Cardiovascular diseases

Non-surgical intervention has many benefits. A recent article published in the Journal1 was widely reported in the popular press, with statements such as the following being quoted: public health messages encouraging people to eat healthy food and to exercise are unlikely to have long-term impact on their weight....

Daniel J Green PhD · Andrew J Maiorana PhD

Plotting the trajectory of some common artery conditions.

on behalf of the REACH Registry Investigators

Do you need to “know your numbers”? “Know your numbers” was the public catchcry on World Hypertension Day 2011, and doctors were once again admonished to measure their patients’ blood pressure levels. The National Institute for Health and Clinical Excellence (NICE) in the United Kingdom has gone one step further and now recommends that all patients in whom hypertension is suspected be offered ambulatory blood pressure monitoring to confirm the diagnosis.1 A recent report suggested this approach is cost-effective,2 although other research findings suggest that the precise measurement of blood pressure may not be very important when selecting whom to treat.3-4 Indeed, a recent report suggested that age alone might be a sufficient basis for decision making.5 What then is the role of ambulatory blood pressure monitoring in clinical practice? The past few decades have seen huge advances in our understanding of how blood pressure causes illness. At the heart of these advances has been the recognition that blood pressure causes disease in a progressive way across a broad range of blood pressure levels, and not just when an individual crosses a diagnostic threshold for “hypertension”.1 “Hypertension” cut-points, as variously set over the past half century, are now recognised as arbitrary levels on a continuous scale; and while they were a pragmatic solution at the time, their limitations are now widely understood.6 The development of risk-based approaches to allocating blood pressure-lowering treatment has been equally important.7 Under the risk-based model, the effects of blood pressure, age, sex, blood lipid levels and the presence or absence of smoking and diabetes all play a role in the decision whether or not to treat the patient with blood pressure-lowering therapy. Further, it is the blood pressure level, not the presence or absence of hypertension, that is incorporated into the decision-making process. Compared with traditional hypertension control programs, strategies that allocate blood pressure-lowering treatment based on measures of risk are projected to avert more disease for fewer people treated and at lower cost.8 Risk-based strategies are superior in this way because they direct treatment towards those most likely to gain from therapy. A diagnosis of hypertension on its own is a poor discriminator of risk, and assessment based on multiple risk factors is much better for identifying those who will benefit.8 The discriminatory power of risk-based strategies is only marginally improved by more precise measurement of the risk factors.3 The usual day-to-day variability of blood pressure for an individual is large, which means that many, many measurements are required to define an individual’s blood pressure level with real precision.9 This is a real problem when trying to categorise a patient as above or below a hypertension cut-point, but less important when blood pressure is treated continuously and is just one of half a dozen factors influencing the treatment decision. In deciding the potential value of ambulatory blood pressure monitoring to clinical practice, it is important to understand that showing that ambulatory blood pressure is more strongly associated with risk is not in itself sufficient. To be of real clinical value, it must also more reliably select those who will benefit from intervention. Recent economic analyses2 showed that routine ambulatory blood pressure measurement was superior compared with strategies based on home or clinic measurements because it made more reliable diagnoses of hypertension and saved treatment costs. However, the analysis did not report how ambulatory blood pressure performed compared to a risk-based approach. This is a serious shortcoming, because it is in this context that NICE makes its recommendations.8 Furthermore, in those cost-effectiveness analyses, ambulatory measurements were assumed to have perfect sensitivity and specificity for the diagnosis of hypertension, and blood pressure-lowering treatment was assumed to provide no benefit to individuals classified as non-hypertensive. Both are dubious assumptions that work substantively in support of strategies based on ambulatory measurements, and, when varied, will change the conclusions drawn.2 Making more measurements to get a better estimate of an individual’s true blood pressure is an inherently appealing concept deeply rooted in clinical practice. But as the evolving evidence shows, it’s not that simple. However precisely blood pressure is measured, it is unlikely to ever be as good a discriminator as an assessment based on multiple risk factors. And while the widespread use of ambulatory blood pressure measurement will more reliably pin down someone’s true blood pressure and better define who has hypertension, it is very unlikely to deliver the clinical and economic benefits that could be achieved by switching to a risk-based strategy.8 The National Vascular Disease Prevention Alliance has released an Australian risk assessment tool10 that supports a risk-based strategy, and management guidelines will follow. Rapid nationwide uptake of this approach to deciding who to treat has the potential to revolutionise the prevention of blood pressure-related diseases. Against this background, ambulatory blood pressure measurement will remain an excellent research tool but will add little to clinical decision making for most patients.

