non-specific T wave changes. He has ongoing pain, is not deemed suitable for an “accelerated diagnostic protocol” pathway, and early computed tomography coronary angiography (CTCA) is performed after 100 mg oral metoprolol with 10 mg ivabradine, to achieve a heart rate of 59 beats per minute, allowing a low dose (< 1 mSv) scan. CTCA shows a normal left coronary system, but an anomalous right coronary artery origin arising from the contralateral cusp, with an interarterial course and a slit-like origin.6 This is a potentially life-threatening anomaly due to potential compression between the aorta and pulmonary artery resulting in sudden death;10 however, this may not have been diagnosed on functional testing (eg, single-photon emission computed tomography). Cardiac CT is the reference test for the assessment of coronary anomalies and coronary fistulae.6

CTCA axial view showing the RCA origin adjacent to the left main sinus and with an interarterial course between the aorta and pulmonary artery (arrow). Ao = aorta. Cx = circumflex. LA = left atrium. LAD = left anterior descending artery. LCC = left coronary cusp. LMCA = left main coronary artery. NCC = non-coronary cusp. PA = pulmonary artery. RCA = right coronary artery. RCC = right coronary cusp.

Recent data from the PROMISE trial in 10 000 patients showed equivalence of a CTCA versus functional testing strategy in symptomatic patients, but with a reduced rate of “normal” invasive angiograms and decreased downstream testing in the CTCA group.11 Further, the SCOT-HEART trial recently demonstrated that adding CTCA to standard care reduced the need for additional stress testing, and was associated with a 38% reduction in fatal and non-fatal myocardial infarction.12

Future directions for CTCA

Rapid technological advancement in both CT hardware and post-processing reconstruction software algorithms are leading to further improvements in spatial and temporal resolution while minimising radiation exposure. CTCA has the ability to detect high risk vulnerable plaques,6,13 and statin therapy may help alter the natural history of atherosclerosis as imaged by CTCA.13 New developments enable functional assessment of a lesion on CTCA, allowing assessment of lesion-specific ischaemia at the same time as evaluating coronary anatomy. Adenosine stress perfusion cardiac CT allows functional assessment of myocardial perfusion in a similar manner to nuclear single-photon emission computed tomography (SPECT), and can be performed at the same time as CTCA with minimal additional radiation.14 Fractional flow reserve can be derived from static CTCA datasets, using computational fluid dynamics, and has been compared favourably with invasive haemodynamic assessment of fractional flow reserve during invasive coronary angiography.15 Overall, CTCA is a very useful tool to non-invasively assess the coronary arteries, with prognostic data now available to support its routine use in clinical practice.

Part 2: Cardiovascular magnetic resonance imaging for clinicians

CMR is a specialised form of magnetic resonance imaging (MRI), which employs specific MRI techniques with ECG gating to capture high resolution images of the heart and cardiac motion, in any imaging plane, without radiation.16 CMR is like a “super-echocardiogram” to assess heart function, but has the additional ability to quantitate vascular flow, myocardial oedema, cardiac perfusion, viability, and the presence of infiltrate or scar using gadolinium-based contrast agents. CMR improves diagnosis and risk stratification, predicts prognosis, and guides treatment decisions in many cardiac disorders.

Left and right ventricular function

Accurate quantitation of left and right ventricular function are essential to making decisions in clinical medicine, from commencement of drug therapy to implantation of costly devices such as automatic defibrillators. CMR is the gold standard for measurements of left ventricular mass, volume and ejection fraction and assessing the presence of regional wall motion abnormalities,17,18 and it is more reproducible than echocardiography.19

CMR offers particular advantages for conditions affecting the right ventricle, which is particularly difficult to assess using echocardiography. Assessment of right ventricular volume and wall motion by CMR are assigned as major criteria in the diagnosis of arrythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), a genetic condition resulting in arrhythmias and sudden death.20 Right ventricular function is important in patients in pulmonary hypertension and with adult congenital heart disease,21 for which CMR is critical to decision making (eg, timing of surgery, replacement of cardiac valves). In patients with dilated right hearts, CMR is useful to detect the underlying causes, which may not be apparent on echocardiography (such as partial anomalous pulmonary venous drainage, or ARVD/C).

Viability and scar imaging

CMR can be used to confirm the diagnosis of myocardial infarction and assess viability before stenting or coronary artery bypass surgery, using gadolinium contrast agents to image scar tissue.

Clinical vignette 3: A 74-year-old man with a late-presentation ST-elevation myocardial infarction is shown to have an occluded left anterior descending artery during coronary angiography. Echocardiography shows an ejection fraction of 40%. Cardiovascular magnetic resonance (CMR) demonstrates that the anterior wall is akinetic, with full thickness infarction and no residual viable myocardium. Based on this information, he does not undergo stenting or coronary artery bypass graft surgery and is treated medically with heart failure therapy.

