Cardiovascular diseases

In reply: Professor Shann raises three issues regarding the recommendation for 24 hours’ prophylaxis for cardiac surgery. First, he states that the trial1 on which this recommendation was made was flawed, because “cephazolin was not given until 20–30 minutes after induction of anaesthesia, which is likely to have been too late”. The trial included patients having coronary artery surgery and/or cardiac valve replacement, and, for these procedures, the time between induction of anaesthesia and surgical incision is about 60–75 minutes, as patients require the placement of intravenous lines and preparation for coronary artery bypass surgery. Antibiotic administration is recommended 30–60 minutes before incision, thus, administration 30 minutes after induction provides optimal serum concentrations at incision, in patients undergoing cardiac surgery. Second, the per-protocol analysis is perhaps less than ideal, but the demographics, clinical characteristics and operative data were comparable for the patients included in the analysis. Third, as stated by Professor Shann, the three earlier studies2-4 were either very small or flawed in design. The McDonald systematic review5 included 28 studies, only two of which were on cardiac surgery, both being the earlier flawed studies2,3 quoted above. The Therapeutic guidelines: antibiotic review process involves a rigorous, evidence-based assessment with input from experts in the field. The medical community of Australia can have every confidence that the recommendations made are current and evidence-based.

Keryn J Christiansen

To the Editor: Observing jugular venous pressure (JVP) is central to cardiovascular examination. Lewis, in 1930,1 was the first to report the use of the external jugular vein as a manometer for recording pressure in the right atrium. Unfortunately, some textbooks on clinical examination and many clinical teachers incorrectly state that the external jugular is unreliable for measuring JVP and that only the internal jugular should be used. The problem with this is that the internal jugular vein is located deep within the neck, where it is covered by the sternomastoid muscle and is therefore not usually visible. Lewis used the sternal angle as a reference point, presuming that it lay 5 cm above the centre of the right atrium in all positions of the patient between lying and sitting. A recent study using computed tomography to examine 160 patients noted that the median vertical distance between the sternal angle and the mid right atrium was 5.4 cm, thus confirming that Lewis’s estimate of the sternal angle in relation to the right atrium was correct (bearing in mind that adults are taller than they were in the 1920s).2 The mean right atrial pressure is the mean of the peak and trough of the external jugular wave above the sternal angle expressed in cm H2O. Over the past few decades, several studies have confirmed that the original findings of Lewis were correct: there is no significant difference in JVP whether it is measured using the internal or external jugular vein, and the external jugular pulse accurately reflects directly measured right atrial pressure.3 In a study of 52 patients with chronic congestive heart failure who had right heart catheterisation, elevation of the JVP showed 57% sensitivity for a raised pulmonary capillary wedge pressure (≥ 18 mmHg) and 93% specificity for non-elevation of JVP, corresponding with a capillary wedge pressure of ≤ 18 mmHg. If elevated JVP was inducible as well, sensitivity increased to 81% and specificity dropped to 80%, with a predicted accuracy of 81%.4 Generations of frustrated medical students and doctors who have stared intently at their patients’ necks awaiting that elusive flicker of the internal jugular pulse have been overlooking an accurate source of clinical information — namely the pulse in the external jugular vein. Lewis was right 80 years ago: measuring the external JVP is a valuable clinical tool and should be practised frequently.

David M Colquhoun · Glenn Jenkins

Debating early invasive versus medical management When there is an apparent threat of myocardial damage from unstable angina or non-ST-elevation myocardial infarction (NSTEMI) (collectively referred to as the non-ST-elevation acute coronary syndromes, or NSTEACS), early opening of the culprit atherothrombotic coronary artery would seem logical. Clinical trials of early coronary intervention (the invasive approach) have shown variable results when applied to all patients with NSTEACS, but clear benefits when applied to high-risk patients.1,2 On this basis, the 2006 National Heart Foundation of Australia (NHFA) guidelines3 concluded that the evidence was strong enough to recommend that all high-risk patients with NSTEACS should be transferred urgently to a cardiac catheterisation facility to permit early coronary angiography and percutaneous coronary intervention or coronary artery bypass surgery, if appropriate. The advice is consistent with United States1 and European2 guidelines and has recently been reaffirmed and followed with recommendations for implementation in Australia.4 But does the invasive approach show true promise, or is it based on a false premise, as suggested by Forge in this issue of the Journal?5 Forge makes the point that the ICTUS (Invasive versus Conservative Treatment in Unstable Coronary Syndromes) trial, published in 2005,6 was overlooked in drawing up the NHFA guidelines and did not show any benefit of an invasive strategy in patients with NSTEACS. It is certainly a valid point that the ICTUS study was conducted with treatments that were more modern and effective than the earlier studies, which were conducted in the 1990s, before the widespread use of enoxaparin, clopidogrel and high-dose statins.7 However, several important points are relevant in analysing the results of the ICTUS study. Firstly, the 1-year mortality in the ICTUS study was 2.5%, which was lower than the 1-year mortality in typical Australian patients with NSTEACS (10.5% for NSTEMI and 3.3% for unstable angina),8 indicating that patients in the ICTUS trial were not high-risk patients. Secondly, the lack of difference in outcome between the conservative and the invasive approach in the ICTUS study was largely due to an apparent increase in minimal myocardial infarction in the interventional group, driven by small rises in creatine kinase MB levels that accompanied the interventional procedure. Such periprocedural infarctions have nowhere near the same long-term prognostic impact as spontaneous infarctions.9 Thirdly, despite the enhanced medical management, selection of a conservative approach in the ICTUS trial did not preclude subsequent coronary intervention. Forty per cent of patients in the conservative treatment arm of the trial required coronary intervention during the initial hospital course. Finally, the ICTUS study was conducted in hospitals with ready access to interventional procedures when they were thought to be necessary. This was not a study whose results can be readily applied to the management of patients in Australian regional hospitals. Forge’s suggestion that modern medical management could render invasive treatment irrelevant takes an unduly optimistic view of the power of medicines. There is no doubt that intensive therapy with statins and antiplatelet agents can significantly improve outcomes for patients with NSTEACS,10,11 but the conclusion that conservative management alone will remove the need to open a blocked artery is hardly justified based on the ICTUS study results, which comprise just over 10% of the evidence base.1-3,6,7 Nor is it valid for Forge to conclude that a strategy of early transfer of patients with NSTEACS to hospitals providing percutaneous coronary intervention is not in agreement with US guidelines. In the 2007 revision of the US guidelines for acute coronary syndromes,1 which considered the ICTUS results in detail, an initial conservative approach treatment option was accorded the status of only a Class IIB recommendation (ie, “may be considered”), whereas the early invasive approach was accorded Class IA status (“recommended”).1 The European guidelines2 concur with these recommendations. The Australian guidelines3 and the recommendations for implementing them4 are also consistent with these conclusions. In summary, the active use of evidence-based medical treatments for NSTEACS should be encouraged, as these are underutilised in patients with acute coronary syndromes in Australia.12 However, if a patient with an acute coronary syndrome with high-risk features presents to a regional hospital, guidelines based on sound evidence support early invasive treatment, and arrangements should be made for early transfer to a hospital that can provide coronary angiography and, if appropriate, percutaneous coronary intervention.

Peter L Thompson MD, FRACP, FACC

Recent National Heart Foundation of Australia (NHFA) guidelines for management of acute coronary syndromes (ACS) recommend increasing the rates of early invasive management of ACS and providing equal access for all Australians to percutaneous coronary intervention (PCI) facilities. For patients with ACS managed in regional hospitals without PCI facilities, review of the evidence does not show unequivocal benefit of early routine PCI over selective PCI for patients with non-ST-segment-elevation ACS or ST-elevation myocardial infarction. The current pattern of transfer based on the NHFA guidelines is expensive and disruptive of patient care, as well as undermining regional health care services. Further increase in transfer rates and increases in PCI facilities would divert resources away from supporting the regional infrastructure needed to provide evidence-based therapies, without any evidence that lives would be saved.

