Cardiovascular diseases

To the Editor: Evidence is beginning to accumulate on the effectiveness of the low-density lipoprotein (LDL) cholesterol-lowering medicine ezetimibe. While there are no completed trials investigating ezetimibe’s effect on clinically important end points, two recent trials investigating its effect on carotid intima media thickness (CIMT) have both reported disappointing results.1,2 After each of these trials, the Journal has published editorials by Hamilton-Craig, who offers reassurance about ezetimibe and encourages ongoing prescription of this drug to patients who have elevated LDL levels despite maximum-tolerated statin therapy.3,4 Such a sanguine opinion seems at odds with the negative trial evidence, and therefore worthy of debate. Briefly, the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, which compared ezetimibe plus simvastatin with simvastatin treatment alone in 720 patients with familial hypercholesterolaemia, found no significant difference (and a trend in the direction of harm) with respect to the primary end point of CIMT.1 The ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 — HDL and LDL Treatment Strategies in Atherosclerosis) trial compared ezetimibe with extended-release niacin in statin-treated patients with coronary heart disease.2 Among 315 patients with available results, the group taking niacin showed a statistically significant reduction in CIMT, but the group taking ezetimibe showed no such reduction. Of concern, increased cumulative exposure to ezetimibe was associated with progression of CIMT (P = 0.05). Although far from definitive, the results of these two trials offer no reassurance of benefit from ezetimibe and, in my view, may portend harm. It may seem counterintuitive that ezetimibe, which significantly lowers LDL cholesterol levels,1,2 could be ineffective or harmful. However, the history of medicine is replete with examples of interventions that improve numerical disease measures without benefit to patients. One recent example was torcetrapib, which, despite increasing high-density lipoprotein cholesterol and reducing LDL cholesterol levels in a promising manner, was found to cause serious adverse events, including death.5 I agree with Hamilton-Craig that we require trials measuring major cardiovascular events to really understand the effects of ezetimibe. Where we disagree is how to manage our patients during the period of uncertainty until publication of the results of these trials. While he argues for continued prescribing of ezetimibe, I suggest we should explicitly share our uncertainty about the safety and efficacy of this drug with our patients by discussing the existing research. Some patients will, like Hamilton-Craig, place their faith in the cholesterol hypothesis and be reassured by an assumption of cardiovascular protection as their LDL falls. Others will choose to wait until we have more robust evidence that ezetimibe is safe and effective. I would wait.

Brett D Montgomery

In reply: I agree with Montgomery that cardiovascular disease (CVD) outcomes are required to determine the role of ezetimibe. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (in which patients with aortic stenosis were treated for 52.2 months with statin plus ezetimibe or statin plus placebo) showed a 4.7% reduction in ischaemic CVD events in the ezetimibe group (P = 0.02; number needed to treat, 23), driven by a reduced need for coronary artery bypass grafting.1 In contrast to previous trials showing regression of atherosclerosis in response to statin therapy, baseline carotid intima media thickness (CIMT) levels in the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial were normal, due to previous statin therapy. This is likely to account for the lack of change in CIMT with ezetimibe treatment in the ENHANCE trial.2 As no placebo group was included, neither lack of benefit nor harm from ezetimibe therapy can be inferred.2 Data from animal studies have shown atherosclerosis regression after ezetimibe treatment through multiple mechanisms.3-5 Prospective randomised controlled trials with statins, resins or surgery have independently shown an approximate 1% reduction in CVD per 1% reduction in low-density lipoprotein cholesterol (LDL-C) level. Evidence for the benefits of lowering LDL-C is among the most robust in medicine. Pending the outcomes of IMPROVE-IT (the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, a multicentre study of ezetimibe plus simvastatin versus simvastatin treatment of patients with acute coronary syndrome [http://clinicaltrials.gov/ct2/show/NCT00202878]), or clinical outcome data confirming those of the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6 — HDL and LDL Treatment Strategies in Atherosclerosis) trial,6 it seems reasonable to continue to use ezetimibe to lower LDL-C levels in patients who are not achieving LDL-C targets despite statin therapy or who are intolerant to statins. Extended-release nicotinic acid (Niaspan [Abbott Laboratories, Chicago, Ill, USA]) may be an appropriate alternative to statins as second-line therapy, and should be made available under the Pharmaceutical Benefits Scheme for treating patients with dyslipidaemia. (Niaspan has approval from the Therapeutic Goods Administration for marketing in Australia, but is not being imported into Australia at this stage.)