CMR imaging: two-chamber view showing a dilated left ventricle with akinetic anterior wall (A), and post-contrast imaging showing full thickness infarction of the entire anterior wall with no residual viable myocardium (B, arrows).

Infiltrative disorders traditionally requiring cardiac biopsy

CMR is a useful tool to diagnose infiltrative disorders which have traditionally required invasive cardiac biopsy, such as cardiac sarcoidosis, cardiac amyloidosis, and detection of fibrosis in hypertrophic cardiomyopathy.22–25 The EuroCMR registry of over 27 000 patients showed that using CMR improves diagnosis and changes clinical management in patients with cardiac conditions.26 Common indications and contraindications for CMR are shown in Box 2.27

Clinical vignette 4: A 26-year-old woman with palpitations has an echocardiogram showing a dilated right heart but with intact atrial and ventricular septum; the cause for right heart dilation was unclear. CMR showed a right ventricular volume index of 143 mL/m² (moderate to severely dilated), and confirmed a diagnosis of partial anomalous pulmonary venous drainage of the right veins to the superior vena cava (significant intracardiac shunt: Qp:Qs, 2:1). She underwent minimally invasive cardiac surgical repair, with normalisation of right heart size at follow-up.

Myocardial fibrosis and iron overload

CMR is a “non-invasive microscope” of the heart, with techniques such as quantitative T1 mapping allowing non-invasive measurement of fibrosis and extracellular volume fraction.28 Cardiac iron overload occurs in haemochromatosis and thalassaemia, and is a significant cause of morbidity and mortality in these conditions.29 In the past, cardiac biopsy was the only means to assess myocardial iron overload. However, using iron-sensitive T2* imaging, CMR has been validated to quantitatively and non-invasively measure myocardial iron stores. Australian guidelines exist for using CMR to assess for iron overload, with T2* values of > 20 ms being normal, < 10–20 ms indicating moderate iron overload, and values of < 10 ms indicating severe iron overload warranting consideration for chelation therapy.29

Ventricular thrombus

CMR is the gold standard test for detection of ventricular thrombus after myocardial infarction and is superior to echocardiography, including microsphere contrast echocardiography (Box 3).30

Valvular dysfunction

Quantitation of valvular regurgitation is more reproducible by CMR than by echocardiography,31 and is particularly useful in assessing aortic and pulmonary regurgitation, which are difficult to quantitate echocardiographically. CMR has been allocated a Class I indication for use in patients with moderate or severe valve disorders and suboptimal or equivocal echocardiographic evaluation (Class I, Level of evidence B).31,32 CMR is validated for the direct planimetric assessment of aortic stenosis, which can be performed using steady-state free precession cine imaging without requiring contrast (this may be useful for patients with renal impairment, such as those being assessed for transcatheter aortic valve implantation).33 CMR is also superior to echocardiography for the assessment of mitral regurgitation after percutaneous mitral valve repair.34 In clinical practice, CMR is useful when a valve lesion is of indeterminate or equivocal severity by echocardiography, when quality echocardiographic images are suboptimal (eg, due to limited acoustic windows), or when the “downstream effect” of a lesion needs further quantitation, such as left ventricular dilation in severe but asymptomatic valve regurgitation.

Stress perfusion CMR

Stress perfusion testing can be performed with CMR and has superior spatial resolution to nuclear SPECT imaging without the exposure to radiation. A large, prospective comparative efficacy trial recently demonstrated that stress perfusion CMR was superior to SPECT for the diagnosis of myocardial ischaemia.35 CMR can also provide information on viability (scar) and the coronary arteries in the same non-invasive test, making it a “one-stop shop” that is increasingly being adopted in Europe and the United Kingdom for stress imaging in cardiology practice.26

Limitations of CMR

The main limitation of CMR is availability, with the technique mainly confined to reference expert centres owing to its complexity and the degree of training required to perform and report CMR. Guidelines exist from the Society of Cardiovascular Magnetic Resonance on the performance and reporting of CMR, and specific Australian and New Zealand guidelines are currently being formulated. The second major limitation is the lack of specific Medicare reimbursement for CMR. At present, two applications are before the Medical Services Advisory Committee (MSAC): one for stress perfusion/viability imaging and one for assessment of cardiomyopathies in patients with abnormal baseline echocardiography (MSAC application 1393: http://www.msac.gov.au/internet/msac/publishing.nsf/Content/1393-public).

While CMR provides superior diagnostic information than echocardiography in virtually all cardiac disorders, it is more resource intensive, time consuming and currently less available than echocardiography. CMR should be targeted for patients in whom echocardiography is inconclusive or non-diagnostic, or in specific circumstances where CMR is more appropriate than echocardiography (such as complex congenital heart disease, or the use of stress perfusion when it is clinically appropriate to assess ventricular function, viability and ischaemia in a single test).