Brett H Forge MB BS, FRACP

Forge 1 has raised specific concerns about our recent position statement2 on implementing the National Heart Foundation of Australia (NHFA)/Cardiac Society of Australia and New Zealand (CSANZ) consensus recommendations for managing patients with acute coronary syndromes (ACS).3 In particular, he questions whether providing all patients with equal access to percutaneous coronary intervention (PCI) services is truly evidence-based. Abbreviations ACS Acute coronary syndromes CSANZ Cardiac Society of Australia and New Zealand ICTUS Invasive versus Conservative Treatment in Unstable Coronary Syndromes NHFA National Heart Foundation of Australia NSTEACS Non-ST-elevation acute coronary syndromes NSTEMI Non-ST-elevation myocardial infarction PCI Percutaneous coronary intervention STEMI ST-elevation myocardial infarction Transferring patients with non-ST-elevation acute coronary syndromes (NSTEACS)The 2006 NHFA/CSANZ guidelines recommend: High-risk patients with NSTEACS should be treated with aggressive medical management . . . and arrangements should be made for coronary angiography and revascularisation, except in those with severe comorbidities.3 Forge is disturbed by the lack of discussion in the 2006 NHFA/CSANZ guidelines around this recommendation. Detailed discussion about the evidence for early angiography and revascularisation was provided in the NHFA/CSANZ unstable angina guidelines produced in 2000.4 At that time, it was recognised that studies that reported the greatest benefit of an invasive strategy were those in which there was a large difference in intervention rates between the two treatment groups. With the completion of further trials, including the ICTUS (Invasive versus Conservative Treatment in Unstable Coronary Syndromes) study,5 this observation has been strengthened. When trials with the largest absolute differences in revascularisation rates are pooled, a significant reduction in death is seen. If the conservatively managed group has a high rate of intervention, as in the ICTUS study (in which 53% of the conservative management group underwent angiography in hospital, and 67% by one year), the differences between strategies diminish.6 A review of 2380 patients with chest pain admitted to 27 Australian hospitals between January 2003 and August 2005 found that only 20% of patients with ACS who were admitted to coronary care units in hospitals without angiographic services underwent coronary angiography.7 Low intervention rates such as these have consistently been shown to be associated with poorer outcomes, prompting our recommendation that access to catheterisation laboratories for high-risk patients with NSTEACS should be increased. We would have particular concern with Forge’s contention that the ICTUS study provides justification for a more conservative approach for these patients than is taken at present. Our recommendation is consistent with contemporary international guidelines.8,9 The American College of Cardiology/American Heart Association 2007 guidelines8 in fact offer a Class 1 recommendation, level of evidence A, for an early invasive strategy in initially stabilised patients with unstable angina or non-ST-elevation myocardial infarction (NSTEMI) who have an elevated risk of experiencing clinical events. The approach of choosing an initial conservative strategy for these patients, as cited by Forge, is afforded a Class 2B recommendation, level of evidence C — in other words, a weaker recommendation, supported by a less robust evidence base. Routine transfer of all patients with ST-elevation acute coronary syndromes (STEACS)The 2006 NHFA/CSANZ guidelines recommend: Patients who have had STEMI should be considered for early transfer to a tertiary cardiac centre with PCI facilities and links to cardiac surgical facilities (Grade B recommendation). If early transfer is not possible, all patients should be transferred or referred as soon as is practicable for assessment of the need for revascularisation (through PCI or coronary artery bypass grafting) (Grade D recommendation).3 Despite Forge’s concerns, we believe that the evidence supporting these recommendations is stronger than it was in 2005, when the guidelines were produced, particularly for anterior and large inferior STEMIs. The CARESS-in-AMI (Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction) trial demonstrated that a strategy of immediate PCI led to a significant reduction in death, reinfarction and refractory ischaemia compared with the standard care of rescue-only angioplasty after fibrinolysis.10 Importantly, only 30% of patients in the standard care arm underwent PCI during hospitalisation, compared with 97% in the immediate PCI arm. Thus, offering angiography to high-risk patients with STEMI receiving fibrinolysis during their admission contributes to a reduced event rate. Forge erroneously cites the TRANSFER-AMI (Trial of Routine Angioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction) study11 as evidence against a strategy of routine transfer after fibrinolysis. In fact, most patients in the “standard treatment” arm were treated in this way: 88.7% underwent coronary angiography a median of 32.5 hours after fibrinolysis.11 Guideline implementation and future guideline developmentThe 2006 guidelines for managing ACS were developed by health professionals with different backgrounds through a consensus approach involving independent assessment of key clinical guidelines and scientific articles (acknowledged to be incomplete in some areas). The recommendations that emerged from the subsequent national acute coronary syndrome implementation forum arrived at a consensus view of the key priority interventions that, if applied Australia-wide, would result in improved clinical outcomes. The forum specifically addressed rural and remote settings, where one identified priority was to implement region-specific systems to facilitate reperfusion treatment and subsequent care, including transfer, if appropriate. We clearly do not accept Forge’s contention that our recommendations are based on flawed interpretation of the evidence, nor his inflammatory assertion that the authors had any pecuniary conflict of interest. Guidelines are becoming increasingly important in influencing clinical practice, and an understanding of the optimal processes for their development is evolving.12 We agree on the need for government support in this area. Australia needs a more formal and strategic approach to prioritising, developing and implementing clinical guidelines. To this end, the NHFA has accepted a commission from the Australian Department of Health and Ageing to work with stakeholders, including the National Health and Medical Research Council, to define potential components of an improved collaborative model for developing cardiovascular disease clinical guidelines in Australia.

David B Brieger MB BS, FRACP, PhD · Constantine N Aroney MD, FRACP · Derek P Chew MB BS, MPH, FRACP · Anne-Maree Kelly MD BS, MClinED, FACEM · Darren L Walters FRACP, FCSANZ, FSCAI · Carrie L Toohey RN, BN · Andrew N Boyden MPH, FRACGP

Objectives: To compare clinical outcomes between patients with ST-elevation myocardial infarction (STEMI) presenting to a hospital with facilities for primary percutaneous coronary intervention (PCI) and patients transferred from a non-PCI-capable unit, and to determine the success rate of meeting clinical guidelines for management of STEMI.Design, setting and participants: Prospective study of patients with STEMI who underwent PCI at Box Hill Hospital (BHH), Melbourne, between 1 July 2002 and 30 June 2008. We compared two patient groups: “BHH patients”, who were admitted directly to BHH (a hospital with PCI capability), and “SHIPEM (Shipping Infarcts for Primary Angioplasty in Eastern Melbourne Registry) patients”, who were transferred from other hospitals without PCI capability.Main outcome measures: Clinical outcomes; symptom-to-first-door time (time between symptom onset and arrival at first hospital); first-door-to-balloon time (time between arrival at the first hospital and inflation of the angioplasty balloon); compliance with Cardiac Society of Australia and New Zealand/National Heart Foundation of Australia (CSANZ/NHFA) guidelines for management of patients with STEMI.Results: There were 598 patients in the BHH group and 189 in the SHIPEM group. The median first-door-to-balloon time was 89 minutes (interquartile range [IQR], 69–107 minutes) for BHH patients and 128 minutes (IQR, 104–157 minutes) for SHIPEM patients. These figures did not vary significantly over the 6 years of the registry. In the BHH group, 180 patients (30.1%) had a symptom-to-first-door time of ≤ 60 minutes, with 32 (17.8%) receiving PCI in ≤ 60 minutes. The corresponding figure for the SHIPEM group was 48 patients (25.4%), with 1 (2.1%) receiving PCI within 60 minutes. In the BHH group, 304 patients (50.8%) had a symptom-to-first-door time of 61–180 minutes, with 166 (54.6%) receiving PCI in ≤ 90 minutes. In the SHIPEM group, 50 patients (26.5%) had a symptom-to-first-door time of > 180 minutes, with 21 (42.0%) receiving PCI in ≤ 120 minutes.Conclusion: Our study demonstrates that transfer for PCI is feasible and safe in selected patients, with outcomes comparable to those of patients presenting to a PCI-capable unit. However, the CSANZ/NHFA targets, predicated by symptom-to-first-door time, are not being met and have not improved over time, which suggests that strategies to improve symptom-to-first-door, first-door-to-balloon and transfer times need to be addressed.

Michael J Moore MB BCh BAO, MRCP, MD · Louise Roberts BSc, PhD · Houng-Bang Liew MB BCh BAO, FRCP · Esther M Briganti MB BS, FRACP, PhD · Gishel New MB BS, FRACP, PhD

Omission of potential competing interests: In “Managing residual risk in patients receiving statin therapy” in the 5 April 2010 issue of the Journal (Med J Aust 2010; 192: 366-367), potential competing interests were omitted. The author, Ian Hamilton-Craig, has received financial support to attend and give presentations at scientific meetings from AstraZeneca, Merck Sharp & Dohme, Schering-Plough, Pfizer, Bristol-Myers Squibb, Solvay, Sanofi-Aventis, Novartis and Abbott Australasia. He is a member of the Lipid Advisory Board of Merck Sharp & Dohme/Schering-Plough, AstraZeneca and Solvay, the Familial Hypercholesterolaemia Committee of the Australian Atherosclerosis Society, and the Council on Genetic Cardiovascular Diseases of the Cardiac Society of Australia and New Zealand.

Ian R Hamilton-Craig

To the Editor: Cardiovascular disease (CVD) and mental disorders are the top two contributors to the total burden of disease in Indigenous Australians and make a substantial contribution to the excess morbidity and mortality in this group.1 There is increasing evidence that mental disorders are risk factors for, or consequences of, CVD.2 Awareness and better understanding of the intertwined relationship between mental disorders and CVD in Indigenous populations can provide opportunities for coordinated and seamless management of these conditions in health care systems. We investigated the association between mental disorders due to substance use and CVD in a remote Indigenous community in the Northern Territory. A cohort of 897 Aboriginal adults aged 20–74 years (85% of the community’s total adult population) was established through a population-based renal disease screening program in the community between 1992 and 1995.3 We followed up 784 participants, who were free of CVD at baseline, to 31 May 2005, using hospital and death records. The study was approved by the Behavioural and Social Sciences Ethical Review Committee of the University of Queensland. Substance use-related mental disorders were determined from participants’ hospital records, using International Classification of Diseases, ninth revision (ICD-9) codes 192, 291 and 303–305; and 10th revision (ICD-10) codes F10–F19. Cases of CVD were identified by the first CVD event recorded in participants’ hospital and death records, using ICD-9 codes 390–459 and ICD-10 codes I00–I99. We used the Kaplan–Meier method to calculate cumulative CVD incidence rates for those with and without substance use-related mental disorders. CVD hazard ratios were estimated using Cox proportional hazards models. During a median follow-up period of 10 years, 177 of the 784 participants (23%) had clinically diagnosed mental disorders due to substance use (mainly alcohol: 140 participants), and 243 (31%) developed CVD. Incidence rates of CVD were 71 (95% CI, 58–87) and 27 (95% CI, 23–32) per 1000 person-years for those with and without substance use-related mental disorders, respectively (Box). Participants with substance use-related mental disorders were 2.6 (95% CI, 2.0–3.3) times more likely to develop CVD than those without. After adjusting for CVD risk factors measured at baseline (age, sex, body mass index, smoking status, alcohol use, blood pressure, serum cholesterol level, diabetes and albuminuria status), the association remained statistically significant, with an adjusted hazard ratio of 2.6 (95% CI, 1.9–3.5). Our findings confirm an association between substance use-related mental disorders and CVD in an Indigenous population, after adjusting for potential confounders. Traditional health care systems tend to separate services and treatment for mental disorders from those for physical health problems such as CVD.4 This separation is even more evident in remote Indigenous settings, where primary health care practitioners are already overwhelmed in providing general medical care to community members, with mental health services being delivered infrequently by visiting psychiatrists.5 The observed intertwined relationship between these two common conditions calls for integration of mental health services into routine primary health care, and enhanced collaboration between primary care practitioners, cardiologists and psychiatrists, in an effort to curb the huge burden imposed by these diseases. The emerging Aboriginal mental health worker program in the NT has the potential to be an effective service model to bridge the gap between mental health care and day-to-day primary health care.5 Dedicated financial resources and ongoing support for recruitment, training and retention of Aboriginal mental health workers will be required for sustained integration of mental health care with primary care in Indigenous communities. Kaplan–Meier estimates of cardiovascular disease (CVD) incidence among Aboriginal adults with and without substance use-related mental disorders