Bruce C Neal MB ChB, MRCP, PhD · Les Irwig MB BCh, PhD

Patients with cardiovascular disease may be especially prone to the adverse effects of complementary medicines Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Australia.1 Given the chronic nature of CVD, medical management is the most common mode of care, and medications are prescribed to most patients with CVD.2 In general practice, treatment of CVD accounts for almost one in five encounters, with hypertension the most commonly treated risk factor, followed by lipid disorders.2 Although effective management of CVD depends on a range of factors, one that is often neglected is the use of complementary medicine (CM). While CM can potentially benefit patients with CVD, it can have an adverse impact on the effectiveness of conventional CVD therapies in two main ways: through drug interaction or through reduced adherence to conventional therapies. In Australia, CM is defined as the use of medicines containing herbs, vitamins, minerals, nutritional supplements and homoeopathic medicines.3 The popularity of CM has increased in recent years,4 and in people with CVD, rates of use have been estimated at up to 42%, with up to 21% of these patients taking herbal supplements.5 The most common types of CM taken by people with CVD are multivitamins and minerals (34% of surveyed cardiac patients), calcium (22%), vitamin E (20%) and vitamin C (14%). The most common herbal agents used are mint or lemon balm (11%), nettle (8%), green tea (7%), echinacea (6%) and garlic (6%). The use of coenzyme Q10 (3%), fish oil or omega-3 fatty acids (2%) and hawthorn (1%) are surprisingly low.5 Although CM is often considered safe by patients, harmful effects associated with its use do exist. The use of CM alongside prescription medications has the potential of reducing the effectiveness or increasing the potency of therapy. These effects may be compounded in people with CVD for several reasons. First, CM users tend to consume more than one CM product concurrently over periods of months to years.5 Second, the likelihood of interference with prescribed therapy is increased since certain medications, such as digoxin and warfarin, have a narrow therapeutic window. Patients with CVD also tend to be elderly, are likely to suffer from multiple comorbidities and therefore are likely to be using multiple long-term medications.5 Several studies in people with CVD indicate that not only do a significant proportion use CM concurrently with prescribed therapy, but about half do not inform treating doctors about their use.5 The relatively widespread use of CM in people with CVD means it is vital that doctors are aware of CM use. Some commonly observed interactions between CM and conventional CVD medications and possible mechanisms are summarised in the Box. Apart from the possibility of drug interactions, the bioactive components of CM products can also directly cause adverse effects. Some examples of CM that are used in the treatment of CVD (and their adverse effects) include Aloe vera (diarrhoea and potassium depletion), fenugreek (diarrhoea and hypoglycaemia), garlic (inhibition of platelet function), ginseng (insomnia), ephedra (stroke and myocardial infarction), Ginkgo biloba (bleeding) and red yeast rice (myopathy and rhabdomyolysis).7 More generally, there are safety issues associated with the quality of CMs. These relate to the lack of standard dosing, which in part is due to variations in potency, depending on where plants are grown; the possibility of contamination by pesticides and heavy metals during cultivation; and the possibility of contamination by bacteria in the storage, transport or manufacturing processes.7 The second main mechanism in which CM use may impact on effective management of CVD is through reduced adherence to prescription medications. However, a limited number of studies investigating the impact of CM on cardiovascular medication adherence show inconsistent results. Some studies report a lower adherence to prescription medications among cardiovascular patients taking CM, while others found the opposite.5 Importantly, we found in our review that CM use was not disclosed by cardiac patients up to 65% of the time. The main reasons were fear of clinician disapproval and because clinicians had not asked about CM use.5,9 This strongly suggests that clinicians need to take a less judgemental and more proactive approach to encourage patient discussion of CM use, regardless of adherence to conventional treatment. What, then, are the identifying characteristics of a CM user? In the general population, use of CM is associated with higher levels of education and income10 but poorer self-reported health status. Although few differences have been found between cardiac patients who are CM users compared with non-users,5 it appears that people with chronic disease are more likely to use CM, especially if they have multiple comorbidities.10 As well as being aware of the potential impact of CM on prescribed therapy, clinicians should also be aware of the reasons patients use CM. About half of CM users with CVD believe that CM is of greater benefit than conventional treatment, or perceive that the CM used has proven benefits for their condition.5 Many CM users also believe that there are fewer side effects associated with “natural” therapies.5 CM therefore meets a real or perceived need for health care, and serves an important psychological function in enabling patients to manage their own health.11 Given the increasing prevalence of both CM use and CVD, it is likely that clinicians will see more cases of patients who are using CM either specifically for their cardiovascular condition or towards improving general health. Regardless of personal viewpoint, CM is now an integral part of the therapeutic armamentarium used by the Australian population. Thus, there is a need to better inform doctors about CM use and the associated potential for adverse reactions and herb–drug interactions. There are significant gaps in clinician knowledge of the risks and benefits associated with CM use, and clinicians report feeling ill-equipped to respond to patient enquiries about CM.12 Medical schools overseas, such as those in Asia, France, Germany, Switzerland and some in the United States, have incorporated CM into their medical curricula. Awareness of CM needs to be integrated into routine medical practice, such as by asking patients about CM as part of a medication review. CM modules should be included in continuing professional education programs for general practitioners and specialists alike. The key issues and complexities of CM that should be understood include the differing definitions of CM in different countries, such as the American and Australian classifications, and the processes underlying its regulation. In Australia, for example, the Therapeutic Goods Administration regulates CM products, and the difference between “listed” medicines (which are not evaluated for efficacy) versus “registered” medicines is important.3 There is growing research on the efficacy of select CMs for various conditions. Results from robust studies show that omega-3 fatty acids may assist in the treatment of hypertriglyceridaemia,13 reduce the incidence of thrombotic stroke14and coronary heart disease,15 and may prevent sudden cardiac death in patients with prior myocardial infarction.16 Coenzyme Q10 supplements appear to reduce the symptom of statin-induced myalgia17 and may have favourable effects in those with heart failure.18 Physical therapies such as qi gong also appear helpful for hypertension19 and are likely to be beneficial in some patient groups as alternatives to higher intensity physical activity. Furthermore, considerable efforts are being made to investigate the efficacy of CM in CVD prevention and risk factor reduction. Research bodies such as the National Institutes of Health in the US and the National Institute of Complementary Medicine in Australia are supporting studies investigating the effects of hawthorn leaf in milder forms of heart failure, the use of disodium edetate (EDTA) chelation therapy to treat coronary artery disease, vitamin D3 for prevention of CVD and melatonin for lowering hypertension. Further research is required to strengthen the evidence base for these and other CM therapies; however, certain CMs may prove to be efficacious for people with CVD, and critical awareness of this work is necessary for effective clinical practice. The use of CM is common among patients with cardiovascular conditions and a high proportion of patients using CM believe they have remedial benefits. Many CM users also believe that CM is as safe as or safer than their prescribed treatments, and are often unwilling to inform their doctors of their use of CM products. Commonly used CM products have the potential to interfere with the intended action of prescription medications although clinician knowledge of these interactions may be limited. We have restricted our discussion to patients with CVD, although the importance of considering CM in medical management applies equally to other patient groups, especially those with chronic disease. We emphasise the need for education about CM, so clinicians become more aware of patients’ CM use, become more knowledgeable about CM, and more capable of advising their patients about this issue. Letter p 660 Potential interactions of commonly used CM with cardiovascular medications6-8 CM (prevalence of use*) Possible herb–drug interactions and mechanism of action Coenzyme Q10 (3%) May partially antagonise antiplatelet effect of clopidogrel and decrease response to warfarin Vitamin E (20%) Contains curbicin, which antagonises the effect of vitamin K on coagulation, which, with clopidogrel, may increase the risk of bleeding and potentiate warfarin effects Garlic (6%) Additive antiplatelet effects may occur with clopidogrel and other anticoagulants Ginkgo biloba (4%) Ginkgo inhibits platelet aggregation and increases the effect of warfarin Fish oil (2%) Increases the effect of antiplatelet agents and vitamin K-dependent coagulation Concomitant use of warfarin and fish oils may increase risk of bleeding Vitamin D (4%) Improves calcium absorption, which increases the toxic effect of digoxin St John’s wort (2%) Reduces the effectiveness of statins, warfarin and digoxin through induction of hepatic enzymes and P-glycoprotein Hawthorn (1%) Increases the inotropic effects of digoxin Ginseng (4%) Has an additive effect with antiplatelet agents Decreases the effect of anticoagulants Glucosamine/chondroitin (4%) Increases the effect of anticoagulants Capsicum (5%) Increases the effect of antiplatelet agents Bilberry (1%) Increases the effect of anticoagulants Aloe vera (4%) Increases the effect of antiplatelet agents Produces hypokalaemia, leading to increased toxic effect of digoxin; enhances the effect of digoxin Liquorice (prevalence of use unknown) Mineralocorticoid effects promote potassium excretion. Causes hypokalaemia when used with some antihypertensive agents CM = complementary medicine. * Prevalence of use is based on figures from a systematic review of the literature combining data from multiple studies.5

Hosen Kiat MB BS, FRACP, FACC · Yu Sun Bin BSc(Hons) · Suzanne Grant BApplSc(TCM), MPS, PhD · Dennis Hsu-Tung Chang MB BS, MSc, PhD

Rowan Nicks was born in New Zealand on 24 February 1913. He studied medicine at the University of Otago in Dunedin and, on graduation in 1937, worked as an intern at Auckland City Hospital. After his internship, he moved to the United Kingdom to further his surgical studies, working as a demonstrator in anatomy at Middlesex Hospital, London. Rowan served as a Surgeon Lieutenant in the Royal Navy during the Second World War. In 1945, he was appointed Officer of the Order of the British Empire and became a Fellow of the Royal College of Surgeons. After the war, he turned his attention to cardiothoracic surgery, and worked at Royal Brompton Hospital, London. In 1947, he returned to New Zealand to pioneer cardiothoracic surgery at Greenlane Hospital in Auckland. In 1956, Rowan was appointed Staff Specialist in Cardiothoracic Surgery at Royal Prince Alfred Hospital in Sydney. He was involved in the beginning of open-heart surgery in New South Wales in 1957 and played a leading role in the design and development of the first automatic cardiac pacemaker. After the death of his wife Mary in 1969, Rowan travelled widely, visiting hospitals in Africa and India in particular. This was the beginning of his second career as a significant philanthropist. After his official retirement in 1973, Rowan continued to travel and work in hospitals in East Africa, India and Malaysia, as well as in remote Aboriginal communities in Australia. Rowan established a series of scholarships and fellowships for young surgeons from Africa, India, Asia, the United Kingdom and Ireland, and the Western Pacific region. In 2005, he established the Rowan Nicks Russell Drysdale Fellowship in Australian Indigenous Health and Welfare. Throughout his life, Rowan had a sustaining love of nature and gardening. In his later years, he developed his interest in chamber music, symphony and opera. Rowan died on 26 May 2011, and is survived by his extended family in Australia and New Zealand.