Relative contraindications are present in patients with arrhythmias that affect ECG gating, claustrophobia, implantable devices, and severe renal impairment (if contrast imaging is required). Most modern pacemaker systems are MRI conditional at a field strength of 1.5 T, but are not compatible with 3 T systems.

Conclusions

Cardiac imaging is a rapidly evolving field, with improvements in the diagnostic capabilities of non-invasive cardiac assessment. CTCA is useful to exclude coronary artery disease non-invasively. CMR is useful to accurately quantitate left ventricular and right ventricular function and investigate cardiomyopathies, or patients with congenital heart disease. CTCA and CMR and are becoming routine clinical practice for cardiologists in Australia and New Zealand, with increasing use in both hospital and outpatient settings. General practitioners and general physicians should be familiar with the basic indications, clinical utility and limitations of these modern techniques to assist in their appropriate use and interpretation in day-to-day practice.

Box 1 –
Appropriate indications for computed tomography coronary angiography endorsed by the Cardiac Society of Australia and New Zealand6

Chest pain with low to intermediate pre-test probability of coronary artery disease (CAD)
Chest pain with uninterpretable or equivocal stress test or imaging results
Normal stress test results but continued or worsening symptoms
Suspected coronary or great vessel anomalies
Evaluation of coronary artery bypass grafts (with symptoms)
Exclude coronary artery disease in new onset left bundle branch block or heart failure

Box 2 –
Common indications and contraindications for cardiovascular magnetic resonance imaging25

Common indications

Myocardial viability (ischaemic cardiomyopathies)
Accurate assessment of left ventricular ejection fraction; eg, before device implantation (implantable cardioverter defibrillator and cardiac resynchronisation therapy)
Detection of interventricular thrombus
Interstitial fibrosis (dilated and infiltrative cardiomyopathies)
Congenital heart disease
Cardiac mass
Right ventricular quantification
Evaluation for arrythmogenic right ventricular dysplasia/cardiomyopathy
Post cardiac transplantation surveillance
Constrictive pericarditis
Quantification of valvular dysfunction
Aortic and vascular measurement
Iron overload quantification (T2*)

Contraindications

Absolute
- Non-magnetic resonance compatible implantable devices
- Severe claustrophobia
Relative
- Magnetic resonance imaging conditional pacemakers (only 1.5 T field strength)
- Arrythmias that affect electrocardiogram gating (atrial fibrillation and ectopy)
- Severe renal impairment (risk of nephrogenic systemic fibrosis)

Box 3 –
Early post-contrast cardiovascular magnetic resonance image showing multiple thrombi in the mid-anterior wall and left ventricular apex (arrows)

Note: on microsphere contrast echocardiography, only the apical thrombus was seen; the thrombi adherent to the mid-anterior wall were not observed.

National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand: Australian clinical guidelines for the management of acute coronary syndromes 2016

These clinical guidelines have been developed to assist in managing patients presenting with chest pain suspected to be caused by an acute coronary syndrome (ACS) and those with confirmed ACS. The development of these guidelines has been informed by reviews of the literature dealing with key aspects of chest pain assessment and ACS care, as well as broad consultation with local opinion leaders, stakeholder groups and the public. The recommendations focus on the core clinical and system-based components of care most associated with improved clinical outcomes. As such, these guidelines should be read in conjunction with the Acute coronary syndromes clinical care standard, developed by the Australian Commission on Safety and Quality in Health Care,1 and the Australian acute coronary syndromes capability framework, developed by the National Heart Foundation of Australia (NHFA).2 Guidance regarding both the strength of evidence supporting the recommendations and their potential impact on outcomes is provided to assist in informing clinical practice.3,4 Additional guidance regarding the timing and considerations informing the use of therapies and management strategies is given in the accompanying practice advice. A full version of the NHFA and Cardiac Society of Australia and New Zealand (CSANZ) Australian clinical guidelines for the management of acute coronary syndromes 2016 is available at: http://heartfoundation.org.au/for-professionals/clinical-information/acute-coronary-syndromes.

Methods

The NHFA, in partnership with the CSANZ, has undertaken an update to the NHFA/CSANZ Guidelines for the management of acute coronary syndromes 2006 and addenda of 2007 and 2011.5–7 The updated guideline will provide a synthesis of current evidence-based guidance for health professionals caring for patients with ACS.

The ACS Guideline Development Working Group comprised an Executive and the four writing groups of which it had oversight, covering the topics of chest pain, ST segment elevation myocardial infarction (STEMI), non-ST segment elevation ACS (NSTEACS) and secondary prevention. In addition, a Reference Group included representatives from stakeholder groups, potential endorsing organisations and regional experts. The Working Group comprised a broad mix of health professionals, including a general practitioner, general physician, cardiac surgeon, consumer representative, pathologist, ambulance service representative, cardiologists, emergency physicians, exercise physiologists and cardiac nurses.