Zhiqiang Wang · Damin Si · Wendy E Hoy

To the Editor: Engaging patients in cardiac rehabilitation (CR), a program of secondary prevention measures, is crucial to improving outcomes after myocardial infarct.1 Rates of participation in CR by Aboriginal and Torres Strait Islander (hereafter Aboriginal) people are extremely low.2,3 We conducted a qualitative study on barriers to CR use from November 2007 to March 2008 with 15 Aboriginal cardiac patients (seven women and eight men, aged 31–74 years) living in Perth, Western Australia. Six had participated in some outpatient CR sessions; nine had not. Participants were interviewed face-to-face using a semistructured interview guide, with questions exploring their views and experiences of CR, barriers to use and suggestions for improvement. Recurring themes included challenges associated with extended family responsibilities and sociocultural inappropriateness of the program. These themes, along with less commonly discussed issues of poor knowledge of CR and the connection between colonialism and health services, reflect findings from previous studies.2,4,5 However, two new themes — media heart health messages and the younger age of the affected Aboriginal population — highlight further factors influencing participation (Box 1). We found that some patients feel constantly reminded of, and therefore come to expect, poor health outcomes, due to dire statistics repeated in the media. While the dominant theme in the Australian media of Aboriginal fatality and futility has been discussed,6 heart health messages are often disempowering, negatively affecting motivation to engage with health programs. This is likely reinforced by regular attendance at funerals for Aboriginal people, who die very prematurely from cardiovascular disease (CVD). This highlights the need for a shift in media and public health campaigns from “shock” headlines and statistics to a focus on strengths and successes, inspiring the groups involved and supporting them to make changes. Younger Aboriginal participants also spoke about feeling isolated in CR sessions among non-Aboriginal people who were 20–30 years older than them. The age demographic of CR program attendees generally reflects CVD epidemiology in the wider community, but the burden of CVD occurs at much younger ages in the Aboriginal population.7 This widening differential7 demands rethinking of how CR should work for this very different demographic group (Box 2). CR programs addressing the needs of younger people may improve receptivity and opportunities for primary prevention in the family and broader community. Although these two themes were reported by a small number of patients, further research into issues for Aboriginal patients with CVD is warranted. Importantly, it will contribute to understanding of how younger Aboriginal people think about their health, and feel motivated and supported by wider society to do something about it. 1 Quotes from Aboriginal cardiac patients reflecting barriers to participating in cardiac rehabilitation (CR) programs ... even with the newspaper, every second page has something to do with the heart ... Turn the radio on, “oh, there’s this new survey about heart conditions”. And I don’t want to know about it! Don’t tell me! ... I don’t want to be told the negatives ... it’s all you used to hear of all the stories regarding the heart. (Aboriginal patient 10) I didn’t like it [the CR program] because everybody else was at least twice my age. I was like the youngest one there and it was just a turn-off for me ... I’d feel more comfortable if people my own age were there for a start, you know? (Aboriginal patient 11) Aboriginal people don’t use [CR and health services] ... as a matter of course because the discrimination that took place in Australia against Aboriginal people ... instead it remained in the psyche of the Aboriginal people that mainstream services are only there for other people. They’re not there for you. (Aboriginal patient 9) 2 Recommendations from Aboriginal patients for improving cardiac rehabilitation (CR) programs Offer CR programs out of working hours Have opportunistic drop-in sessions rather than allocated times Make CR programs more appealing to younger clients Hold CR programs in Aboriginal community health centres Build trust and relationships with patients (the importance of yarning) Develop programs for use at home by the whole family Tailor lifestyle and diet advice to modern Aboriginal family situations Have both male and female Aboriginal health staff delivering CR if possible Target youth with heart health education messages Refocus public health messages away from being negative and fear-based to being positive and strength-based Encourage Aboriginal patients to attend CR sessions together (buddy system)

Kate P Taylor · Julie S Smith · Lyn Dimer · Mohammed Ali · Narelle Wilson · Tyra R Thomas · Sandra C Thompson

Decisions regarding the use of triple therapy should take into account the balance between thromboembolism and bleeding risk in individual patients The combined use of warfarin and dual antiplatelet therapy (aspirin plus clopidogrel) — so-called triple therapy — is a challenging management problem in patients with a coronary stent who also have an indication for oral anticoagulation. One of the most common clinical scenarios is a patient with atrial fibrillation (AF) who undergoes percutaneous coronary intervention with stenting. Guidelines for antithrombotic therapy recommend that patients with AF who are at high risk of stroke (ie, prior history of stroke or more than one of: age ≥ 75 years, hypertension, diabetes, and congestive cardiac failure) receive warfarin;1 and guidelines for percutaneous coronary intervention management recommend dual antiplatelet therapy in all stent patients to prevent stent thrombosis.2 Both warfarin and clopidogrel increase the risk of bleeding in patients treated with aspirin, and combining all three drugs can be expected to further increase bleeding risk. However, the efficacy and safety of triple therapy have not been evaluated in randomised controlled trials. What is the evidence concerning the efficacy of anticoagulation or antiplatelet therapy in patients with AF who have recently received a coronary artery stent? In patients with AF who are at risk of stroke, warfarin compared with placebo or no treatment reduces the risk of stroke by about two-thirds, whereas aspirin reduces the risk by about one-fifth.3 Adding clopidogrel to aspirin improves the effectiveness of antiplatelet therapy for stroke prevention,4 but warfarin is substantially more effective than dual antiplatelet therapy.5 In patients with a recent coronary artery stent, dual antiplatelet therapy compared with the combination of aspirin and warfarin reduces death or myocardial infarction by half.6 Premature discontinuation of clopidogrel (less than 3 months of treatment for sirolimus-eluting stents; less than 6 months for paclitaxel-eluting stents) is the single most important risk factor for stent thrombosis.7 The efficacy and safety of triple therapy have been examined in multiple observational studies. Meta-analysis of 10 observational studies involving 1349 patients with AF who received triple therapy after stent insertion revealed a weighted mean incidence of major bleeding at 30 days of 2.2% (95% CI, 0.7%–3.7%).8 Increasing the duration of triple therapy to longer than 6 months doubles the risk of major bleeding compared with 1 month of treatment.9 The guidelines recommend at least 4 weeks of dual antiplatelet therapy for patients who receive a bare metal stent and at least 1 year for those who receive a drug-eluting stent.2 What is the optimum antithrombotic management of patients with AF who undergo coronary stent insertion? Decisions regarding the use of triple therapy should take into account the balance between thromboembolism and bleeding risk in individual patients. Dual antiplatelet therapy alone is likely to be adequate for stent patients with AF if they are at low or moderate risk of stroke (CHADS2 stroke risk score [congestive heart failure, hypertension, age ≥ 75 years, diabetes, 1 point each; previous stroke or transient ischaemic attack, 2 points10], 0–1), or if they are at high risk of stroke (CHADS2 stroke risk score, > 1) and deemed to be at unacceptably high risk of bleeding with triple therapy. The most important risk factors for bleeding are older age (eg, > 75 years), severe renal dysfunction (eg, creatinine clearance < 30 mL/min), recent gastrointestinal bleeding (eg, within 6 months), previous stroke, and uncontrolled hypertension (eg, systolic blood pressure > 160 mmHg, diastolic blood pressure > 110 mmHg).11 All other patients with AF who are at high risk of stroke (CHADS2 stroke risk score, > 1) and have recently undergone coronary artery stenting should probably receive warfarin in addition to dual antiplatelet therapy (Box).8 Cardiologists and primary care physicians should communicate closely to optimise antithrombotic therapy and minimise the risk of bleeding in patients who may be candidates for triple therapy. Firstly, the duration of exposure to triple therapy should be limited where possible by selecting a bare metal stent, which requires a shorter duration of antiplatelet therapy than a drug-eluting stent.2 Secondly, aspirin should be used at the lowest proven effective dose of 50–100 mg/day to minimise the risk of gastrointestinal bleeding.12 Thirdly, in patients at high risk of gastrointestinal bleeding, consideration should be given to the use of acid-suppressive therapy, either with a histamine H2-receptor antagonist (eg, ranitidine) or a proton-pump inhibitor.13 Retrospective analyses of administrative databases have suggested that the concomitant use of a proton-pump inhibitor (particularly omeprazole) reduced the efficacy of clopidogrel,14,15 but subsequent analyses of data from randomised controlled trials indicated no loss of benefit of clopidogrel when the two were used in combination.16 If a proton-pump inhibitor is used, it may be reasonable to avoid the use of omeprazole. Finally, warfarin therapy should, ideally, be monitored by an expert anticoagulation clinic to optimise the quality of international normalised ratio (INR) control (target INR, 2–3).11 What are the unresolved issues? Our recommendations for the use of triple antithrombotic therapy in patients with AF and a stent are based on observational studies8 and extrapolations of evidence from randomised controlled trials of antithrombotic therapy for prevention of stent thrombosis and thromboembolism in patients with AF. Dedicated randomised studies are urgently needed to obtain more reliable estimates of the risks and benefits of triple antithrombotic therapy in patients with a coronary artery stent who have AF, as well as in stent patients with other indications for warfarin therapy, such as mechanical heart valves or recent venous thromboembolism. Treatment decision algorithm for patients with atrial fibrillation and a coronary artery stent8 * CHADS2 stroke risk score (congestive heart failure, hypertension, age ≥ 75 years, diabetes, 1 point each; previous stroke or transient ischaemic attack, 2 points).10

Jeremy S Paikin MD · Shamir R Mehta MD, MSc, FRCPC · John W Eikelboom MB BS, MSc

As the population ages, the prevalence of aortic stenosis is increasing. There is an unmet clinical need for the treatment of aortic stenosis in high-risk patients, who are often older, frail and have multiple comorbidities. Percutaneous aortic valve replacement (PAVR) is a new and innovative technique for the management of high-risk patients with aortic stenosis. There are currently two devices under evaluation in clinical trials in Australia: the CoreValve ReValving System and the Edwards SAPIEN valve. These devices are generally deployed retrogradely, mainly transfemorally or via the subclavian artery or, less commonly, transapically. Initial experience has been encouraging, with good short-term outcomes. However, there is a lack of long-term data. PAVR is presently only advocated for high-risk older patients with symptomatic aortic stenosis. Where PAVR lies in the treatment algorithm for aortic stenosis will be determined by randomised controlled trials, but for now it offers a genuine treatment alternative for high-risk patients.