John Masterton · and Brian Morgan

Earlier concerns put to rest as new evidence confirms their safety and efficacy The three sentinel developments in percutaneous coronary intervention (PCI) have been the groundbreaking use of balloon angioplasty from 1977, the widespread uptake of bare metal stents (BMS) in the early 1990s, and the era of drug-eluting stents (DES) commencing in 2002. DES greatly reduce the incidence of vessel restenosis, and this has allowed the application of PCI to increasingly complex coronary anatomy that had previously been untreatable due to prohibitive restenosis rates. Uptake of this technology was immediate and widespread, with near ubiquitous use (95%) of DES for PCI in the Australian private sector by 2005 despite a fourfold higher cost and uncertain incremental cost-effectiveness over BMS.1 However, the initial unbridled optimism was tempered by case reports of “very late” stent thrombosis, and then shattered by the release of data at the 2006 World Congress of Cardiology in Barcelona suggesting DES were associated with higher mortality rates.2 This dramatically shook confidence in the use of this new technology with an immediate effect on DES use worldwide.3 In early 2007, the widely reported Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, in which outcomes were similar for medically and percutaneously treated patients with stable angina, further challenged the interventional paradigm.4 Criteria for drug-eluting stent use in Victorian state hospitals6 One or more of: Diabetes mellitus Chronic renal failure Small diameter target vessel (< 2.5 mm diameter) Long target lesion (> 20 mm in length) Ostial lesion Bifurcation lesion Chronic total occlusion Previous coronary artery bypass grafting In-stent restenosis So what was the effect on Australian DES use? In this issue of the Journal, the Melbourne Interventional Group (MIG) present their registry data for DES use in selected Melbourne public hospitals over a 4-year period spanning this crucial time.5 Even though there was already a selective policy in place restricting DES use to patients with lesions at high risk of restenosis (Box), DES implantation fell from a peak of 54% of all stents used between April 2004 and March 2005 to 32% in 2007–2008.5 Even more dramatic falls in DES use (91% to 34%) have been reported in the Melbourne private sector over this period.7 The change in DES use in public hospitals demonstrated by the MIG is revealing, as they have previously reported underuse of DES and calculated that greater than 65% of patients undergoing stent implantation met the criteria for selective use of DES.8 Of further interest is the decrease in the absolute number of patients undergoing PCI, and in particular elective PCI, that is perhaps related to the release of the COURAGE study. It is likely that the change in practice reflects uncertainty over safety of DES at that time. It is therefore reassuring that data reported from the MIG registry affirm the safety and efficacy of DES, with DES use being the only independent predictor of better clinical outcomes at 12 months (driven, as expected, by reduced target vessel revascularisation rates). Given this finding, we would have expected to have seen deterioration in clinical outcomes during the period of low DES use. Surprisingly, this did not happen — the MIG investigators report that the reduction in DES shown by their data was not associated with an adverse effect on overall clinical outcomes. One possible explanation for this is that there was concurrent change in several other variables including referral patterns, stent technologies, implantation techniques, and adjunctive pharmacological therapy (eg, increased use of dual antiplatelet therapy). These changes may have acted favourably on clinical outcomes, masking an adverse impact of reduced DES use. The inability to separate out these confounding influences is one of the limitations of registry data. Following the Barcelona Congress, there was a rigorous reappraisal of the available studies using patient-level data, review by regulatory authorities (including the Australian Therapeutic Goods Administration) and further randomised trials. The safety and efficacy of DES were reaffirmed. Analyses showed they were not associated with an increased rate of myocardial infarction or death, but were associated with a reduction in need for revascularisation of up to 70% compared with BMS.9,10 Moreover, there has been an evolution to “second generation” stent platforms with very low stent thrombosis and restenosis rates,11 and greater understanding of the importance of dual antiplatelet therapy. Indeed, new registry data have provocatively shown a mortality benefit with liberal utilisation of DES.12 So who should receive a DES? If there was no cost difference, it would be appropriate to implant DES in the majority of patients. The main exceptions would be patients unlikely to tolerate 12 months of dual antiplatelet therapy because of increased bleeding risk, an anticipated need for elective surgery, or poor medication compliance. However, a significant cost differential remains and, therefore, rationing to those most likely to benefit (Box) is appropriate. This will, nonetheless, still result in much higher DES utilisation rates than those documented in the MIG registry in 2007. The reassurance that DES are safe has had an effect on practice at our institution, with implantation rates increasing from 43% to 70% over the past 3 years, bringing us back in line with the proportion of patients reported to meet selective utilisation criteria in Victoria.8 The information presented by the MIG gives a fascinating insight into physician behaviour by documenting the local change of practice that followed concerns regarding DES. Confidence has been restored by evidence affirming DES safety, the introduction of “second generation” platforms, and a better understanding of the importance of optimal medical therapy. It would be interesting to see how these more recent developments have affected DES use, and we look forward to ongoing insights from this important local registry.

Christopher J K Hammett MBChB, FRACP, FCSANZ · Peter J Stewart MB BS, FRACP, FCSANZ · John J Atherton PhD, FRACP, FCSANZ

Objectives: To describe temporal trends in the use of evidence-based medical therapies and management of patients with acute coronary syndromes (ACS) in Australia and New Zealand.Design, setting and participants: Our analysis of the Australian and New Zealand cohort of the Global Registry of Acute Coronary Events (GRACE) included patients with ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation ACS (NSTEACS) enrolled continuously between January 2000 and December 2007 from 11 metropolitan and rural centres in Australia and New Zealand.Results: 5615 patients were included in this analysis (1723 with STEMI; 3892 with NSTEACS). During 2000–2007 there was an increase in the use of statin therapy, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and thienopyridines (P < 0.0001 for each). Among patients with STEMI, there was an increase in emergency revascularisation with PCI (from 11% to 27% [P < 0.0001]), and inhospital coronary angiography (from 61% to 76% [P < 0.0001]). Among patients with NSTEACS, there was an increase in revascularisation with PCI (from 20% to 25% [P = 0.004]). Heart failure rates declined substantially among STEMI and NSTEACS patients (from 21% to 12% [P = 0.0002], and from 13% to 4% [P < 0.0001], respectively) as did rates of hospital readmission for ischaemic heart disease at 6 months (from 23% to 9% [P = 0.0001], and from 24% to 15% [P = 0.0001], respectively).Conclusions: From 2000 to 2007 in Australia and New Zealand, there was a fall in inhospital events and 6-month readmissions among patients admitted with ACS. This showed an association with improved uptake of guideline-recommended medical and interventional therapies. These data suggest an overall improvement in the quality of care offered to contemporary ACS patients in Australia and New Zealand.