The Working Group consulted state-based cardiac clinical networks and the Reference Group on the scope determination for the updated guideline. Based on this consultation, the expert Working Group generated clinical questions to inform the literature search of evidence required for the guideline’s development. The separate writing groups reviewed and graded the evidence, generated and graded recommendations, and produced draft sections for the four topic areas. The Executive group provided oversight for this process and approved the final document.

A draft of the guideline was open for a 30-day period of public consultation in April 2016 to capture stakeholder views and aid engagement with the guideline once completed. Attention has been paid to ensuring appropriate governance processes were in place, to ensure transparency, minimise bias, manage conflict of interest and limit other influences during guideline development.

Key evidence-based recommendations

Each recommendation is presented with a Grading of Recommendations Assessment, Development and Evaluation (GRADE) strength of recommendation (Appendix 1) and a National Health and Medical Research Council level of evidence (Level) (Appendix 2). Practice points (PPs) are also provided.

Assessment of possible cardiac causes of chest pain

It is recommended that a patient with acute chest pain or other symptoms suggestive of an ACS receives a 12-lead electrocardiogram (ECG), and this ECG is assessed for signs of myocardial ischaemia by an ECG-experienced clinician within 10 minutes of first acute clinical contact.8 GRADE: Strong; Level: IIIC
- PP: Oxygen supplementation. The routine use of oxygen therapy among patients with a blood oxygen saturation (SaO₂) level > 93% is not recommended, but its use when the SaO₂ is below this level is advocated, despite the absence of clinical data.9,10 However, care should be exercised in patients with chronic obstructive pulmonary disease where the target SaO₂ level is to be 88–92%.
- PP: Initial aspirin therapy. In all patients with possible ACS and without contraindications, aspirin (300 mg orally, dissolved or chewed) should be given as soon as possible after presentation. Additional antiplatelet and anticoagulation therapy, or other therapies such as β-blockers, should not be given to patients without a confirmed or probable diagnosis of ACS.
A patient presenting with acute chest pain or other symptoms suggestive of an ACS should receive care guided by an evidence-based Suspected ACS Assessment Protocol (Suspected ACS-AP) that includes formal risk stratification.11 GRADE: Strong; Level: IA
- PP: Selecting and implementing a Suspected ACS-AP. For hospitals using sensitive or highly sensitive troponin assays, the ADAPT or modified ADAPT protocol, respectively, identifies low risk patients (< 1% major adverse cardiac events [MACE] at 30 days) on the basis of negative troponin test results at both 0 and 2 hours, a Thrombolysis in Myocardial Infarction (TIMI) risk score of 0 (ADAPT) or 0 or 1 (modified ADAPT), and no ischaemic changes on ECG at both 0 and 2 hours.12,13
Using serial sampling, cardiac-specific troponin levels should be measured at hospital presentation and at clearly defined periods after presentation using a validated Suspected ACS-AP in patients with symptoms of possible ACS.14 GRADE: Strong; Level: IA
- PP: Timing of troponin testing. Most patients with an underlying diagnosis of acute myocardial infarction (AMI) have elevated troponin levels within 3–6 hours of symptom onset, although some assays may not show elevated levels for up to 12 hours (Box 1). Validated rapid rule-in and rule-out algorithms for AMI incorporated into Suspected ACS-APs and/or using highly sensitive troponin assays may reduce the serial testing time to 1–2 hours after presentation.18,19,21,24,25 Incorporating sensitive or highly sensitive troponin assay results into the ADAPT or modified ADAPT protocol, respectively, allows early (2 hours after emergency department presentation) risk stratification.12,13
Non-invasive objective testing is recommended in intermediate risk patients, as defined by a validated Suspected ACS-AP, with normal serial troponin and ECG testing and who remain symptom free.26 GRADE: Weak; Level: IA
- PP: Timing of testing. High risk patients require further objective testing during the index admission (Box 2). Intermediate risk patients may be safely accelerated for early inpatient testing or discharged for outpatient testing, ideally within 7 days but acceptable up to 14 days after presentation. Investigation before discharge from the emergency department is desirable among patients with characteristics associated with significant failure to re-attend for medical review, given the higher rates of MACE in such patients.27
Patients in whom no further objective testing for coronary artery disease is recommended are those at low risk, as defined by a validated Suspected ACS-AP: age < 40 years, symptoms atypical for angina, in the absence of known coronary artery disease, with normal troponin and ECG testing and who remain symptom free.26 GRADE: Weak; Level: III-3C