Jamie J Layland MB ChB, MRCP, FRACP · Brendan Bell MB BS, FRACP · Dan Mullany MB BS, FRACA, FJFICM · Darren L Walters MB BS, MPhil, FRACP

Until the results of several statin trials are available, it is recommended that the current indications and usage of ezetimibe be continued Patients receiving statin therapy to reduce total and low-density lipoprotein cholesterol (LDL-C) levels still have a residual risk of cardiovascular (CV) events. In most statin trials, CV events are reduced by about 30% compared with placebo, leaving about 70% residual risk of CV events that occur in spite of statin therapy. Factors that may contribute to residual risk are listed in Box 1. The Treating to New Targets Study1 showed that residual risk of CV disease increased with low levels of high-density lipoprotein cholesterol (HDL-C), even in patients who had low levels of LDL-C as a result of statin therapy. This suggested that raising HDL-C levels may be beneficial for such patients, a hypothesis investigated in the recent ARBITER 6-HALTS trial (ARBITER [Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol]; HALTS [HDL and LDL Treatment Strategies in Atherosclerosis]). The ARBITER 6-HALTS trial was a study of carotid intima-media thickness (CIMT) in statin-treated patients who had achieved LDL-C goal levels. It compared an HDL-C-raising strategy (additional treatment with extended-release nicotinic acid titrated to 2 g daily) with an LDL-C-lowering strategy (additional treatment with ezetimibe 10 mg daily).2,3 The trial was stopped prematurely at its interim analysis of 180 of the planned 300 patients, on the basis of differences in the primary end point and other secondary analyses.4 The trial included subjects aged 30 years or over with coronary heart disease (CHD), known atherosclerotic vascular disease at other sites, diabetes, a 10-year CHD risk of > 20% (based on Framingham Heart Study criteria), or a coronary calcium score > 400 in men or > 200 in women, who were stabilised on statin therapy equivalent to simvastatin 20 mg/day, with LDL-C levels < 2.5 mmol/L and HDL-C levels < 1.3 mmol/L in men or < 1.4 mmol/L in women.2 Exclusion criteria included raised transaminase levels more than three times the upper limit of normal, current use of or intolerance to ezetimibe or nicotinic acid, a history of chronic liver disease, or the potential for pregnancy. Results of the ARBITER 6-HALTS trial showed that nicotinic acid reduced CIMT more effectively than ezetimibe (Box 2). Importantly, as no control group was included, no comparison can be made between ezetimibe and placebo with regard to their possible effects on CIMT. Atherogenic dyslipidaemia may be an important contributor to residual risk and is typically associated with obesity, the metabolic syndrome and type 2 diabetes. It is accompanied by impaired glycaemic control, hypertension, and procoagulant and inflammatory states, and is characterised by low HDL-C levels, high triglyceride levels, the presence of triglyceride-rich “remnant” lipoproteins, and a preponderance of small, dense, highly-oxidisable LDL particles. Levels of total cholesterol and LDL-C may be close to normal. Patients in the ARBITER 6-HALTS trial had a mean body mass index in the obese range (30.8–31.0 kg/m2) and a waist circumference above normal (mean, 103 cm and 104 cm in the two groups); 32%–40% were diabetic; and 85%–86% were hypertensive.2 Mean glucose levels (5.55–5.77 mmol/L) and triglyceride levels (1.38–1.42 mmol/L) were also in the high-normal range. Patients were selected for inclusion in the trial on the basis of low HDL-C levels. HDL-C levels increased, as expected, in the nicotinic acid treatment group (by about 18%), but unexpectedly decreased in the ezetimibe treatment group (by about 5%).2 The results of the trial may thus be partially explained by the fact that a significant proportion of patients had atherogenic dyslipidaemia, which responds to nicotinic acid therapy but not to ezetimibe therapy. Conclusions from the ARBITER 6-HALTS trial about the LDL-C-lowering effects of ezetimibe and the HDL-C-raising effects of nicotinic acid may be questioned, as ezetimibe and nicotinic acid affect different lipoproteins and metabolic pathways that may influence atherosclerosis. Nicotinic acid lowers levels of triglycerides and triglyceride-rich lipoproteins by reducing free fatty acid flux to the liver; it also lowers lipoprotein (a) and LDL-C levels. Ezetimibe has less pronounced effects on lowering triglyceride levels and raising HDL-C levels. In addition, the protective functions of HDL-C (including reverse cholesterol transport, anti-inflammatory and antioxidant effects) may not necessarily be reflected in HDL-C levels, and functional assessment of HDL-C may assist in assessing the potential benefits of intervention.5 The implication of the ARBITER 6-HALTS trial results is that targeting atherogenic dyslipidaemia with nicotinic acid therapy reduces CIMT and is likely to improve residual risk of CV events because CIMT is a validated surrogate marker for CV events — an important consideration for all patients receiving statins.6 The HATS (HDL-Atherosclerosis Treatment Study) trial demonstrated that CV events could be reduced by treating atherogenic dyslipidaemia with nicotinic acid.7 Previous CIMT studies (ARBITER 2 and 3) showed that a combination of nicotinic acid and statin therapy was superior to statin therapy alone for atherosclerosis stabilisation and regression.8 These results, together with those of the ARBITER 6-HALTS trial, indicate that nicotinic acid may be appropriate supplementary therapy for reducing residual risk in patients taking statins. The results also provide an evidence base for extended-release nicotinic acid to be made available once again under the Pharmaceutical Benefits Scheme. Long-term clinical outcomes trials are already underway to investigate the primary findings of the ARBITER 6-HALTS trial (Box 3).2 Until the results of these trials are available, it is recommended that the current indications and usage of ezetimibe be continued (Box 3). Lifestyle change is an important component of managing residual risk (Box 1). Stopping smoking, controlling weight and increasing physical exercise can all increase HDL-C levels and may contribute independently to reduction in residual risk of CV events. 1 Possible contributors to residual risk in patients receiving statin therapy Cigarette smoking Uncontrolled hypertension Impaired glucose tolerance Reduced physical exercise Central abdominal obesity Inflammation Prothrombotic tendency Proarrhythmic tendency Myocardial ischaemia Left ventricular dysfunction Reduced high-density lipoprotein cholesterol (HDL-C) level Increased low-density lipoprotein cholesterol (LDL-C) level Atherogenic dyslipidaemia: Increased apolipoprotein B and small, dense LDL particles Reduced HDL-C level Increased level of triglycerides and triglyceride-rich lipoproteins 2 Results of the ARBITER 6-HALTS trial2 Treatment group Ezetimibe (n = 111) Nicotinic acid (n = 97) P Baseline Mean CIMT (mm) (SE) 0.8957 (0.1484) 0.9001 (0.1558) 0.93 At 8 months* Mean change in CIMT (mm) (SE) 0.0014 (0.0020) – 0.0102 (0.1650) 0.90 P (change from baseline) 0.48 0.001 At 14 months* Mean change in CIMT (mm) (SE) – 0.0007 (0.0035) – 0.0142 (0.0041) 0.01 P (change from baseline) 0.84 0.001 ARBITER = Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol; HALTS = High-density Lipoprotein and Low-density Lipoprotein Treatment Strategies in Atherosclerosis. CIMT = carotid intima-media thickness. * Change compared with baseline. 3 Summary and future prospects The ARBITER 6-HALTS trial showed that a strategy of raising high-density lipoprotein cholesterol (HDL-C) levels using nicotinic acid therapy was more successful than a strategy of lowering low-density lipoprotein cholesterol (LDL-C) levels further with ezetimibe, at least with regard to reducing carotid intima-media thickness. Results of the trial are relevant to patients receiving statin therapy who have LDL-C levels < 2.5 mmol/L. Many of these patients have atherogenic dyslipidaemia, with low levels of HDL-C and high levels of triglycerides, as well as increased levels of apolipoprotein B and small dense atherogenic LDL particles. Despite having statin therapy, such patients may continue to experience a high rate of cardiovascular disease events — in part because of lack of control of atherogenic dyslipidaemia, which is not targeted by statins or ezetimibe but is alleviated by fibrates and nicotinic acid. The demonstrated superiority of nicotinic acid therapy in the ARBITER 6-HALTS trial is probably the result of improved control of atherogenic dyslipidaemia. Although the results of the trial are potentially important, their relevance to Australian practice is limited because extended-release nicotinic acid, although approved for prescription by the Therapeutic Goods Administration, is not reimbursed by the Pharmaceutical Benefits Scheme. The few patients who can tolerate non-extended-release nicotinic acid at doses of 2 g daily may benefit from this agent when added to statin therapy. An alternative strategy may be to combine statin therapy with fenofibrate therapy (the effectiveness of this approach will be determined by the results of the ACCORD trial, to be presented in early 2010). Other trials are in progress to determine the long-term clinical outcomes of statin therapy combined with ezetimibe (IMPROVE-IT [estimated completion date, 2015]) and with extended-release nicotinic acid (AIM HIGH and HPS2-THRIVE [estimated completion dates, 2011 and 2013, respectively]). Pending the results of these trials, the continued use of ezetimibe is recommended for patients unable to tolerate statins and for those whose LDL-C level is uncontrolled in spite of maximum-tolerated doses of statins. ACCORD = Action to Control Cardiovascular Risk in Diabetes. AIM HIGH = Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes. ARBITER = Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol; HALTS = HDL and LDL Treatment Strategies in Atherosclerosis. HPS2-THRIVE = Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events. IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial.