Bernadette Aliprandi-Costa RN · Isuru Ranasinghe MB BS, MMed · Vincent Chow MB BS · Shruti Kapila MB BS · Craig Juergens MB BS, FRACP, FCSANZ · Gerard Devlin MBChB, FRACP, FCSANZ · John Elliott MBChB, FRACP, FCSANZ · Jeff Lefkowitz MB BS, FRACP, FCSANZ · David B Brieger MB BS, PhD, FRACP

Objective: To evaluate percutaneous coronary intervention (PCI) practice trends and 12-month outcomes in Australia in the era of drug-eluting stents (DES).Design, setting and patients: Prospective study of consecutive patients undergoing 9204 PCIs between 1 April 2004 and 31 March 2008 at seven Victorian public hospitals.Main outcome measures: Temporal trends in baseline characteristics and in-hospital and 12-month clinical outcomes including death, myocardial infarction (MI), target vessel revascularisation (TVR) and composite major adverse cardiac events (MACE), from year to year.Results: Between 2004–2005 and 2007–2008, the mean age of patients undergoing PCI was stable (65 ± 12 years), and comorbidities such as hypertension, hyperlipidaemia, peripheral arterial disease and stroke increased (P < 0.05). There were fewer elective and more urgent PCIs, especially for MI < 24 hours (17.6% in 2004–2005 to 27.2% in 2007–2008, P < 0.01). Overall stent use remained high (mean, 94.6%), but use of DES declined steadily (53.9% in 2004–2005 to 32.0% in 2007–2008, P < 0.01), despite increases in complex lesions. Planned clopidogrel therapy of ≥ 12 months after insertion of DES increased from 54.7% in 2004–2005 to 98.0% in 2007–2008 (P < 0.01). The overall procedural success rate was high (mean, 95.9%), and 12-month rates of mortality (3.8%), MI (4.8%), TVR (6.8%) and stent thrombosis (1.8%) remained low. Selective use of DES was an independent predictor of freedom from MACE at 12 months (odds ratio, 0.68; 95% CI, 0.56–0.81).Conclusions: Use of DES declined steadily from 2004–2005 to 2007–2008, despite increasing patient risk profile and lesion complexity. Procedural success remained high and 12-month adverse outcomes remained low, with increasing use of prolonged dual antiplatelet therapy.

Bryan P Yan MB BS, FRACP, FACC · Andrew E Ajani MB BS, FRACP, MD · David J Clark MB BS, FRACP · Stephen J Duffy MB BS, PhD, FRACP · Nick Andrianopoulos MB BS, MBiostat · Angela L Brennan RN, CCRN · Philippa Loane BSc · Christopher M Reid BA, MSc, PhD

To the Editor: A review by Harper and Lefkovits favoured increased use of prehospital thrombolysis (PHT) for the management of ST-elevation myocardial infarction (STEMI).1 The acknowledged importance of early reperfusion and the ready application of PHT make this a sound recommendation for settings that are remote from percutaneous coronary intervention (PCI) centres. However, the recommendation of using PHT for patients presenting within 2 hours of symptom onset in metropolitan areas is more controversial. Recent enthusiasm for this strategy has been buoyed by the 5-year data from the randomised CAPTIM study that compared PHT with primary PCI.2 This French study, conducted from 1997 to 2000, was prematurely terminated after recruiting 840 of the planned 1200 patients. There was no difference in the primary composite end point at 30 days. A post-hoc analysis subsequently reported that among the 460 patients randomly assigned to PHT or PCI within 2 hours of symptom onset, there was a trend towards lower mortality among those receiving PHT (2.2% [five patients] v 5.7% [13 patients] at 30 days; P = 0.058).3 By 5 years, an additional eight patients receiving PHT and 12 patients receiving primary PCI had died, resulting in a P value of 0.04 for mortality difference.2 This result reflected one component of a composite end point in a post-hoc subgroup analysis from a prematurely terminated, underpowered trial. Harper and Lefkovits comment that French registry data support the CAPTIM findings. However, data from a more than 10-fold larger Swedish registry do not.4 Important to the successful implementation of PHT is the transport of patients directly to PCI centres where early angiography can be performed if required. However, PCI and fibrinolysis do not make good bedfellows — a lesson learnt through the counterintuitive results of facilitated PCI trials, which showed no benefit and some harm when offering thrombolysis as a prelude to PCI.5,6 This adverse interaction is ameliorated if PCI is deferred for 3 to 24 hours after thrombolysis; however, there is a real risk that early PCI will be overused when STEMI patients arrive rapidly at a staffed PCI facility after receipt of PHT. We need stronger evidence than currently exists to be sure that, in metropolitan settings, the temptation for zealous application of PCI after PHT does not effectively result in over-application of a facilitated PCI strategy, with untoward consequences. In metropolitan regions, the current focus on reducing delays from onset of symptoms to percutaneous revascularisation should remain. Based on the evidence to date, PHT may be a cost-effective but not clinically superior alternative for reperfusion, and should be encouraged as the strategy of choice in circumstances when logistic or resource constraints limit ready access to primary PCI.

David B Brieger

A recently published critique of a set of Australian clinical practice guidelines (CPG) highlighted problematic issues in guideline development concerning conflicts of interest of guideline panellists, validity and strength of recommendations, and involvement of end users and external stakeholders. Management of financial or intellectual conflicts of interest requires: full disclosure; limitations on industry or agency financial support during guideline development; a representative panel that includes conflict-free members; and only conflict-free panellists to be involved in drafting guideline recommendations. Guideline panels should consider adopting the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system to assist in determining the validity and strength of recommendations. Guideline panels should seek formal feedback from external stakeholders and end users. Enacting such policies aims to lend greater transparency and credibility to CPG, limit protracted and unhelpful interpretive debates, and promote wider use of CPG.

Ian A Scott FRACP, MHA, MEd · Gordon H Guyatt MD, MSc, FRCP(C)

To the Editor: Harper and Ko recently suggested radically changing the way we investigate patients with stable coronary artery disease (CAD), stating that they should initially undergo computed tomography coronary angiography (CTCA), with subsequent stress testing if CTCA shows atherosclerosis.1 To save costs, they recommend excluding stress nuclear myocardial perfusion imaging (MPI) because it has similar accuracy to stress echocardiography and involves ionising radiation. To suggest that the available evidence supports CTCA as the first-line investigation of stable CAD is premature, and likely to cause more therapeutic confusion than it resolves. Of particular concern is the assertion that all patients with any detectable atherosclerosis on CTCA should undergo intensive medical therapy for CAD. The clinical significance of mild atherosclerosis detected on CTCA in patients with chest pain that is unlikely to be of cardiac origin is uncertain, with no clinical studies demonstrating a benefit of medical management for CAD based on CTCA findings. Conversely, were such patients investigated first with a stress test, those with a negative test could be reassured that their chest pain is not cardiac and their intermediate-term prognosis is excellent. Importantly, the directive for unproven lifelong medical therapy for CAD is averted. It is also incorrect to imply that different stress-testing modalities may be seen as equivalent because they have comparable diagnostic accuracies, because their strengths and weaknesses remain complementary. This allows referring physicians to choose the modality that most suits the individual patient. For example, stress echocardiography is more operator-dependent, with known limitations in patients with obesity, airways disease, arrhythmias, poorly controlled hypertension, and contraindications for β-blocker cessation. It also cannot be fused with CTCA images, as myocardial perfusion images can.2 While we agree that measurement of fractional flow reserve (FFR) is an extremely important advance in interventional cardiology, it has the limitation of underestimating ischaemia in patients with small-vessel disease (eg, patients with diabetes).3 We agree that demonstrating ischaemia is the critical component in the decision to perform either percutaneous coronary intervention or coronary artery bypass graft surgery — and until now the largest body of evidence has been accumulated with MPI.4 Moreover, demonstration of regional ischaemia on MPI associated with an angiographic stenosis obviates the need for FFR. Electrocardiographic stress testing alone cannot provide these localising data. The advent of CTCA promises to reshape how we assess and manage CAD in the future, but today we should be guided by the clinical evidence, and be mindful not to put the cart before the horse.