Diagnostic issues, risk stratification and acute management of ACS

The routine use of validated risk stratification tools for ischaemic and bleeding events (eg, GRACE score for ischaemic risk and CRUSADE score for bleeding risk) may assist in patient-centric clinical decision making in regards to ACS care.28–30 GRADE: Weak; Level: IIIB
- PP: Choice of risk score. For ischaemic risk, the GRACE risk score is superior to the TIMI risk score in terms of discriminating between high risk and intermediate or low risk patients.28 However, estimating risk of death or recurrent myocardial infarction (MI) for an individual patient depends on local validation. For bleeding risk, the CRUSADE risk score is preferred, although it has limited validation in the Australian setting.31

Acute reperfusion and invasive management strategies for ACS

For patients with STEMI presenting within 12 hours of symptom onset, and in the absence of advanced age, frailty and comorbidities that influence the individual’s overall survival, emergency reperfusion therapy with either primary percutaneous coronary intervention (PCI) or fibrinolytic therapy is recommended.32,33 GRADE: Strong; Level: IA
- PP: ECG interpretation. In situations where expertise in ECG interpretation may not be available, an electronic algorithm for ECG interpretation (coupled with review by an expert) can assist in diagnosing STEMI. Local or state care pathways should incorporate means for allowing expert ECG reading within 10 minutes of first contact, integrated with clinical decision making to enable timely reperfusion.
Primary PCI is preferred for reperfusion therapy in patients with STEMI if it can be performed within 90 minutes of first medical contact; otherwise, fibrinolytic therapy is preferred for those without contraindications.34–36 GRADE: Strong; Level: IA
- PP: Strategies for reducing the time to reperfusion therapy. Coordinated protocols with planned decision making that incorporates ambulance services and paramedics, first-responder primary care physicians, and emergency and cardiology departments are critical for achieving acceptable reperfusion times. Strategies need to be tailored to the local community and the distribution of emergency services. Strategies that effectively shorten the time to reperfusion include: developing hospital networks with pre-determined management pathways for reperfusion; pre-hospital ECG and single call catheter laboratory activation; pre-hospital fibrinolytic therapy administered by suitably trained clinicians (eg, paramedics); the bypassing, where appropriate, of non-PCI-capable hospitals; and bypassing the emergency department on arrival in PCI-capable centres. Furthermore, an established capability for timely expert consultation for complex clinical scenarios is highly desirable. In the context of a system-based approach to reperfusion, the capacity for continuous audit and feedback is also advocated.
Among patients treated with fibrinolytic therapy who are not in a PCI-capable hospital, early or immediate transfer to a PCI-capable hospital for angiography, and PCI if indicated, within 24 hours is recommended.37 GRADE: Weak; Level: IIA
Among patients treated with fibrinolytic therapy, for those with ≤ 50% ST recovery at 60–90 minutes and/or with haemodynamic instability, immediate transfer for angiography with a view to rescue angioplasty is recommended.38 GRADE: Strong; Level: IB
- PP: Hospital networks. Systems of care should be developed to provide advice and enable, when appropriate, immediate or early transfer for angiography of patients treated with fibrinolytic therapy who are not in a PCI-capable hospital.
Among high and very high risk patients with NSTEACS (except type 2 MI [secondary to ischaemia due to either increased oxygen demand or decreased supply]), a strategy of angiography with coronary revascularisation (PCI or coronary artery bypass grafting [CABG]), where appropriate, is recommended.39 GRADE: Strong; Level: IA
- PP: Mode of revascularisation. Patient comorbidities, fitness for major surgery and coronary anatomy are the main determinants. Urgent revascularisation with CABG may be indicated for patients with failed PCI, cardiogenic shock or mechanical defects resulting from MI (eg, septal, papillary muscle or free-wall rupture). A combined Heart Team approach may provide the best consensus decision about the care of an individual patient.
- PP: Invasive management for type 2 MI. Type 2 MI remains a challenging diagnosis, and no trials have examined the benefits of a routine invasive strategy in patients with type 2 MI. In the absence of any trial evidence, angiography with a view to revascularisation may be considered if there is ongoing ischaemia or haemodynamic compromise despite adequate treatment of the underlying acute medical problem that provoked the type 2 MI.
Patients with NSTEACS who have no recurrent symptoms and no risk criteria are considered at low risk of ischaemic events and can be managed with a selective invasive strategy guided by provocative testing for inducible ischaemia.39 GRADE: Strong; Level: IA
Very high risk patients: Among patients with NSTEACS with very high risk criteria (ongoing ischaemia, haemodynamic compromise, arrhythmias, mechanical complications of MI, acute heart failure, recurrent dynamic or widespread ST segment and/or T wave changes on ECG; Box 3), an immediate invasive strategy is recommended (ie, within 2 hours of admission).40 GRADE: Strong; Level: IIC
High risk patients: In the absence of very high risk criteria, for patients with NSTEACS with high risk criteria (GRACE score > 140, dynamic ST segment and/or T wave changes on ECG or rise and/or fall in troponin compatible with MI; Box 3), an early invasive strategy is recommended (ie, within 24 hours of admission).40 GRADE: Weak; Level: IC
Intermediate risk patients: In the absence of high risk criteria, for patients with NSTEACS with intermediate risk criteria (such as recurrent symptoms or substantial inducible ischaemia on provocative testing; Box 3), an invasive strategy is recommended (ie, within 72 hours of admission).40–42 GRADE: Weak; Level: IIC