Ian R Hamilton-Craig

To the Editor: In his letter1 regarding Heeley et al’s article on cardiovascular risk perception and evidence–practice gaps in Australian general practice,2 Radford quotes, “no [automated blood pressure-measuring machines] were accurate enough to ... replac[e] a manual sphygmomanometer”. The citation dates from 1973, when oscillometric blood pressure monitors such as the Omron HEM-907 — distributed by the High Blood Pressure Research Council of Australia (HBPRCA) with support from the Servier Foundation — did not exist. In defence of digital blood pressure devices, a cluster randomised controlled trial conducted in Australian general practice has demonstrated their superiority compared with existing manual devices.3

Mark R Nelson

Objectives: To assess whether a collaborative interdepartmental pathway involving emergency department (ED) physicians activating the cardiac catheterisation laboratory (CCL) with immediate patient transfer to the CCL reduces door-to-balloon (DTB) times for patients with suspected ST-elevation myocardial infarction (STEMI).Design, setting and participants: A quasi-experimental before-and-after observational study using a prospective database, supplemented by chart review, of consecutive patients transferred from the ED to the CCL for suspected STEMI, from January 2007 to October 2009, at Sir Charles Gairdner Hospital, an adult tertiary-care hospital, Western Australia.Main outcomes measures: Median DTB time and proportion of patients with DTB time of < 90 minutes. Secondary outcomes, based on analysis of predefined subgroups, included door-to-activation time, activation-to-balloon time and false-positive activations of the CCL.Results: Two hundred and thirty-four patients underwent emergency coronary angiography for suspected STEMI, with 188 (80%) undergoing percutaneous coronary intervention (118 before and 70 after implementation of the new pathway). Following implementation of the new pathway, median DTB time reduced from 97 to 77 minutes (P < 0.001), median door-to-activation time from 28 to 15 minutes (P = 0.002) and median activation-to-balloon time from 66 to 53 minutes (P < 0.001). The proportion of patients with recommended DTB time of < 90 minutes increased from 41% to 77% (P < 0.001) with no change in false positive CCL activation rates (12% v 11%; P = 0.38).Conclusion: ED physician activation of CCL with immediate patient transfer is associated with highly significant improvements in DTB time without increased false positive rates.

Alexander B Willson MB BS(Hons), MPH, FRACP · David Mountain MB BS, FACEM · Joanne M Jeffers MB BS · Cheryl G Blanton MSc · Brendan M McQuillan MB BS, PhD, FRACP · Joseph Hung MB BS, FRACP, FCSANZ · Michael H Muhlmann MB BS, FRACP · Michael C Nguyen MB BS, FRACP

Prompt myocardial reperfusion, particularly if achieved within 2 hours of the onset of symptoms, improves outcomes in patients with ST-elevation myocardial infarction (STEMI). Recent data suggest that ambulance-administered prehospital thrombolysis, if given within 2 hours of the onset of STEMI, produces superior outcomes to primary percutaneous coronary intervention (PCI); if given within 4 hours, the outcomes are similar. For optimal results after thrombolysis, patients require angiography (and PCI where appropriate) within 24 hours of the event. These developments have major implications for the practice of cardiology and for the organisation of health services in Australia.