Ian R Hamilton-Craig MB BS, FRACP, PhD

Objectives: To examine trends and predictors of prescription medications on discharge after first (index) hospitalisation for heart failure (HF), and the effect on all-cause mortality of evidence-based therapy.Design: A retrospective multicentre cohort study, with medical record review.Setting: Three tertiary-care hospitals in Perth, Western Australia.Patients: WA Hospital Morbidity Data were used to identify a random sample of 1006 patients with an index admission to hospital for HF between 1996 and 2006.Main outcome measures: Proportion of patients prescribed evidence-based therapy for HF on discharge from hospital; and 1-year all-cause mortality.Results: Among 944 patients surviving to hospital discharge, the prescription rate of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) (74.3%) and loop diuretics (85.5%) remained high over the study period, whereas that of β-blockers and spironolactone increased (10.5% to 51.3% and 1.4% to 23.3%, respectively), and digoxin prescription decreased (38.1% to 20.7%). The temporal trends in use of β-blockers, spironolactone and digoxin were in line with clinical trial evidence. Age ≥ 75 years was a significant, negative predictor of β-blocker and spironolactone prescription. In-hospital echocardiography, performed in 53% of patients, was associated with a significantly greater likelihood of treatment with ACE inhibitors/ARBs, β-blockers and spironolactone. Both ACE inhibitors/ARBs and β-blockers prescribed on discharge were associated with a lower adjusted hazard ratio (HR) for mortality at 1-year (HR, 0.71; P = 0.003; and HR, 0.68; P = 0.002, respectively).Conclusion: ACE inhibitors/ARBs and β-blockers, prescribed during initial hospitalisation for HF, are associated with improved long-term survival. Therapy became more evidence based over the study period, but echocardiography, an important predictor of evidence-based therapy, was underutilised.

Tiew-Hwa Katherine Teng MPH · Joseph Hung MB BS(Hons), FRACP, FACC · Judith Finn RN, PhD, FRCNA

More sensitive assays may provide more information, but we are not yet sure of the clinical relevance of this information The introduction of troponin measurement into clinical practice in Australia 10 years ago led rapidly to its widespread use as the marker of choice for diagnosis and risk stratification of patients with acute coronary syndrome (ACS). However, opportunities remain for improving risk assessment in “troponin-negative” patients, many of whom will have adverse events. This has led to the development of new, improved assays that are able to measure down to much lower concentrations than before (10–100-fold lower than current assays), and that increase the detection of acute myocardial infarction, as shown in two recent cohort studies.1,2 The improved analytical performance of these assays may be particularly useful in the early period following the onset of chest pain. These two studies indicated improved diagnostic accuracy of samples taken from patients with chest pain, both at the time of presentation to the emergency department (ED), and within 3 hours of symptom onset.1,2 This improved early sensitivity may lead to significant benefits in ruling out ACS, and in risk assessment, diagnosis and management of patients with ACS, although neither of these studies provided corroboration with clinical outcome. The development of these new “highly sensitive” assays for cardiac troponin raises many questions about their clinical application, including the degree of analytical precision, the medicolegal definition of myocardial infarction, earlier detection and improved management of patients with ACS, as well as the interpretation of elevated cardiac troponin levels in other clinical situations. The current accepted international definition of myocardial infarction — the “universal definition of myocardial infarction”3 — requires a rise or fall in the level of cardiac biomarkers (preferably troponin) with at least one value above 99th percentile of the upper reference limit, along with at least one clinical indicator (symptoms of ischaemia, new ischaemic changes or new Q waves on electrocardiogram, new imaging evidence of loss of viable myocardium or a new regional wall motion abnormality). The use of assays that do not have optimal precision (coeffficient of variation [CV] < 10% at the decision level) is not recommended, although, a variety of the older, less precise assays are still in clinical use. New, highly sensitive (hs) assays have the recommended degree of analytical precision, and the first (Roche hsTnT, Roche Diagnostics) has been launched while others are in preparation. Their use would lead to an increase in the diagnosis of myocardial infarction. Measuring low levels of troponin introduces an additional confounder — that of significant biological variability4 — which would require an increase in the traditionally accepted 20% serial change of troponin level over baseline values that is required to meet the definition of myocardial infarction.5 The application of cardiac troponin measurement in risk stratification of patients presenting with ACS has been strongly supported by clinical data. Measurable cardiac troponin levels in these patients, even concentrations below that corresponding to the recommended assay precision (CV < 10%), are associated with adverse clinical outcomes. In addition, aggressive management has been shown to improve clinical outcome in these high-risk patients. It is possible that the hs assays will improve the identification of high-risk patients who benefit from aggressive management, but this will require clinical validation. From an ED perspective, the new assays present the possibility of identifying patients at very low risk of 7-day or 30-day adverse events at a much earlier stage. Two hs troponin assays at least 3 hours apart, or one assay taken at least 6 hours after symptom onset may be accurate in ruling out myocardial infarction in the ED, but the evidence for this approach is so far limited.2 This should allow for more immediate decision making in relation to proceeding to further testing (such as an exercise stress test or stress echocardiography) and discharge from the ED, and could significantly decrease overnight admissions of patients with possible cardiac chest pain. The use of any biomarker assay in managing chest pain or possible ACS should always be done in conjunction with a full clinical assessment to ensure appropriate risk stratification. The other common clinical question is how to interpret cardiac troponin levels in patients without clinical features of ACS. There have been several reports suggesting that normal healthy people without cardiac disease may have very low, but detectable levels of troponin present at all times.6,7 This raises the intriguing possibility of cardiomyocyte turnover and renewal.8 Low levels of cardiac troponin have also been identified, and have been shown to be correlated with structural heart disease, diabetes mellitus and chronic kidney disease in a small percentage of the general population.9 Screening of asymptomatic elderly men for serum troponin predicted the risk of future cardiac events.10 Although troponin release has traditionally been thought to be caused by cardiomyocyte necrosis, recent information suggests that troponin may be released after ischaemia without necrosis in patients undergoing stress testing.11 A 10-fold increase in low-level troponin concentration has also been identified in athletes after marathon running.7 Elevated troponin levels are not uncommon in patients in intensive care units, and possible causes include supply/demand ischaemia and alterations in myocyte membrane permeability or leakage. The likelihood of ACS in these patients is low in the absence of usual symptoms or evidence of acute ischaemia or infarction. Cardiac troponin levels may also be elevated by non-coronary causes including myocarditis, aortic dissection, Tako-tsubo syndrome, pulmonary embolism, cardiac trauma, sepsis, tachycardia, severe heart failure, and “false positives” that include heterophile antibodies and analytical imprecision. All elevations in cardiac troponin concentrations, and particularly in low-level measurements, should be interpreted in the context of the pretest probability of ACS, as well as possible non-coronary causes of troponin release. In conclusion, our understanding and interpretation of troponin concentration and use of the new highly sensitive assays continue to evolve. This may offer us greatly enhanced opportunities for early diagnosis, risk assessment and improved management, but their widespread use will require clinical validation. More than ever before, however, there is a clinical imperative not to immediately equate detectable troponin concentration with ACS, but to interpret each result in its clinical context.

Con N Aroney MD, FRACP, FCSANZ · Peter E Hickman MB BS, PhD, FRCPA · Hans G Schneider MD, FRACP, FRCPA · Jillian R Tate BSc(Hons), MSc · Martin Than FACEM, FCEM

Objective: To examine the perception and management of cardiovascular disease (CVD) risk in Australian primary care.Design, setting and participants: The Australian Hypertension and Absolute Risk Study (AusHEART) was a nationally representative, cluster-stratified, cross-sectional survey of 322 general practitioners. Each GP was asked to collect data on CVD risk factors and their management in 15–20 consecutive patients aged ≥ 55 years who presented between April and June 2008, and to estimate each patient’s absolute risk of a cardiovascular event in the next 5 years.Main outcome measures: Estimated 5-year risk of a cardiovascular event, proportion of patients receiving appropriate treatment.Results: Among 5293 patients, 29% (1548) had established CVD. A further 22% (1145), when categorised according to the 2009 National Vascular Disease Prevention Alliance guideline, to 42% (2211), when categorised according to National Heart Foundation (NHF) 2004 guideline, had a high (≥ 15%) 5-year risk of a cardiovascular event. Of the 1548 patients with established CVD, 50% were prescribed a combination of a blood pressure (BP)-lowering medication, a statin and an antiplatelet agent, and 9% were prescribed a BP-lowering medication and a statin but not an antiplatelet agent. Among high-risk patients without established CVD, categorised using NHF 2004 adjustments, 34% were prescribed a combination of a BP-lowering medication and a statin. GPs estimated 60% of patients with established CVD as having a risk of less than 15%. The GPs’ estimates of risk among patients without established CVD agreed with the centrally calculated estimate (according to the NHF 2004 guideline) in 48% of instances (κ = 0.21).Conclusions: These data confirm substantial undertreatment of patients who are at high risk of a cardiovascular event. We recommend that GPs assess absolute risk for older patients and ensure that high-risk patients receive evidence-based pharmacotherapy.