Pharmacology for ACS

Aspirin 300 mg orally (dissolved or chewed) initially, followed by 100–150 mg/day, is recommended for all patients with ACS, in the absence of hypersensitivity.43 GRADE: Strong; Level: IA
Among patients with confirmed ACS at intermediate to very high risk of recurrent ischaemic events, use of a P2Y₁₂ inhibitor (ticagrelor 180 mg orally, then 90 mg twice a day; or prasugrel 60 mg orally, then 10 mg daily; or clopidogrel 300–600 mg orally, then 75 mg daily) is recommended in addition to aspirin (ticagrelor or prasugrel preferred; see below).44–47 GRADE: Strong; Level: IA
- PP: Choosing between P2Y₁₂ inhibitors. Given their superior efficacy, ticagrelor and prasugrel are the preferred first-line P2Y₁₂ inhibitors. Use of ticagrelor is advised for a broad spectrum of patients with STEMI or NSTEACS who are at intermediate to high risk of an ischaemic event, in the absence of atrioventricular conduction disorders (second and third degree atrioventricular block) and asthma or chronic obstructive pulmonary disease. Prasugrel may be considered for patients who have not received a P2Y₁₂ antagonist and in whom PCI is planned, but it should not be used for patients > 75 years of age, of low bodyweight (< 60 kg) or with a history of transient ischaemic attack or stroke. Use of either prasugrel or ticagrelor, rather than clopidogrel, is also recommended for patients who have experienced recurrent events while taking clopidogrel or who have experienced stent thrombosis. Clopidogrel is recommended for patients who cannot receive ticagrelor or prasugrel, as an adjunctive agent with fibrinolytic therapy or for those requiring oral anticoagulation (refer to relevant prescribing information documentation). Ticagrelor or clopidogrel should be commenced soon after diagnosis, but due consideration should be given to ischaemic and bleeding risks, the likelihood of need for CABG (more likely in patients with extensive ECG changes, ongoing ischaemia or haemodynamic instability) and the delay to angiography. Prasugrel should be commenced immediately after diagnosis among patients undergoing primary PCI for STEMI, or after the coronary anatomy is known among those undergoing urgent PCI. Initiation of prasugrel before coronary angiography outside the context of primary PCI is not recommended.
- PP: Combination of P2Y₁₂ inhibition with long term anticoagulation. Among patients with an indication for oral anticoagulation, a careful assessment of thrombotic and bleeding risks is required, using CHA₂DS₂-VASc and HAS-BLED scores, respectively. The following advice is based on consensus opinion. In patients with a strong indication for long term anticoagulation (ie, mechanical heart valves, atrial fibrillation with CHA₂DS₂-VASc score ≥ 2), the anticoagulant should be continued at a reduced dose, and clopidogrel, rather than ticagrelor or prasugrel, should be used for these patients. The duration of triple therapy (ie, aspirin, clopidogrel and oral anticoagulation) should be determined by the bleeding risk.
Intravenous glycoprotein IIb/IIIa inhibition in combination with heparin is recommended at the time of PCI among patients with high risk clinical and angiographic characteristics or for treating thrombotic complications among patients with ACS.48 GRADE: Strong; Level: IB
Either unfractionated heparin or enoxaparin is recommended in patients with ACS at intermediate to high risk of ischaemic events.49,50 GRADE: Strong; Level: IA
- PP: Choosing between indirect thrombin inhibitors. Enoxaparin may be preferred over unfractionated heparin as it does not require monitoring of partial thromboplastin time and is simpler to administer. Swapping between enoxaparin and unfractionated heparin has been shown to increase bleeding risk and is not recommended.
Bivalirudin (0.75 mg/kg intravenously with 1.75 mg/kg/h infusion) may be considered as an alternative to glycoprotein IIb/IIIa inhibition and heparin among patients with ACS undergoing PCI with clinical features associated with an increased risk of bleeding events.51 GRADE: Weak; Level: IIB