Victor Kalff · Stephen J Duffy · Andrew J Taylor

To the Editor: Harper and Ko have ignored significant facts regarding myocardial perfusion scintigraphy and made unsubstantiated conclusions regarding computed tomography coronary angiography (CTCA) and fractional flow reserve (FFR).1 Their investigation algorithm for suspected and known stable coronary artery disease (CAD) is flawed. By definition, stable CAD patients cannot be categorised into a “suspected CAD” subgroup. CTCA is not an appropriate first-line investigation for patients presenting with atypical chest pain or equivalent syndromes. Being purely anatomical, CTCA cannot determine the functional significance of CAD, rendering it ineffective in intermediate disease. Furthermore, CTCA often overestimates stenoses due to partial voluming and blooming. Guidelines from the United Kingdom National Institute for Health and Clinical Excellence (NICE) state that “questions remain about the ability of multislice CT coronary angiography to accurately identify stenoses of functional significance ... in people with stable chest pain”.2 Harper and Ko’s algorithm will lead to more investigation, provide no differentiation over and above Step 2 (functional imaging), and increase radiation dose, contrast burden and delays between presentation and definitive treatment. The real potential of CTCA lies in its ability to non-invasively assess plaque burden and therefore help rationalise long-term pharmacotherapy in high-risk, asymptomatic patients. However, because there is a lack of evidence for this approach, it has been largely ignored and instead the CTCA community has been “sidetracked” into comparing CTCA with functional imaging. Harper and Ko claim that additional costs from the inevitable increase in CTCA scans would be “minor in comparison to the savings”. This is unproven, and not supported by NICE.2 For atypical symptoms, Harper and Ko recommend “the less expensive ECG [electrocardiogram] exercise test” to risk-stratify patients; however, stress ECG testing is poor at predicting the degree of myocardium at risk, a key factor in risk-stratifying patients. The exercise ECG lacks specificity, leading to unnecessary invasive testing, and many patients are unable to comply. NICE has abandoned exercise ECG testing completely.2 The authors state that a “wealth of data has validated the accuracy of FFR”. The original papers demonstrating a significant FFR of 0.75 were based on perfusion imaging.3,4 The review cited quotes a lower sensitivity and specificity of FFR compared with perfusion scintigraphy, and lists scintigraphy as the “clinical gold standard of ischemia”.5 This is because scintigraphy is the most sensitive technique for identifying functionally significant CAD, as it detects the first abnormality in the ischaemic cascade (reduced myocardial perfusion). Furthermore, the exact level of FFR significance (0.75 v 0.80) is debated. In practice, there is a large degree of operator “discretion” in deciding to revascularise, irrespective of the FFR value, which is often “intermediate” in itself. Harper and Ko question the cost of scintigraphy; however, it is more than $300 cheaper than FFR measurement. They overstate the cost of a standard guidewire by threefold.1 In just one study of over 5000 patients (three times the population of a recent FFR meta-analysis6), increasingly abnormal perfusion scans predicted death and myocardial infarction. There was a reduction in death following revascularisation according to defect severity.7 The nuclear substudy of the COURAGE trial confirmed this.8 No study of CTCA or FFR has been able to predict survival with revascularisation, as the technology is unable to define area at risk. Despite this, Harper and Ko conclude that the Medicare rebate for nuclear testing should be abolished. The authors state that “instituting these changes would undoubtedly result in improved outcomes and substantial savings”. This comment is opinionated, inflammatory and not based on current evidence. The only reasonable conclusion is that before a rebate for CTCA is even proposed, it should be proven diagnostically and prognostically equivalent to myocardial perfusion scintigraphy in predicting ischaemia.

William J van Gaal · Kevin Allman

To the Editor: Although Harper and Ko’s effort at proposing an algorithm1 to reduce unnecessary cardiac catheterisation and stenting is laudable, it is concerning that they advocate investigating patients with stable coronary artery disease (CAD) using computed tomography coronary angiography (CTCA), with an algorithm, furthermore, that has not been validated in terms of patient outcomes. The COURAGE trial demonstrated that percutaneous coronary intervention (PCI) provided no survival advantage or reduction in myocardial infarction over 5 years of follow-up compared with optimal medical management in patients with chronic stable angina.2 PCI provided a relative symptomatic benefit only within the first 3 years. Therefore, it is debatable whether imaging most of these stable patients — much less catheterising them — provides any enduring favourable patient outcomes. For those who do require intervention, fractional flow reserve (FFR) measurement does obviate unnecessary stenting during a cardiac catheterisation. But why perform CTCA — which cannot diagnose ischaemia — in the first place, only to then perform an expensive invasive catheterisation to compensate for it? Why not diagnose ischaemia with an initial non-invasive stress test (nuclear or echocardiography) and only proceed to catheterisation if revascularisation is warranted, thus also lessening the radiation dose? Modern gamma cameras allow nuclear stress studies with radiation doses as low as 2–3 mSv. Yes, CTCA can (as opposed to does) achieve comparable doses with prospective gating, but without the left-ventricular function analysis that nuclear or echocardiography studies provide. Advocating the elimination of the rebate for nuclear stress studies is thus premature, if not ill informed. Harper and Ko’s algorithm relies on the assumption that medical therapy is appropriate in asymptomatic patients for any degree of coronary atherosclerosis, hence justifying the use of CTCA for its detection. However, there is considerable uncertainty about the benefits of medical therapy for primary prevention in low-risk patients.3 Furthermore, the use of CTCA has not been validated as a determinant of appropriate medical management leading to favourable patient outcomes. This contention remains speculative. Indeed, contrary to the claims of CTCA supporters, the United States Centers for Medicare and Medicaid Services has declared that there is uncertainty regarding any potential health benefits or patient management alterations from including coronary CTA [computed tomography angiography] in the diagnostic workup of patients who may have CAD. No adequately powered study has established that improved health outcomes can be causally attributed to coronary CTA ... the body of evidence is of overall limited quality and limited applicability ... in community practice.4 Consequently, the technology also poses significant potential to unnecessarily increase the population radiation burden.5

Peter Karamoskos

To the Editor: Harper and Ko stress the importance of differentiating the presence of atherosclerosis from ischaemia,1 a concept that has been well understood for years. We agree that identifying myocardial ischaemia is important in the management of atherosclerosis; there are a variety of well validated non-invasive tools for this, including exercise electrocardiography, stress echocardiography, and nuclear myocardial perfusion imaging (MPI). However, we have concerns about some of the sweeping changes suggested by the authors — in particular, replacing nuclear MPI with stress echocardiography. While published studies report similar accuracy for these modalities, it is clear that each has strengths and weaknesses. Stress echocardiography is an excellent tool that will often suffice but it is operator-dependent, while MPI is more accurate for single-vessel ischaemia. It is well known that a diagnostic stress echocardiogram cannot be achieved in some patients, so an alternative modality may be required. This is particularly problematic in Australia, where there is no mechanism in place to fund the use of ultrasound contrast imaging. MPI remains a widely accepted technique globally, with a substantial evidence base to support its diagnostic and prognostic impact. For instance, a negative MPI study is generally associated with a cardiac event rate of < 1% in the following year.2 Further, its role in directing the mode of treatment on the basis of extent of ischaemia and its cost-effectiveness as the “gatekeeper” to cardiac catheterisation have been amply demonstrated.3 The use of radiation in medical procedures is always subject to the ALARA (as low as reasonably achievable) principle, and prescribed doses in Australia are typically lower than those quoted in the American literature cited by Harper and Ko. Recent advances in hardware and software with MPI have achieved additional gains in reducing radiation exposure.4 The cost of MPI is greater than stress echocardiography, but remains less than angiography and fractional flow reserve (FFR) measurement. Further, Harper and Ko’s proposed cost savings will not be realised with their call for an increased use of computed tomography coronary angiography and FFR measurement. The job of a good clinician is to choose the right test for the patient; in some cases this is a stress echocardiogram but it is often an MPI study, as supported by international guidelines.5 Thus, readers should be mindful that Harper and Ko’s views about replacing nuclear stress tests with stress echocardiography and abolishing the Medicare item number for nuclear stress tests are personal and may be contrary to sound evidence.