Emma L Heeley BSc(Hons), MSc, PhD · David P Peiris MB BS, MIPH, FRACGP · Anushka A Patel MB BS, PhD, FRACP · Alan Cass MB BS, FRACP, PhD · Andrew Weekes BMedSci, BM BS · Claire Morgan BPhysio · Craig S Anderson MB BS, PhD, FRACP · John P Chalmers MD, PhD, FRACP

Clinical record An 88-year-old man presented to our emergency department with sudden loss of vision in his right eye. Past ocular history included amblyopia in his right eye and bilateral neovascular age-related macular degeneration (AMD). Previously recorded best corrected visual acuities were 6/120 and 6/18 in his right and left eye, respectively. The patient’s past medical history included acute myocardial infarction, atrial fibrillation, hypertension, hypercholesterolaemia and polymyalgia rheumatica. He had no history of diabetes, cerebrovascular accident or transient ischaemic attack. His medications included warfarin, aspirin, metoprolol, perindopril and simvastatin. His international normalised ratio (INR) had ranged between 1.3 and 2.3 over the preceding 12 months, with a target of 2.0. Visual acuity in the right eye was count fingers. Dilated slit lamp examination revealed a large submacular haemorrhage with associated vitreous haemorrhage (Figure A). An electrocardiogram showed atrial fibrillation with a heart rate of 72 beats/min. His blood pressure was 110/80 mmHg. His INR was 2.8. The eye was managed conservatively and, following resolution of the vitreous haemorrhage, vision remained at count fingers. Four months later, the patient reported sudden loss of vision in his left eye. Visual acuity was light perception, and dilated fundus examination revealed dense subretinal and associated vitreous haemorrhage (Figure B). The patient was still taking warfarin, and his INR at this time was 2.7. As this had been his better eye, he underwent pars plana vitrectomy and clearance of the vitreous haemorrhage. After surgery, his visual acuity was count fingers. After further discussion with the patient’s cardiologist, a decision was made to cease warfarin. A: Fundus photograph of the right eye at presentation, showing macular subretinal and intraretinal haemorrhage. The mild haziness of the photograph is indicative of vitreous haemorrhage. B: Fundus photograph of the left eye at the time of presentation of visual loss in this eye. Extensive subretinal haemorrhage is seen in the macula. Again, the haziness of the photograph is indicative of vitreous haemorrhage. This report highlights a potential interaction between a commonly used anticoagulant, warfarin, and an increasingly common ocular condition — AMD. The risk of AMD increases with age, with prevalence reaching 20% of people aged over 75 years in white populations.1 Neovascular (“wet”) AMD accounts for 10%–20% of cases,2 and for 80%–90% of patients who become legally blind from AMD.3 Peripheral vision is typically retained, and most patients are able to maintain a degree of functional independence. Development of large subretinal and vitreous haemorrhages in neovascular AMD is uncommon. Treatment options are limited and, even with surgical intervention, visual outcomes are in the range of light perception to counting fingers only, with significant loss of paracentral and peripheral vision.4 The functional effects are therefore profound. Previous studies have demonstrated an association between the use of anticoagulant medication, particularly warfarin, and large intraocular haemorrhages among patients with neovascular AMD.5,6 The largest of these, a retrospective case–control study comprising 100 patients, found that those with massive intraocular haemorrhage were 11.6 times more likely to be taking anticoagulant medication.6 Among these patients, INR ranged from 3.0 to 4.0. Patients with massive haemorrhage were twice as likely to be taking aspirin, although the significance of this finding is less certain, as the lower limit of the 95% confidence interval was less than 1. No patient was taking anticoagulants and aspirin concurrently.6 In our patient, the role of concurrent aspirin therapy is unclear, as there is no evidence in the literature to support or refute the hypothesis that concurrent antiplatelet therapy may have contributed to the development of haemorrhage. However, both instances of haemorrhage were noted to occur at times when his INR was high compared with those recorded over the previous 12 months. Our patient was taking aspirin at all times during this period. Although it is possible that intraocular haemorrhage may have occurred purely as a result of his underlying neovascular AMD, the temporal relationship between the development of the haemorrhages and the high INRs strengthens the case for the implication of warfarin therapy as a contributing factor. Application of the Naranjo probability scale7 indicates that this adverse drug event was probable (Naranjo score, + 5). The association between anticoagulant therapy and intraocular haemorrhage is of key importance for several reasons. Firstly, massive intraocular haemorrhage is an important diagnosis to consider in an anticoagulated patient who presents with loss of vision, and who has a background of neovascular AMD. Secondly, patients with neovascular AMD in one eye are at risk of developing neovascular AMD in the second eye,8 and therefore at risk of developing large intraocular haemorrhages in both eyes if long-term anticoagulation is continued. There are several clinical situations in which the indication for anticoagulation is relative. There are key roles for the ophthalmologist, cardiologist, and general practitioner to ensure that an appropriate risk–benefit evaluation is made before initiating anticoagulant therapy for patients with neovascular AMD. Patients taking anticoagulants who develop neovascular AMD, and in particular those with neovascular AMD who are taking anticoagulants and who develop intraocular haemorrhage in one eye, should have their therapy carefully re-evaluated. Importantly, awareness of the poor outcomes of intraocular haemorrhage in neovascular AMD, the role of anticoagulants as a risk factor, and effective communication between health professionals may help reduce the incidence of this devastating complication. Lessons from practice Patients with neovascular age-related macular degeneration (AMD) have a small but significant risk of intraocular haemorrhage, which may be increased in severity if patients are taking anticoagulant medication. The outcomes of intraocular haemorrhage are poor, with significant deterioration in paracentral and peripheral vision, and subsequent implications for ability to maintain functional independence. When considering anticoagulation therapy for patients with neovascular AMD, liaison between the general practitioner, cardiologist and ophthalmologist will ensure that an appropriate risk–benefit evaluation is made. If patients who take anticoagulant medication develop signs of neovascular AMD, it is essential that the ophthalmologist liaise with the GP and/or cardiologist to ensure that the need for anticoagulation, and the target international normalised ratio, are carefully reviewed.

Rajeev Chalasani MB BS · Salmaan Qureshi FRANZCO

The latest evidence for the essential elements of surgical prophylaxis protocols There is no question that antibiotic prophylaxis for cardiac surgery reduces surgical site infections.1 The successful implementation of prophylactic regimens, however, is often inconsistent or inadequate. The use of prophylaxis protocols or decision-support systems as either a single measure2 or as part of a patient care pathway3 has been demonstrated to improve adherence to prophylaxis, with a reduction in surgical site infections. In this issue of the Journal (page 141), a study by Haydon and colleagues4 shows that antibiotic prophylaxis protocol use in 45 Australian cardiac surgery units increased significantly between 2004 and 2008 (from 58% to 80%), but concordance with version 13 of the Australian Therapeutic guidelines: antibiotic5 was poor when both choice of agent and duration of administration were considered. In particular, there was an increased use of multidrug regimens, an increased use of vancomycin for routine prophylaxis, and a prolonged duration. The study did not examine surgical site infection rates. As prophylaxis protocols improve patient outcomes, and adherence to protocols in Australian cardiac surgery units seems to be high, it is timely to consider the optimum elements of such protocols in terms of timing of prophylaxis, duration of prophylaxis, and choice of agent. There have been a number of studies that show the relationship between timing of antibiotic administration and surgical site infections. An observational cohort study in a consecutive series of 3836 surgical procedures (vascular, trauma and abdominal) showed the optimal time for administration of β lactams was 30–60 minutes before incision.6 The risk-adjusted odds ratio of surgical site infections was 3.16 (95% CI, 1.4–7.0) if given 75–120 minutes before, 2.82 (95% CI, 1.5–5.3) for administration 15–29 minutes before, and 1.75 (95% CI, 0.9–3.4) if given in the last 14 minutes before incision. In a prospective study of 2048 patients given vancomycin prophylaxis for cardiac surgery (coronary artery bypass graft [CABG] or valve replacement), the optimum time for the start of a vancomycin infusion was shown to be 16–60 minutes before incision.7 The relative risk of infection was 7.8 (95% CI, 2.5–24.7) if started 0–15 minutes before incision and 2.2 (95% CI, 0.99–5.09) if started 61–120 minutes before. Duration of prophylaxis has been a controversial issue. The Society of Thoracic Surgeons practice guidelines8 recommend that prophylactic antibiotics be given for 48 hours or less, citing some evidence for effectiveness of single-dose or 24-hour regimens, but comment that additional studies are required to confirm the effectiveness of shorter courses. This has been addressed in a study on 838 patients undergoing CABG or valve replacement.9 Patients received cephazolin as either a single dose before incision or a prolonged regimen, with a dose before incision, then 8-hourly for 24 hours. There was a statistically significant difference in surgical site infections between the two groups (8.3% v 3.6%; P = 0.004). The choice of agent is mainly between a β lactam and vancomycin, although alternative choices are possible (eg, flucloxacillin plus gentamicin). The Society of Thoracic Surgeons practice guidelines10 recommend cephazolin for standard practice in populations that do not have a high incidence of methicillin-resistant Staphylococcus aureus (MRSA). Haydon et al’s study showed that routine vancomycin use for CABG surgical prophylaxis increased from 13% in 2004 to 44% in 2008, with similar increases seen for valve surgery — from 31% to 62% over the same period.4 Vancomycin prophylaxis for cardiac surgery is recommended in the current Therapeutic guidelines: antibiotic for institutions with a high prevalence of MRSA, for β lactam-allergic patients, or for procedures where there is a higher risk of infection with a coagulase-negative staphylococcus (eg, valve surgery, reoperations).5 Excessive vancomycin use is to be discouraged, as its activity is inferior to β lactam antibiotics for susceptible organisms and it will add selective pressure for hVISA (heteroresistant vancomycin-intermediate S. aureus), particularly if the duration of administration is prolonged. With the advent of rapid MRSA molecular detection tests, it is now possible to screen patients before surgery and use vancomycin selectively in those found to carry MRSA. An alternative is to use intranasal mupirocin routinely in the absence of a documented negative test for MRSA (and methicillin-sensitive S. aureus [MSSA]), as this agent has been shown to reduce both MSSA and MRSA surgical site infections.11 How do these recommendations relate to the Therapeutic guidelines: antibiotic? The current guidelines, version 13 (published in 2006),5 are concordant, except for the duration of therapy. It is very likely that this is the major issue that has resulted in the lack of adoption of the guidelines’ cardiac surgery prophylaxis regimens found by Haydon and colleagues. Version 14 of Therapeutic guidelines: antibiotic is currently in preparation and due to be published in 2010, and the recent studies described here have been noted by the writing committee. It is very likely that version 14 will recommend a 24-hour prophylaxis regimen and that the recommended antibiotic agents will remain unchanged. The purpose of any surgical prophylaxis protocol is to ensure adherence to the optimum choice of agent, timing of administration and duration of prophylaxis. With such adherence, surgical site infections will be minimised, thereby reducing morbidity and mortality for patients undergoing cardiac surgery.