Discharge management and secondary prevention

Aspirin (100–150 mg/day) should be continued indefinitely unless it is not tolerated or an indication for anticoagulation becomes apparent.43 GRADE: Strong; Level: IA
Clopidogrel should be prescribed if aspirin is contraindicated or not tolerated. GRADE: Strong; Level: IA
Dual antiplatelet therapy with aspirin and a P2Y₁₂ inhibitor (clopidogrel or ticagrelor) should be prescribed for up to 12 months in patients with ACS, regardless of whether coronary revascularisation was performed. The use of prasugrel for up to 12 months should be confined to patients receiving PCI. GRADE: Strong; Level: IA
Consider continuation of dual antiplatelet therapy beyond 12 months if ischaemic risks outweigh the bleeding risk of P2Y₁₂ inhibitor therapy; conversely, consider discontinuation if bleeding risk outweighs ischaemic risks.52 GRADE: Weak; Level: IIC
Initiate and continue indefinitely, the highest tolerated dose of an HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor (statin) for a patient following hospitalisation with ACS, unless contraindicated or there is a history of intolerance.53 GRADE: Strong; Level: IA
- PP: Target cholesterol levels. There is additional benefit from progressive lowering of cholesterol levels, with no apparent lower limit. Within the context of an individualised care plan, a target low density lipoprotein cholesterol level of less than 1.8 mmol/L is suggested in the first instance.
Initiate treatment with vasodilatory β-blockers in patients with reduced left ventricular systolic function (left ventricular ejection fraction ≤ 40%) unless contraindicated.54 GRADE: Strong; Level: IIA
Initiate and continue angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers) in patients with evidence of heart failure, left ventricular systolic dysfunction, diabetes, anterior MI or co-existent hypertension.55 GRADE: Strong; Level: IA
Attendance at cardiac rehabilitation or undertaking a structured secondary prevention service is recommended for all patients hospitalised with ACS.56,57 GRADE: Strong; Level: IA
- PP: Individualisation of cardiac rehabilitation or secondary prevention service referral. A wide variety of prevention programs improve health outcomes in patients with coronary disease. After discharge from hospital, patients with ACS and, where appropriate, their companion(s) should be referred to an individualised preventive intervention according to their personal preference and values and the available resources. Services can be based in the hospital, primary care, the local community or the home.

System considerations

Continuous audit and feedback systems, integrated with work routines and patient flows, are strongly advocated to support quality assurance initiatives and provide data confirming continued, cost-efficient improvement in patient outcomes as a result of new innovations in care.

Box 1 –
Timing of troponin testing

Timing of sampling

Strategy*

Assays

0 hour (single sample)

Patients whose pain and symptoms resolved 12 hours prior to testing (cut points are the assay-specific 99th percentile

Both sensitive and highly sensitive (HS) assays

0 hour (single sample)

Patients with value < LoD of the specific assay (not > 99th percentile cut point) and symptom onset > 3 hours^†15–17

HS assays

0 hour and 1 hour after presentation

Rule-in and rule-out AMI algorithms (cut points are assay-specific and not the 99th percentile)18–20

HS assays

0 and 2 hours after presentation

ADAPT protocol13

Sensitive assays

Modified ADAPT protocol12,21(cut points are the assay-specific 99th percentile)

HS assays

0 and ≥ 3 hours after presentation

Previous NHFA protocol7

HS assays

HEART Pathway22,23 (cut points are the assay-specific 99th percentile)

Both sensitive and HS assays

0 and ≥ 6–12 hours after presentation

Rule-in and rule-out AMI algorithms5 (cut points are the assay-specific 99th percentile)

Sensitive and point-of-care assays

ADAPT = 2-Hour Accelerated Diagnostic Protocol to Assess Patients with Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker. AMI = acute myocardial infarction. HEART = History, Electrocardiogram, Age, Risk factors and Troponin. LoD = limit of detection. NHFA = National Heart Foundation of Australia. * With concurrent clinical risk stratification. † Reports on the use and outcomes of the biomarker strategy in clinical practice are not currently available.

Box 2 –
Risk classification for possible cardiac causes of chest pain

High risk

Ongoing or recurrent chest discomfort despite initial treatment
Elevated cardiac troponin level
New ischaemic changes on electrocardiogram (ECG), such as persistent or dynamic ECG changes of ST segment depression ≥ 0.5 mm; transient ST segment elevation (≥ 0.5 mm) or new T wave inversion ≥ 2 mm in more than two contiguous leads; or ECG criteria consistent with Wellens syndrome
Diaphoresis
Haemodynamic compromise — systolic blood pressure < 90 mmHg, cool peripheries, Killip Class > I and/or new onset mitral regurgitation
Sustained ventricular tachycardia
Syncope
Known left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 40%)
Prior acute myocardial infarction, percutaneous coronary intervention or coronary artery bypass grafting

Low risk

Age < 40 years
Symptoms atypical for angina
Remain symptom free
Absence of known coronary artery disease
Normal troponin level
Normal ECG

Intermediate risk

Neither high risk nor low risk criteria

Box 3 –
Markers of increased risk of mortality and recurrent events among patients with confirmed acute coronary syndrome