Nathan Better · Myles B Webb · David L Prior · Steven A Unger · George Larcos

In reply: We thank the authors of these letters for their comments on our article. In response to Kalff and colleagues, we firmly believe stress testing should be reserved for the diagnosis of ischaemia in patients with known coronary artery disease (CAD), and computed tomography coronary angiography (CTCA) is the investigation of choice for anatomical diagnosis of CAD in patients with suspected CAD. In this, we are supported by recent guidelines from the American Heart Association and others.1 Most heart attacks occur as a result of plaque rupture in coronary lesions of insufficient severity to cause ischaemia on stress testing, but that would be detected on CTCA.2 In view of the undoubted benefits of medical therapy in both primary3 and secondary prevention of CAD events, do Kalff et al seriously suggest that coronary atherosclerosis detected on CTCA should not be treated with proven anti-atherosclerotic therapy? Regarding comments made by van Gaal and Allman, and Karamoskos, we believe the upfront use of CTCA in our proposed algorithm would substantially decrease downstream referrals for both stress testing and invasive angiography in patients with suspected CAD. The current practice of referrals for invasive angiography based on clinical assessment and functional tests results in a low yield of obstructive disease.4 Furthermore, we believe the responsible use of CTCA can be promoted by restricting its use to the anatomical diagnosis of CAD as a once-only investigation. Once the diagnosis is established, further functional testing can be pursued if clinically indicated. Multicentre studies designed to determine the optimal role of CTCA are underway and will provide important insights regarding our viewpoint.5 Van Gaal and Allman place considerable emphasis on the 5000-patient study of myocardial perfusion imaging.6 We point out, however, that this was an observational study. In contrast, the FAME study on which we base our views of fractional flow reserve (FFR) was a randomised study.7 In addition, we are bemused by their statement that “The review cited quotes a lower sensitivity and specificity of FFR compared with perfusion scintigraphy, and lists scintigraphy as the ‘clinical gold standard of ischaemia’”. To quote directly from the review article: ... scintigraphy, although considered the clinical gold standard of ischemia, has limitations in identifying the hemodynamic significance of individual lesions in patients with multivessel CAD.8 Regarding comments made by Better and colleagues, we believe both stress echocardiography and nuclear stress testing are overused in clinical practice. In most circumstances, a standard electrocardiographic stress test is sufficient to exclude significant ischaemia and thus to determine who should undergo invasive angiography. In circumstances requiring stress imaging, our preference is to perform stress echocardiography, as its accuracy is comparable to nuclear stress testing, with no additional radiation. Notably, in multilesion CAD, none of the stress testing modalities are sufficiently accurate to determine which lesions require intervention.9,10 Only FFR, a proven cost-effective investigation, can decide this.9,10 Rather than putting the cart before the horse, as suggested by Kalff et al, our algorithm provides a horse with the potential to win the Melbourne Cup.

Richard W Harper · Brian S Ko

To the Editor: Warfarin is an orally administered vitamin K antagonist and has many well described interactions with commonly prescribed medications.1 However, only a handful of case reports worldwide have shown that flucloxacillin, a widely used antibiotic, may affect warfarin therapy by reducing its anticoagulant effect — in one instance contributing to the development of ischaemic stroke.2,3 There are several reports describing potential mech-anisms of interaction for flucloxacillin with warfarin.4,5 We describe the case of a 64-year-old man who was diagnosed with infective endocarditis on the basis of mitral valve vegetations and blood cultures that were positive for methicillin-sensitive Staphylococcus aureus. The patient underwent mitral valve replacement with a prosthetic valve and received prolonged antibiotic therapy with intravenous flucloxacillin for 8 weeks. Initially, for nearly 4 weeks, therapeutic anticoagulation with warfarin was difficult to achieve with warfarin doses ranging between 5 and 10 mg per day (target international normalised ratio [INR], 2.5–3.5). During this time, the patient was receiving intravenous flucloxacillin at a total daily dose of 8 g (2 g every 6 h). Flucloxacillin was increased to 12 g per day (2 g every 4 h) and there was a subsequent fall in the patient’s INR, which was sustained despite increasing the dose of warfarin to 25 mg per day (Box). Completion of flucloxacillin therapy was associated with a rise in the patient’s INR and a reduction in his warfarin dose requirement. No other relevant medications were commenced during this period of observation. This case highlights the potential for a dose-related effect of intravenous high-dose flucloxacillin (up to 12 g per day) on warfarin metabolism and the need for vigilance when prescribing antibiotics in conjunction with oral vitamin K antagonists. Other penicillins such as amoxicillin can, conversely, enhance the anticoagulant effects of warfarin, so the warfarin–flucloxacillin interaction may not be intuitive for many clinicians. Doses* for oral warfarin and intravenous flucloxacillin administered to a 64-year-old man with infective endocarditis, and corresponding INR INR = international normalised ratio. * Graph shows abbreviated, not daily, data. Intervals are weekly up to Week 9, then vary according to when INR was measured.