Richard W Harper MB BS, FRACP, FACC · Jeffrey Lefkovits MB BS, FRACP, FCSANZ

Evidence concerning the safety of rosiglitazone continues to evolve In February 2010, the United States Senate Committee on Finance released a report on the safety of rosiglitazone.1 The report concluded that there were possible cardiac risks associated with rosiglitazone and that the manufacturer, GlaxoSmithKline (GSK), was aware of this well before it became public. The authors further stated that, rather than warn patients and regulatory authorities promptly, GSK executives chose to intimidate independent physicians who publicised the possible risks, minimise the impact of adverse findings, and downplay the possibly beneficial cardiovascular effects of the other available drug in the class, pioglitazone.1 A week before the Finance Committee report was released, an editorial by Steve Nissen, lead author of the meta-analysis that first raised cardiovascular concerns regarding rosiglitazone in 2007,2 was published online.3 The editorial related to an article on the increased risk of heart failure, a recognised adverse effect of glitazones, found in the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial.4 However, it was more a detailed account of the sequence of events surrounding rosiglitazone’s possible adverse cardiovascular effects, starting with its US approval in 1999. The editorial viewed the RECORD trial (the main results of which were published mid 20095 but not considered in the Finance Committee report) as underpowered, despite demonstrating that rosiglitazone was non-inferior to metformin or sulfonylurea for the primary endpoint of cardiovascular hospitalisation or death. Although there were no new safety concerns or efficacy data in either the Finance Committee report or Nissen’s editorial, there was a prompt media response. The New York Times, for example, highlighted a suggestion by the Finance Committee that if every diabetic patient in the US taking rosiglitazone was given pioglitazone instead, 500 heart attacks and 300 cases of heart failure would be averted every month.6 There was also a quick response from GSK, which categorically rejected the findings of the Finance Committee and the assertions of the New York Times in separate media statements, and published a point-by-point response to Nissen’s editorial.7 More recently, the results of a retrospective analysis of US Medicare data for older patients8 and an expanded meta-analysis from Nissen’s group,9 both suggesting adverse cardiovascular effects of rosiglitazone, have contrasted with a post-hoc analysis of data from the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes study, in which rosiglitazone was found to be of significant benefit in patients with established coronary artery disease.10 At present, rosiglitazone remains approved for use in Australia as monotherapy or as part of dual oral combination therapy with metformin or a sulfonylurea,11 although only the combination therapy is subsidised by the Pharmaceutical Benefits Scheme. The product information contains a boxed warning for patients with known ischaemic heart disease, particularly those taking nitrates, and highlights the increased risk of myocardial ischaemia found in pooled short-term clinical studies.11 In the US and Europe, rosiglitazone remains available despite the recent media reports. The US product information has similar warnings to those of the Australian version, while the European version has the general recommendation that the drug not be used by patients with ischaemic heart disease and/or peripheral arterial disease. One possible reason why rosiglitazone was not withdrawn in 2007 is that the statistical methods used in the original meta-analysis2 were questionable. Alternative reasonable approaches can yield increased or decreased risks that are either statistically significant or not significant for both myocardial infarction and cardiovascular death.12 As there are no trials with cardiovascular events as the primary endpoint showing benefit of pioglitazone over other therapies, the most compelling evidence for its apparently better cardiovascular profile comes from a similar meta-analysis to that for rosiglitazone.3 A cardiovascular disease outcome study of rosiglitazone versus pioglitazone is, therefore, justifiable and in progress (Thiazolidinedione Intervention with Vitamin D Evaluation [TIDE]; ClinicalTrials.gov NCT00879970). Nevertheless, TIDE might become a casualty of the recently reactivated controversy before it reports in 2015, as the Endocrinologic and Metabolic Drugs Advisory Committee of the US Food and Drug Administration (FDA) continues to review the ethical and clinical implications of the available rosiglitazone safety data. Although the debate about the safety of rosiglitazone has centred on cardiovascular risk, a further potential concern is fracture.13 The deleterious effects of glitazones on bone emerged in animal studies dating back to 1996. Unfortunately, despite knowledge of these data, neither glitazone manufacturer included prespecified bone loss parameters and endpoints in any clinical trial. However, retrospective analyses of data from blood glucose-lowering efficacy trials involving rosiglitazone and pioglitazone, reported in 2006 and 2007, respectively, confirmed an increased fracture risk in humans.13 Given that these drugs have been available in Australia and most other countries for only 10 years, their long-term effect on fracture rates is worrying, especially in postmenopausal women. Glitazone therapy can improve glycaemic control in patients with type 2 diabetes, but patients should be selected according to drug-specific contraindications and warnings, the glycaemic effect should be reviewed after at least 3 months to confirm response, and adverse effects including weight gain, fluid retention and reduced bone density should be monitored during continued use. The recent adverse publicity regarding rosiglitazone highlights issues that can arise when drugs are approved and marketed without definitive efficacy and safety data. There is a need for pharmaceutical companies, academia and regulatory authorities to use preclinical and early phase clinical data to identify, through careful phenotyping, the patient population with the most potential for benefit and the least potential for harm when new drugs are being evaluated for registration. One important consequence of the rosiglitazone controversy is that adequately powered Phase IV cardiovascular safety studies are now required by the FDA when new therapies for diabetes are registered.3 The promise of the glitazones was that they targeted one of the central pathophysiological defects in type 2 diabetes, namely insulin resistance, and improved markers of cardiovascular risk including serum C-reactive protein and microalbuminuria. Unfortunately, based on a variety of clinical trials and observational studies, they do not appear to have a consistent cardiovascular advantage over established blood glucose-lowering agents, including metformin and sulfonylureas.