Keryn J Christiansen MB BS, FRCPA

Objectives: To determine population lipid profiles, awareness of hyperlipidaemia and adherence to Australian lipid management guidelines.Design and setting: Population survey in rural south-eastern Australia, 2004–2006.Participants: Stratified random sample from the electoral roll. Data from 1274 participants (40%) aged 25–74 years were analysed.Main outcome measures: Population mean total, low-density lipoprotein and high-density lipoprotein cholesterol (TC, LDL-C and HDL-C) and triglyceride (TG) concentrations, prevalence of dyslipidaemia, and treatment according to 2001 and 2005 Australian guideline target levels.Results: Population-adjusted mean TC, TG, LDL-C and HDL-C concentrations were 5.38 mmol/L (95% CI, 5.30–5.45), 1.50 mmol/L (95% CI, 1.43–1.56), 3.23 mmol/L (95% CI, 3.16–3.30) and 1.46 mmol/L (95% CI, 1.44–1.49), respectively. Prevalence of hypercholesterolaemia (TC > 5.5 mmol/L or on treatment) was 48%. Lipid-lowering medication use was reported by 12%. Seventy-seven of 183 participants with established cardiovascular disease (CVD) or diabetes were untreated, and of the 106 treated, 59% reached the target LDL-C. Of those without CVD or diabetes already treated, 38% reached target LDL-C, and 397 participants at high absolute risk did not receive primary prevention. Ninety-five per cent of treated individuals with CVD or diabetes and 86% of others treated had cholesterol measured in the previous year. Sixty-nine per cent of individuals at low risk aged over 45 years had their cholesterol measured within the previous 5 years.Conclusions: A comprehensive national strategy for lowering mean population cholesterol is required, as is better implementation of absolute risk management guidelines — particularly in rural populations.

Edward D Janus MD, FRACP, PhD · Philip A Tideman MB BS, FRACP · James A Dunbar MD, FRCPE, FRACGP · Annamari Kilkkinen MSc, PhD · Stephen J Bunker PhD · Benjamin Philpot BSc, GradDip(ActuarialStud) · Rosy Tirimacco BSc · Kevin Mc Namara BSc, MSc · Sami Heistaro MD, PhD · Tiina Laatikainen MD, PhD

Objective: To evaluate national practice for antibiotic prophylaxis in cardiac surgery with respect to the use of protocols, agent selection and duration of administration.Design, setting and participants: Two point-prevalence surveys of intensive care units in 24 public and 27 private hospitals performing cardiac surgery in Australia, conducted in 2004 and 2008, using a structured telephone questionnaire of the attending senior intensive care clinician in each unit.Main outcome measures: Existence of a protocol in the unit for antibiotic prophylaxis, specific antibiotic agents used and their duration of administration.Results: Between 2004 and 2008, reported protocol use increased from 58% to 80% (P = 0.02), while concordance with version 13 of the Australian Therapeutic guidelines: antibiotic for both choice of agent and timing (duration of administration) remained around 10%. Use of multiple agents was common, as was continued antibiotic administration after completion of surgery. Over 4 years, the proportion of cardiac surgical units reporting vancomycin administration for routine valve surgery prophylaxis doubled to 62% (P < 0.001).Conclusion: Despite an increase in reported protocol use for antibiotic prophylaxis in cardiac surgery, concordance with national antibiotic guidelines remained low, with duration of antibiotic administration deviating most from recommendations. Prophylactic vancomycin use appears to have increased substantially in recent years. Clinical implementation of recommended perioperative cardiac surgical antibiotic prophylaxis may not occur until supported by evidence from either a large prospective randomised study or standardised national surveillance of cardiac surgical site infection rates.

Timothy P Haydon FRACP, FJFICM, FANZCA · Jeffrey J Presneill MB BS, MBiostat, PhD · Megan S Robertson FRACP, FJFICM, FANZCA

To the Editor: Congratulations on the 21 September 2009 issue of the Journal, highlighting preventive cardiology in Australia. I believe that the “working class man” of the well known Jimmy Barnes song has trouble affording preventive cardiology care in Australia. Assuming that he is currently employed, he will not be entitled to a Health Care Card and will be paying full price for care in general practice. There will be a gap of $20 to $60 between what he pays and the Medicare rebate per visit. He will have to pay about $30 per prescription. Assuming that he is taking antiplatelet agents, statins, and a blood pressure agent such as an angiotensin-converting enzyme inhibitor, he would be paying about $90 per month for medication. On an average income of $1200 per week1 ($800 after tax), and assuming that he visits his general practitioner monthly, preventive cardiology care might cost him about 4% of his disposable income. If our working class man is earning $900 weekly ($600 after tax), then preventive cardiology care would cost him 5% of his disposable income. Of course, the costs are similar for a wealthy man. However, the costs represent a far smaller percentage of his income than for the working class man. In this regard, the costs of preventive medicine are similar to the poll tax imposed in England in the 14th century. This regressive capitation tax was raised to pay for the imperial wars in France. However, the disproportionate burden it imposed on the serfs resulted in such anger that it led to the Peasants’ Revolt in 1381. Until medicine is funded more equitably, there will be a major disincentive to pursue preventive cardiology care for poorer people, who experience cardiovascular disease at an earlier age than their wealthier counterparts.2 The problem is not which model to use for absolute risk assessment,3 but the money to apply it.

V Michael Jelinek

Practical cardiology (+ CD ROM). 2nd ed. Tracey Baker, George Nikolic, Simon O’Connor. Sydney: Churchill Livingstone, 2008 (xxiii + 391 pp). ISBN 9780729538411. The first edition of Practical cardiology: an approach to the management of problems in cardiology, by Baker and O’Connor, appeared in 1999. This second edition includes a third author, George Nikolic. Baker is a Canberra general practitioner, while Nikolic and O’Connor are cardiologists at the Canberra Hospital. Larger than the first edition (391 pages versus 192), and including a supplementary CD of angiographic and echocardiographic video images, it is excellent value at $89.95. It is likely to be useful for GPs and their trainees, medical students and cardiac nurses, and could be read with profit by those training in general medicine or beginning advanced training in cardiology. The sections on case- or problem-based learning are practical, well done and worthwhile exercises for senior medical students and trainee physicians. There is a helpful chapter on clinical trials, although there is no mention of some of the important earlier studies (GISSI, ISIS, GUSTO, LATE, etc). There are useful sections on electrocardiography, arrhythmias, heart disease and non-cardiac surgery, coronary revascularisation, antiplatelet therapy, anticoagulants, heart disease in pregnancy and congenital heart disease. My primary concerns relate to the illustrations. Some of these have been reproduced poorly, so that, for example, the demonstration of rib notching in a chest radiograph of a patient with coarctation of the aorta is unconvincing, as are the illustrations of Kerley B lines and valve calcification. Some images of echocardiograms need more comprehensive labelling. The CD images are a worthwhile addition, but their value would also be enhanced by explanatory labels, diagrams or cartoons: intravascular or transoesophageal studies are unlikely to mean much to the uninitiated without such help. This book retains the attractive features of the first edition, in that it is concise, simple, authoritative and as up to date as we might expect of any publication when it deals with so rapidly changing a field as cardiology.

J H Nicholas Bett

Many patients with heart failure do not have reduced left ventricular ejection fraction, and it is not yet clear whether their treatment should be the same as that of patients who do The syndrome of heart failure is one that is familiar to most clinicians. The cardinal symptoms of dyspnoea and fatigue when combined with signs of fluid retention — lung crackles, elevated jugular venous pressure and peripheral oedema — usually lead one to the diagnosis. Indeed, the Framingham criteria for diagnosis of heart failure are based largely on clinical findings that can be elicited at the bedside.1 When combined with what most of us have been taught in medical school, namely, that heart failure is usually caused by the loss of the pumping capacity of the left ventricle (eg, after myocardial infarction or due to cardiomyopathy), clinicians have become familiar with the concept that most cases of heart failure are associated with impaired left ventricular systolic function, shown by a reduction in the left ventricular ejection fraction (LVEF). As if to reinforce this mindset, major trials of new treatments for heart failure have historically focused on the group of patients with reduced LVEF. Applying echocardiography and other diagnostic imaging modalities to patients with heart failure has led to the realisation that many patients, as many as half in some series, do not have a reduced LVEF. Several terms have been used to describe this population, such as “diastolic heart failure’”, “heart failure with normal systolic function” and “heart failure with preserved systolic function”. All three terms are problematic. Diastolic dysfunction is common in patients with impaired LVEF2 and many patients with preserved LVEF have unequivocal evidence of systolic dysfunction.3 My personal preference is for the term “heart failure with preserved ejection fraction” (HFPEF), as it makes no assumptions about the pathophysiology of heart failure in affected patients. Even this descriptor is not without its problems, as different investigators appear to have differing opinions as to what should be considered a “preserved” LVEF. Investigators in different studies have drawn the line between preserved and reduced LVEF at 50%,4 45%,5,6 40%,7 or even 35%.8 Needless to say, this diagnostic confusion does nothing to help clinicians who are trying to care for these patients. Is it important to distinguish HFPEF from heart failure with reduced ejection fraction (HFREF)? Are they simply different ends of a continuous disease spectrum, or do they represent distinct entities with different causes and different natural histories? Given that they present with the same clinical syndrome, should they be treated the same way? These are important questions for which we currently lack answers. Multiple studies that have compared the demographics and natural history of HFPEF and HFREF have now been published,9 including the study by Wong and colleagues in this issue of the Journal.10 A reasonably consistent finding across these studies has been that, compared with patients with HFREF, patients with HFPEF were older, more likely to be female and more likely to have pre-existing hypertension and atrial fibrillation. Conversely, ischaemic heart disease was more common in those with HFREF. Comparison of the survival of patients with HFPEF versus HFREF has produced conflicting data. While some studies have suggested that those with HFPEF have better survival than those with HFREF, others, including Wong et al,10 have shown no difference in survival. A recently published meta-analysis of the natural history of HFPEF compared with HFREF collected data from 17 studies that included 24 501 patients.9 In that analysis, patients with HFPEF had a significantly better survival than those with HFREF, although it is noteworthy that over an average follow-up of 47 months, almost a third of those with HFPEF had died, indicating that the life expectancy of this group of patients is far below that of the healthy age-matched population. The poor survival of patients with HFPEF was also emphasised in the study by Wong et al,10 and in another recent publication from the Framingham investigators.6 An important observation made by Wong and colleagues is that comorbid conditions and psychosocial factors are important determinants of the outcome of patients with HFPEF.10 They found that anaemia, chronic obstructive pulmonary disease, cancer and dementia were all more common in patients with HFPEF compared with those with HFREF.10 A higher rate of comorbid conditions in patients with HFPEF has also been noted by other investigators.6 In addition, patients with HFPEF had fewer social supports, were more likely to live in nursing homes, and were more likely to require readmission to hospital — mainly for management of comorbid conditions rather than for heart failure. The prognosis and quality of life for patients with HFREF has been markedly improved by the implementation of evidence-based treatments including therapy with β-blockers and inhibitors of the renin–angiotensin–aldosterone system. On the other hand, no treatment has been proven to alter the natural history of HFPEF. Treatment remains empirical, and is aimed at controlling associated conditions such as hypertension and symptoms and signs of fluid retention. Thiazide diuretics, a class of drugs that has largely fallen out of favour for treating hypertension and HFREF, may yet prove to be the most effective drug class for preventing HFPEF. In a recent analysis of the very large ALLHAT trial of patients with hypertension and aged over 55 years,4 antihypertensive treatment with chlorthalidone was associated with a lower risk of developing HFPEF when compared with treatment with lisinopril, amlodipine or doxazosin. Therapeutic trials of other drug classes in HFPEF have been limited, and generally disappointing. Angiotensin-receptor blockers have been the most studied class of drugs, and have been shown in two large trials to have no impact on survival.5,7 β-Blockers appear more promising. In a prespecified analysis of the SENIORS study of the vasodilating β-blocker nebivolol in older patients with heart failure,8 the investigators reported similar benefits of nebivolol in patients with either HFPEF or HFREF; however, the definition of HFPEF in that study was an LVEF of greater than 35%. Clearly, more trials are needed. As our population continues to age, we are facing an impending epidemic of HFPEF together with other diseases associated with ageing. More effective blood pressure control of patients with systemic hypertension stands out as the most obvious preventive strategy, but it is clear that hypertension is only one of a number of antecedents to HFPEF. There is an urgent imperative to gain a better understanding of the pathogenesis of HFPEF in order to identify additional preventive and treatment approaches. This will be particularly challenging in a population exposed to multiple comorbid conditions, increasing physical frailty, and social isolation, as highlighted by Wong and colleagues.10 Optimal management of these patients will require a multidisciplinary approach with the general practitioner taking the central role.