Philip Y-I Choi · Katherine L Phillips · Ian Rae

We report a case of compassionate use of a haemoglobin-based oxygen carrier in a severely injured Jehovah’s Witness patient, for whom survival was considered unlikely. Severe anaemia and cardiac hypoxia were reversed after slow infusion of this agent. No vasoactive side effects were associated with the treatment, possibly due to the slow infusion, and the patient survived. (MJA 2011; 194: 471-473) Clinical recordA healthy 32-year-old woman was a passenger in a vehicle involved in a high-speed collision with a truck, and she was entrapped for 2 hours. Initially, her heart rate was 100 beats/min, blood pressure was 90/50 mmHg, respiratory rate was 28 breaths/min and oxygen saturation measured by pulse oximetry (SpO2) was 92% on air. Her Glasgow Coma Scale score was 9 (eye opening, 2; verbal response, 1; motor response, 6) and her pupils were equal and reactive to light. Her family indicated that she was a Jehovah’s Witness and would not accept the units of blood that had been transported to the accident site. Paramedics performed endotracheal intubation, immobilisation, left femoral splinting and resuscitation with a 7000 mL crystalloid infusion, and applied dressings to wounds. The patient was transported by helicopter to The Alfred’s trauma centre. On arrival at the trauma centre, she was ventilated, her heart rate was 120 beats/min, blood pressure was 62/26 mmHg and SpO2 was 79% on 100% fraction of inspired oxygen (FiO2). Following discussions with the family, the trauma team agreed not to treat the patient with packed red cells, platelets or fresh frozen plasma. Thoracostomies for a right tension pneumothorax and a left pneumothorax were performed, which increased her blood pressure to 105/65 mmHg and SpO2 to 100% on FiO2 100%. Intercostal drains were inserted and connected to a cell salvage device. She was administered 1400 mL of succinylated gelatin, 10 units of cryoprecipitate and 5 mg of recombinant factor VIIa. Bleeding was controlled with direct pressure, and a scalp wound was closed. Ultrasonography demonstrated a moderate pericardial effusion with systolic right ventricular collapse and free intraperitoneal fluid. Electrocardiography demonstrated sinus tachycardia with no ST segment changes. Initial blood tests showed a haemoglobin (Hb) level of 67 g/L (reference range [RR], 113–159 g/L), activated partial thromboplastin time of 44.3 s (RR, 26–38 s), international normalised ratio of 1.9 (RR, 1.0–1.3), serum fibrinogen level of 3.2 μmol/L (RR, 5.9–11.8 μmol/L, lactate level of 3.9 mmol/L (RR, 0.6–2.2 mmol/L) and serum creatinine level of 55 μmol/L (RR, 60–105 μmol/L). Imaging showed a fractured right orbit and maxilla, bilateral rib fractures, a grade 4 splenic laceration, a likely jejunal injury with intramural haematoma, a left distal humerus fracture, a comminuted open left femoral shaft fracture, an unstable T12/L1 fracture dislocation (60% off-ended), and multilevel spinous process and transverse process fractures. Laparotomy and fixation of the patient’s thoracolumbar injury were deferred because of the likelihood of associated bleeding. Instead, she underwent splenic embolisation, external fixation of her open left femoral shaft fracture and debridement of her left humerus injury. She received 1000 mL of 4% albumin and 1000 mL of crystalloid fluid during these procedures, and 10 mg of intravenous vitamin K afterwards. On postoperative admission to the intensive care unit, her Hb level was 36 g/L and her coagulation profile was normal. Low-dose noradrenaline was required to support her blood pressure until Day 2. Her urine output over the first 24 hours was 4500 mL. A follow-up transthoracic ultrasound showed abatement of the pericardial effusion. An abdominal computed tomography (CT) scan with oral contrast excluded jejunal injury. To protect renal function, intravenous contrast was not used. Placement of an inferior vena cava filter was deferred because of anatomical distortion secondary to the thoracolumbar injury. Several strategies were used to manage the patient’s anaemia. Sedation minimised metabolic demand. A ventilation cycle of 2 hours of 90% FiO2, followed by 2 hours of 90% SpO2 and then 20 hours of 95% SpO2 was used. This was employed to maximise oxygen delivery while minimising shunt from absorption atelectasis and to promote erythropoiesis. Recombinant erythropoietin (36 000 units daily for 6 days), folic acid (5 mg daily continued until discharge), vitamin B12 (1 mg daily for 6 days) and a single iron infusion of 500 mg were administered to maximise haematopoiesis. Menses was inhibited with progesterone. Blood testing was performed using paediatric-sized samples. Pneumatic calf compressors were applied and regular lower-limb sonography was performed to exclude venous thrombosis. The trauma team considered using a synthetic haemoglobin-based oxygen carrier (HBOC) to increase oxygen delivery to the patient’s tissues. On Day 3, OPK Biotech (Cambridge, Mass, USA), the Therapeutic Goods Administration (TGA), the Australian Quarantine and Inspection Service and airline carriers were contacted to determine availability and import permissions. HBOC-201 was supplied by OPK Biotech without charge. Informed consent for use of HBOC-201 was obtained from the patient’s family. Approval for emergency compassionate use of HBOC-201 was obtained from The Alfred Ethics Committee on Day 4. The published and unpublished in-vivo and in-vitro research into HBOC-201 was reviewed at a multidisciplinary meeting, and its use was agreed to. Ten 250 mL units of HBOC-201 were imported under Category A of the TGA’s Special Access Scheme. By Day 5, the patient’s Hb level had dropped to 29 g/L and her serum troponin I level was 0.33 μg/L (RR, < 0.10 μg/L), indicating cardiac hypoxia (Box). An electrocardiogram showed widespread ST depression and an episode of non-sustained ventricular tachycardia was documented. Survival with this degree of metabolic demand, the associated anaemia, and resultant end-organ hypoxia was considered unlikely. Following advice from experienced United States physicians, 3 units of HBOC-201 were administered on Day 5, and a further 2 units were administered on Day 6 with ascorbic acid (1 g twice daily continued until discharge). Each unit of HBOC-201 was infused over 8 hours to minimise any adverse effects related to volume overload, vasoactivity or methaemoglobin. Intravenous glyceryl trinitrate was the agreed treatment in the event of hypertension,1 but this was not necessary. After the slow administration of 5 units of HBOC-201, the patient’s Hb level increased from 35 g/L to 62 g/L (Box). Echocardiography performed before and after HBOC-201 treatment showed a reduction in cardiac output from 6.8 L/min to 5.0 L/min. Electrocardiography findings and troponin I levels returned to normal and no further arrhythmias were noted. Somatosensory evoked potentials revealed intact lower-limb neurological pathways. On Day 7, closed reduction was performed and a body cast was applied to treat the T12/L1 fracture dislocation. Imaging showed improved alignment, and an inferior vena cava filter was placed. From Day 6, the patient’s temperature began spiking, secondary to femoral pin site infections and pneumonia. Despite treatment with antibiotics, temperature spiking continued. Cooling was commenced to minimise metabolic demand. A transoesophageal echocardiogram on Day 11 showed right ventricular regional wall motion abnormality but no evidence of endocarditis. A CT scan showed persistent bilateral pneumothoraces, a left pleural effusion and an epidural haematoma at L1 level. Bilateral tube thoracostomies were re-performed and an antifungal was added to the anti-infective regimen. A percutaneous tracheostomy was performed on Day 12. Low-dose heparin therapy for thromboprophylaxis was deferred until Day 17. By Day 21, the infections had resolved and the tracheostomy tube was removed. The femoral and humeral fractures were internally fixed on Day 20 with minimal blood loss. On Day 30, the patient’s Hb level was 107 g/L and operative reduction and internal fixation of her thoracolumbar spine was performed. She was well when discharged to a rehabilitation facility on Day 43 — her cognition was formally assessed as normal, lower-limb neurological pathways were intact and Hb level was 101 g/L. DiscussionWe have described compassionate use of HBOC-201 in a severely injured Jehovah’s Witness patient. To our knowledge, this is the first report to describe reversal of documented cardiac hypoxia secondary to anaemia following trauma. Haemorrhagic shock is responsible for one-third of deaths following high-energy trauma.2 Integrated trauma care systems coordinate rapid haemorrhage control, shock recognition and surgical interventions to minimise blood loss and coagulopathy.3 Healthy volunteers can tolerate Hb levels of 50 g/L without evidence of end-organ hypoxia.4 However, it is estimated that the median Hb concentration associated with mortality is about 25 g/L.5 During the phase of increased metabolic demand in our patient, there was evidence of cardiac hypoxia when her Hb level reached 29 g/L. This prevented further operative interventions and placed her at high risk of cardiac dysrhythmias and death. HBOC-201 is a modified lactated Ringer’s solution containing 130 g/L of polymerised Hb of bovine origin. It is compatible with all blood types, stable for 3 years when stored at 2–30°C and stable for 2 years when stored at 40°C. When fully saturated, HBOC-201 has the same oxygen-carrying capacity as whole blood with the same Hb concentration. The partial pressure of oxygen at which HBOC-201 is 50% saturated (40 mmHg) is higher than that for cellular Hb (27 mmHg), which facilitates oxygen delivery to tissues. The half-life of HBOC-201 is approximately 20 hours.6 Polymerisation of the Hb reduces its glomerular diffusion and nephrotoxicity. A potential complication of HBOC-201 administration is hypertension and increased left ventricular afterload. Infusing each unit slowly (over 8 hours) in our patient may have diminished any vasoactive side effects. Two case reports of using HBOC-201 to treat severe anaemia following blunt trauma have been published. The first described improved cerebral oxygen delivery, but not survival, in a patient with head injuries.7 The second described successful reversal of haemorrhagic shock in a patient whose Hb level dropped to 45 g/L before HBOC-201 administration.8 However, the lack of clear HBOC-201 transfusion indications and end points, as well as the lack of data to support widespread use of HBOCs, has been criticised.9 A meta-analysis of data from HBOC trials has demonstrated an increased incidence of myocardial infarction and death in anaemic patients without life-threatening haemorrhagic shock.10 However, the analysis did not address the issue of “risk versus benefit” for use of these agents, including HBOC-201, in cases where blood transfusion for severely anaemic patients is not possible. A subsequent series of 54 consenting non-trauma patients with a median Hb level of 40 g/L demonstrated improved chances of survival with no serious adverse events following HBOC-201 administration.11 When blood transfusion is not possible, HBOCs can sustain oxygen delivery to hypoxic tissues.12 Such treatment may represent a life-saving intervention for patients with acute anaemia.13 Interest in safe and effective red blood cell substitutes for oxygen transport is increasing. Agents such as HBOC-201 show particular promise and could make a large difference to survival of trauma patients when blood is not accessible, available or acceptable. Haemoglobin and troponin I levels of a woman who was treated with a haemoglobin-based oxygen carrier (HBOC) following severe trauma * Troponin I levels were measured using the Architect i2000 immunoassay analyser (Abbott Diagnostics, Abbott Park, Ill, USA).