Timothy M E Davis MB BS, DPhil, FRACP · Johannes B Prins MB BS, PhD, FRACP

To the Editor: As a long-time resident of the “swamp of uncertainty” which is general practice — where specialists dare not go — I am accustomed to receiving guidelines and consensus statements from esteemed colleagues and friends who have taken to studying some specific part of the human condition. But these statements inevitably involve primary care, where general practitioners try to achieve balance. Balance is hard to achieve. The “gastro-partialist” thinks that everyone should be on a proton-pump inhibitor. On the other hand, the “osteo-partialist” thinks no-one should be on a proton-pump inhibitor because they stop calcium absorption and double the risk of hip fracture after 10 years. I could go on. However, here I wish to comment on Heeley and colleagues’ article on the perception and management of cardiovascular disease (CVD) risk in Australian primary care.1 Two of the authors are paid by Servier — the company which provided GPs with free automated blood pressure-measuring machines (ABPMs). A review in the American Journal of Cardiology concluded that no ABPMs were accurate enough to be recommended for replacing a manual sphygmomanometer,2 particularly in older people, in whom vessel stiffness leads to overestimation.3 In the study by Heeley et al, ABPMs were used by 90% of the GPs. Australia’s Therapeutic guidelines: cardiovascular say that the blood pressure treatment target should be 140/90 mmHg for all patients.4 It quotes the Cochrane review, which states: A sensitivity analysis in diabetic patients and in patients with chronic renal disease ... did not show a reduction in ... mortality and morbidity outcomes with lower targets as compared to standard targets.5 Heeley et al have used other guidelines. Based on the data provided by Heeley et al, about 17% of the patients in their study were aged over 75 years. Risk calculators do not usually go beyond 74 years, but it appears that with all risk factors at optimum levels, a 75-year-old man still has greater than 15% 5-year risk of a cardiovascular event (ie, a high risk). Being 75 years old is risky! Trying to treat a 75-year-old man’s blood pressure is particularly risky because evidence suggests that there is a paradoxical increase in cardiovascular mortality in men aged over 75 years whose blood pressure is lowered by treatment.6 Heeley and colleagues also stated that “two thirds of patients at high risk of a first CVD event were not prescribed a combination of a [blood pressure]-lowering medication and a statin”. Considering the 17% of patients who were older than 75 years, although the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial showed a reduction in cardiovascular mortality within this age group, there was no reduction in overall mortality.7 So why would a GP treat such patients when overall mortality is not reduced? I imagine that some GPs undertreat because they anticipate poor compliance, because uncorrectable factors are so great that pharmacological interventions will have a miniscule effect, or because the side effects of drug doses needed to achieve guideline targets will be problematic. Maybe they also feel that their ABPMs read a bit high! Balance is an unconscious compromise between real evidence and what is achievable. We need to consider the whole as well as the part if guidelines are to be clinically relevant.

Peter J Radford

In reply: We thank Radford for his insightful comments, seasoned with spice from the frontline of primary care. Although guidelines are an accepted part of clinical practice, they are just recommendations and are not without their limitations. Treatments need to be individually tailored according to many factors. Our aim, therefore, was to provide a current snapshot of adherence to cardiovascular guidelines in primary care in Australia.1 It would be naive of us to think that there would be complete adherence to the guidelines in the “real world”. We wished to obtain an overall benchmark figure and, more importantly, identify treatment gaps or disparities in care across important patient subgroups defined by risk of cardiovascular event. We recognise that digital blood pressure (BP) monitors are no better than mercury sphygmomanometers and require frequent (6-monthly) calibration. However, BP measurement technique is a far more important issue. The use of digital BP monitors in our study provided a standardised measurement machine, but we had no influence on their use or on BP measurement technique. Radford makes a good point regarding the absence of direct randomised trial evidence for the benefit of more intensive BP lowering. The BP target of less than 140/90 mmHg in individuals who are at high risk of a cardiovascular event, such as those with diabetes or chronic renal failure, is a sensible extrapolation from consistent observational epidemiological data. There is, however, convincing evidence of the benefits of multifactorial cardiovascular risk intervention among individuals at high risk.2 We also believe that the available data from randomised trials3,4 provide support for the efficacy of lowering BP in the elderly, and are more robust than the observational data cited by Radford. Similarly, systematic analysis of randomised trials of statin therapy supports efficacy of treatment in older patients.5 Despite their limitations, we believe that current evidence-based recommendations regarding preventive therapies are appropriate guidelines for managing patients who are at risk of a cardiovascular event. As with any guidance for clinical decision making, the application of these recommendations needs to take into account individual patient characteristics and circumstances. Finally, we believe that Servier’s support for this study demonstrates a successful academia–industry partnership. The academic partners had full control of the study design, analyses and publications.