Risk classification

Clinical characteristic

Very high

Haemodynamic instability, heart failure, cardiogenic shock or mechanical complications of myocardial infarction (MI)
Life-threatening arrhythmias or cardiac arrest
Recurrent or ongoing ischaemia (ie, chest pain refractory to medical treatment) or recurrent dynamic ST segment and/or T wave changes, particularly with intermittent ST segment elevation, de Winter T wave changes or Wellens syndrome, or widespread ST segment elevation in two coronary territories

High

Rise and/or fall in troponin level consistent with MI
Dynamic ST segment and/or T wave changes with or without symptoms
GRACE score > 140

Intermediate

Diabetes mellitus
Renal insufficiency (glomerular filtration rate < 60 mL/min/1.73 m²)
Left ventricular ejection fraction ≤ 40%
Prior revascularisation: percutaneous coronary intervention or coronary artery bypass grafting
GRACE score > 109 and < 140

GRACE = Global Registry of Acute Coronary Events.

The uptake of coronary fractional flow reserve in Australia in the past decade

The use of coronary pressure wires (or fractional flow reserve [FFR]) has been shown to reduce the frequency of major adverse cardiac events and of unnecessary stent procedures, and to lower treatment costs in both the public and private sectors in Australia.1–3 FFR is a tool for assessing physiological ischaemia in coronary artery stenosis, measuring pre- and post-stenosis pressures during adenosine-induced hyperaemia. Because it is evidence-based and quantifiable, it may be discussed during the upcoming Medicare reform. Data on its uptake across Australia, however, have not been published.

We examined trends in FFR use after its addition to the Medicare Benefits Schedule 10 years ago. We analysed Australian Government Department of Human Services data on Medicare items for coronary flow reserve, coronary angiography and percutaneous coronary angiography.

A total of 14 160 FFR services were processed by Medicare during the past 10 years. FFR use grew during this period, with a mean annual increase of 55%, from 131 services in 2007 to 3869 in 2015 (non-parametric analysis, P = 0.004). Time series analysis identified a Gompertz non-linear trend of FFR against time, indicating that national FFR use is continuing to increase, although growth began to slow in 2014. Further, FFR use increased on a population basis by an average of 45% each year, from 1 per 100 000 in 2007 to 16 per 100 000 in 2015, when these figures were highest in New South Wales (23 per 100 000) and Queensland (19 per 100 000) (Box).

The national rate of FFR per coronary angiogram increased from 0.02% in 2006 to 4.8% in 2015 (P = 0.004), when the highest rate was in NSW (5.8%). The rate of FFR per percutaneous coronary intervention (PCI) increased from 0.1% in 2006 to 19.2% in 2015 (P = 0.004), when the highest rate was in Queensland (26.6%). In 2015, there were 5.2 PCIs per FFR used; the rate was not related to the population size of the state or territory (Spearman non-parametric correlation, ρ_S = 0.07; P = 0.87) or to total PCI use (ρ_S = 0.12, P = 0.78). There was marked variation between states and territories (Box), highlighting heterogeneity across Australia in the use of FFR.

The data summarised in the Box allow operators and hospitals to compare their use of FFR with state and national averages, and they facilitate more standardised care across Australia. Barriers to the uptake of FFR include operator and centre experience, availability and cost. It has been suggested that FFR is discouraged by the lower remuneration received if stenting is not performed.4 From a national perspective, however, there is a mean saving of $1200 per patient in the public sector and $5000 per patient in the private sector when FFR makes stenting unnecessary,2 representing a total annual saving of $4 million.4

The use of FFR across Australia is heterogeneous, but it has grown over the past decade, both in absolute numbers and as proportions of coronary angiograms and PCI.

Box –
Summary of Medicare items for use of a coronary pressure wire (fractional flow reserve [FFR]) processed during 2015

Australia

NSW

Vic

Qld

Tas

ACT

Total FFR services

3869

1764

688

944

146

225

FFR per 100 000 population

FFR per angiogram

1/21 (4.8%)

1/17 (5.8%)

1/28 (3.6%)

1/17 (5.7%)

1/30 (3.4%)

1/29 (3.5%)

1/21 (4.8%)

1/83 (1.2%)

1/38 (2.7%)

FFR per percutaneous coronary intervention

1/5.2 (19.2%)

1/4.6 (21.6%)

1/7.0 (14.3%)

1/3.8 (26.6%)

1/6.8 (14.7%)

1/7.7 (13.0%)

1/6.2 (16.2%)

1/34.1 (2.9%)

1/4.3 (23.3%)

Source: Australian Government Department of Human Services. Medicare Australia Statistics, medical item reports (http://medicarestatistics.humanservices.gov.au/statistics/mbs_item.jsp) for coronary flow reserve (item number, 38241), coronary angiogram (38215, 38218, 38220, 38222, 38225, 38228, 38231, 38234, 38237, 38240, 38246) and percutaneous coronary angiogram (38243, 38246).