Peter S MacDonald MB BS, FRACP, PhD

Objective: To determine whether heart failure with preserved systolic function (HFPSF) has different natural history from left ventricular systolic dysfunction (LVSD).Design and setting: A retrospective analysis of 10 years of data (for patients admitted between 1 July 1994 and 30 June 2004, and with a study census date of 30 June 2005) routinely collected as part of clinical practice in a large tertiary referral hospital.Main outcome measures: Sociodemographic characteristics, diagnostic features, comorbid conditions, pharmacotherapies, readmission rates and survival.Results: Of the 2961 patients admitted with chronic heart failure, 753 had echocardiograms available for this analysis. Of these, 189 (25%) had normal left ventricular size and systolic function. In comparison to patients with LVSD, those with HFPSF were more often female (62.4% v 38.5%; P = 0.001), had less social support, and were more likely to live in nursing homes (17.9% v 7.6%; P < 0.001), and had a greater prevalence of renal impairment (86.7% v 6.2%; P = 0.004), anaemia (34.3% v 6.3%; P = 0.013) and atrial fibrillation (51.3% v 47.1%; P = 0.008), but significantly less ischaemic heart disease (53.4% v 81.2%; P = 0.001). Patients with HFPSF were less likely to be prescribed an angiotensin-converting enzyme inhibitor (61.9% v 72.5%; P = 0.008); carvedilol was used more frequently in LVSD (1.5% v 8.8%; P < 0.001). Readmission rates were higher in the HFPSF group (median, 2 v 1.5 admissions; P = 0.032), particularly for malignancy (4.2% v 1.8%; P < 0.001) and anaemia (3.9% v 2.3%; P < 0.001). Both groups had the same poor survival rate (P = 0.912).Conclusions: Patients with HFPSF were predominantly older women with less social support and higher readmission rates for associated comorbid illnesses. We therefore propose that reduced survival in HFPSF may relate more to comorbid conditions than suboptimal cardiac management.

Dennis T Wong MB BS(Hons) · Robyn A Clark PhD, FRCNA · Benjamin K Dundon MB BS, FRACP · Andrew Philpott MB BS, FRACP · Payman Molaee MB BS, FRACP · Sepehr Shakib PhD, FRACP

To the Editor: We describe two liver transplant patients who presented with unexplained dyspnoea and were subsequently found to have unilateral right diaphragmatic palsy, an uncommon complication of orthotopic liver transplantation.1-3 Both transplant recipients were male. One, aged 64 years, had a liver transplant in 2005 for hepatitis C-related chronic liver disease. The other, aged 66 years, had a liver transplant in 2004 for end-stage alcoholic liver cirrhosis. Both patients had presented with exertional dyspnoea several weeks after transplantation. Both were reformed smokers with no prior respiratory symptoms or established respiratory or cardiac condition. Preoperative pulmonary function tests had been essentially normal in both patients (Box 1). Chest x-rays of both patients during the postoperative convalescence period showed unilateral elevation of the right hemidiaphragm compared with the immediate pre-transplant images. (Images for Patient 1 are shown in Box 2.) Fluoroscopic study (the “sniff test”) and a computed tomography scan of the chest confirmed the presence of right hemidiaphragmatic palsy in both patients. Follow-up chest x-rays and pulmonary function tests over 2 years showed no significant improvement. In both patients, the postoperative clinical course over these 2 years was characterised by recurrent hospital admissions with hypoxaemia and intercurrent respiratory tract infections, some requiring supplemental oxygen therapy, non-invasive positive pressure ventilation and invasive ventilation in the intensive care unit. Currently, one of these patients is well, apart from dyspnoea on moderate exertion. The other patient died from a cause unrelated to his diaphragmatic palsy. Unilateral diaphragmatic palsy following liver transplantation is thought to be related to traumatic crush injury to the right phrenic nerve from a clamp placed on the inferior vena cava (IVC) during surgery.1 The proximity of the phrenic nerve to the IVC renders it very vulnerable to this type of injury from side-to-side cross-clamping of the suprahepatic IVC.1,2 In 2008, we modified our technique to avoid cross-clamping of the IVC by performing cavocavostomy, a type of “piggyback” technique that involves “side-biting” (partial clamping) of the retrohepatic IVC away from the diaphragm.4 Unilateral diaphragmatic palsy can reduce exercise tolerance5 and may place additional mechanical stress on ventilation, which could exacerbate hypoxaemia if these patients develop intercurrent pulmonary infections. Reporting on a series of patients with phrenic nerve injury after liver transplantation, McAlister and colleagues1 found right hemidiaphragmatic palsy in 38% of patients after transplantation, but most of the patients recovered their diaphragmatic function within 9 months. In contrast, our patients did not show any signs of recovery for over 2 years, indicating that loss of diaphragmatic function after liver transplantation may be longstanding or permanent. 1 Comparison of pulmonary function tests before and after orthotopic liver transplantation* Patient 1 Patient 2 Pulmonary function test Before transplant After transplant Difference Before transplant After transplant Difference FEV1 (% of predicted) 2.72 L (80%) 1.73 L (51%) – 29% 2.78 L (85%) 1.40 L (47%) – 38% FVC (% of predicted) 3.79 L (87%) 2.41 L (56%) – 31% 3.83 L (92%) 2.17 L (57%) – 35% FEV1/FVC 0.72 0.72 0.73 0.65 TLC (% of predicted) 5.81 L (87%) 4.28 L (62%) – 25% 7.09 L (110%) 5.18 L (86%) – 24% FEV1 = forced expiratory volume in 1 second. FVC = forced vital capacity. TLC = total lung capacity. * Tests were performed while the patients were in a clinically stable condition. 2 Erect chest x-rays before and after orthotopic liver transplantation, Patient 1 A: In 2005, before liver transplant. B: In 2006, 6 months after liver transplant. Note marked elevation of the right hemidiaphragm and presence of bilateral calcified pleural plaques.

H S Subhash · John W C Chen · Libby John · Jeffery J Bowden · Dimitar Sajkov · Peter Frith

Objectives: To compare the use of evidence-based pharmacological and invasive treatments and 12-month mortality rates between patients with and without diabetes who present with acute myocardial infarction (MI), and to explore the relationship between these treatments and late clinical outcomes.Design and setting: Prospective, nationwide multicentre registry: the Acute Coronary Syndrome Prospective Audit (ACACIA).Patients: Patients presenting to 24 metropolitan and 15 non-metropolitan hospitals with acute coronary syndrome (ACS) and a final discharge diagnosis of acute MI between November 2005 and July 2007.Main outcome measure: All-cause mortality at 12 months.Results: Nearly a quarter of 1744 patients with a final diagnosis of acute MI had a history of diabetes on presentation. Patients with diabetes were older, with a greater prevalence of comorbidities than non-diabetic patients, and were less likely to be treated at discharge with evidence-based medications (aspirin, clopidogrel, a statin and/or a β-blocker) or to receive early invasive procedures. After adjusting for baseline characteristics and therapeutic interventions, diabetes at presentation was independently associated with a higher mortality at 12 months after MI (hazard ratio, 1.79; 95% CI, 1.18–2.72; P = 0.007). Early invasive management and discharge prescription of guideline-recommended medications were associated with a significantly reduced hazard of mortality at 12 months.Conclusion: Patients with diabetes have a higher risk than non-diabetic patients of late mortality following an acute MI, yet receive fewer guideline-recommended medications and early invasive procedures. Increased application of proven pharmacotherapies and an early invasive management strategy in patients with diabetes presenting with ACS might improve their outcomes.Study protocol number (sanofi-aventis): PML-0051.

Joseph Hung FRACP, FACC, FCSANZ · David B Brieger PhD, FRACP, FCSANZ · John V Amerena FRACP, FACC, FCSANZ · Steven G Coverdale MB ChB, FRACP · James M Rankin MB BS, FRACP · Carolyn M Astley RN, BN(Hons) · Ashish Soman MB BS, MRCP(UK) · Derek P Chew MB BS, MPH, FRACP