Emma L Heeley · Craig S Anderson · Anushka A Patel · Alan Cass · David P Peiris · John P Chalmers

To the Editor: It seems that the perceived value of invasive therapy for different acute coronary syndromes varies according to how one chooses and values the various trials.1-3 The differing opinions may have been enriched had they not only considered short-term cardiovascular outcome but also weighed quantitatively — in absolute terms — the purported benefits (or lack thereof) of invasive therapy against the immediate complications and the long-term risks and burden of the combined aspirin and clopidogrel antiplatelet therapy usually necessary after stent placement. It may be that with all this information, patients also have a range of opinions regarding benefits and risks.4 It is difficult to deny that cardiologists in general and the industry sponsors of academic cardiology have an enormous vested interest in complicated, expensive therapies. It does not necessarily follow that the current guidelines and their defenders are unduly biased, but nevertheless the conflict of interest should be confronted and addressed, not taken personally, defensively and indignantly.2 Ideally, the guidelines would both be genuine and seen to be so. For conservative physicians, there is also a conflict of interest of sorts in that a conservative interpretation of the literature supports their practice. Forge’s suggestions regarding this issue should be taken more seriously.1 This problem of vested interest is, however, not confined to cardiology. Recently, while highlighting vested interest in mammography, Quanstrum and Hayward broadened their scope and suggested that “independent panels of generalists . . . [be] responsible for objectively synthesizing the medical evidence around a given question or process of care”.5

Stephen P Fitzgerald

To the Editor: In her editorial, Christiansen states that the 2010 edition of Therapeutic guidelines: antibiotic (version 14) is very likely to recommend 24 hours of antibiotic prophylaxis for cardiac surgery,1 rather than the present regimen, which recommends that patients having routine cardiac surgery be given a large dose of cephazolin at induction, with a second dose if the operation is prolonged for more than 3 hours, and no doses after surgery.2 The only evidence presented in support of this proposed change is a single randomised controlled trial that purported to show a higher rate of surgical site infections after a single dose of cephazolin, than after a prolonged, multidose regimen.3 The study was flawed, for two reasons. First, cephazolin was not given until 20–30 minutes after induction of anaesthesia, which is likely to have been too late, because, as Christiansen points out, β-lactams should be given 30–60 minutes before incision.1 Second, the trial was analysed on a per-protocol, rather than an intention-to-treat basis, and 189 of the 1027 participants (18%) were excluded, so the findings may be seriously biased.4 Three other trials have compared one or two doses of a cephalosporin with multiple doses of the same antibiotic in patients having cardiac surgery; none found that multiple doses were superior, although all three were small studies with faults in their design.5-7 In 1998, McDonald and colleagues published a detailed review of single versus multiple doses of antimicrobial prophylaxis for major surgery. The analysis was in response to a suggestion by Christiansen and others that single-dose antibiotic prophylaxis may be inadequate for patients undergoing vascular surgery.8 McDonald and colleagues pointed out that the recommendation for single-dose surgical prophylaxis in Therapeutic guidelines: antibiotic (version 13),2 is based on microbiological first principles, published studies reporting efficacy, convenience of administration, reduced antibiotic resistance and toxicity, and relatively low cost. Their careful analysis of 28 randomised trials, in which the same antimicrobial was used in each arm, showed no advantage from the administration of multiple doses; the odds ratio for infection was 1.06 (95% CI, 0.89–1.25). There is no microbiological reason to suppose that the crucial interaction between contaminating bacteria and the prophylactic antibiotic in the heart is any different from that in the lung, biliary tree, uterus, bowel, prostate or bone.8 In the absence of such evidence, there is no sound reason to change the current, long-standing Therapeutic guidelines: antibiotic2 recommendation.

Frank Shann

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