Mark C Fitzgerald MB BS, FACEM · Julie Y Chan MB BS(Hons), BMedSci · Andrew W Ross MB BS, FANZCA · Susan M Liew MB BS(Hons), FRACS(Orth) · Warwick W Butt MB BS, FCICM, FRACP · David Baguley MB ChB, BSc(Hons) · Hatem H Salem MB BS, FRACP · Matthias K Russ Orthopaedic and Trauma Surgeon (Germany) · Conor Deasy FACEM, FCEM, MB BCh BAO · Katherine E Martin MB BS, BMedSci, FRACS · Joseph K Mathew MB BS, MS · Jeffrey V Rosenfeld FRACS, FRCS(Edin), FACS

Chronic heart failure (CHF) is a complex and lethal clinical syndrome accounting for an increasing number of Australian hospital separations and more than 2700 Australian deaths in 2008. In 2006, the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand published Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. Results from recently published clinical trials provide additional information to be considered in the prevention, detection and management of CHF. In some cases, this new evidence strengthens recommendations previously made in the 2006 guidelines; in others, it provides new approaches to current recommended practice. Areas in which there have been significant new developments include: Use of B-type natriuretic peptide (BNP) or N-terminal proBNP plasma level measurement in guiding treatment of CHF New pharmacological approaches to the treatment of systolic heart failure Drugs to avoid or use with caution in CHF Treatment of cardiac arrhythmias in patients with CHF Multidisciplinary care and post-discharge management programs. While patient circumstances and clinical judgement should guide the interpretation of these findings in the clinical context, this update, together with the 2006 guidelines, provides current clinical guidance on CHF.

Henry Krum PhD, FRACP, FCSANZ · Michael V Jelinek MD, FRACP, FCSANZ · Simon Stewart PhD, FAHA, FCSANZ · Andrew Sindone MD, FRACP, FCSANZ · John J Atherton PhD, FRACP, FCSANZ

To the Editor: A 61-year-old man presented to the emergency department (ED) of a tertiary hospital seeking treatment for alcohol withdrawal after 36 hours of abstinence. He reported central chest pain radiating to the jaw and left arm that had been present for 2 hours before his arrival at the hospital. He had no history of cardiac disease and no known risk factors for coronary artery disease. An electrocardiogram (ECG) showed sinus tachycardia with T-wave inversion in leads V1, V2 and V3. Two hours after the patient’s arrival at the ED, he tested positive for troponin-T. Over the next hour, his ECG showed development of ST elevation of 1–2 mm in leads V3, V4 and V5. Because of severe alcohol withdrawal, his clinical status precluded urgent coronary angiography; and after treatment with diazepam was commenced, the ST elevation that was evident no longer met criteria for urgent angiography. The patient was given standard medical therapy for acute coronary syndrome, including aspirin, clopidogrel and intravenous heparin, while in the ED, along with ongoing diazepam for alcohol withdrawal. He was later admitted to the coronary care unit with a diagnosis of acute coronary syndrome. The next day, an ECG showed development of widespread T-wave inversion in leads V1 to V5. The dynamic ECG changes were not associated with ongoing chest pain. On Day 3 of the patient’s admission, coronary angiography showed normal coronary arteries, and ventriculography showed apical ballooning of the left ventricle, consistent with a diagnosis of takotsubo cardiomyopathy (Box). Treatment with an angiotensin-converting enzyme inhibitor and a β-blocker was commenced. Three months later, follow-up echocardiography showed a return to normal regional and global left ventricular function. Takotsubo cardiomyopathy takes its name from a traditional Japanese octopus trap that has a similar shape to the abnormally contracting left ventricle seen with this condition.1 Typical findings in a patient with takotsubo cardiomyopathy are chest pain associated with emotional or physical stress, with ST segment changes on electrocardiography and apical ballooning on ventriculography, which is generally expected to resolve within weeks to months; troponin level may or may not be positive. The mechanism of this condition has not yet been determined, but it appears likely that it is due to hyperadrenergic-hypercatecholaminergic states (such as alcohol withdrawal) resulting in localised or diffuse coronary vasospasm.2 Takotsubo cardiomyopathy has only rarely been associated with alcohol withdrawal, and has once been reported in a patient with alcohol withdrawal associated with seizures.3,4 Coronary ventriculography image showing apical ballooning of the left ventricle

Angus G Thompson · Joseph Hung

The prevalence of cardiovascular disease, a major cause of disease burden in Australia and other developed countries, is increasing due to a rapidly ageing population and environmental, biomedical and modifiable lifestyle factors. Although cardiac rehabilitation (CR) programs have been shown to be beneficial and effective, rates of referral, uptake and utilisation of traditional hospital or community centre programs are poor. Home-based CR programs have been shown to be as effective as centre-based programs, and recent advances in information and communication technologies (ICT) can be used to enhance the delivery of such programs. The Care Assessment Platform (CAP) is an integrated home-based CR model incorporating ICT (including a mobile phone and the internet) and providing all the core components of traditional CR (education, physical activity, exercise training, behaviour modification strategies and psychological counselling). The mobile phone given to patients has an integrated accelerometer and diary application for recording exercise and health information. A central database, with access to these data, allows mentors to assess patients’ progress, assist in setting goals, revise targets and give weekly personal feedback. Mentors find the mobile-phone modalities practical and easy to use, and preliminary results show high usage rates and acceptance of ICT by participants. The provision of ICT-supported home-based CR programs may enable more patients in both metropolitan and remote settings to benefit from CR.

Marlien Varnfield MSc · Mohanraj K Karunanithi BEng, MBiomedEng · Antti Särelä MSc · Elsa Garcia MEng · Anita Fairfull BSpPath · Brian F Oldenburg BSc(Hons), MPsychol, PhD · Darren L Walters MB BS, MPhil, FRACP

Computed tomography coronary angiography is the most reliable diagnostic test for coronary atherosclerosis. Stress testing should be reserved for diagnosis of myocardial ischaemia. Revascularisation, either by stenting or bypass grafts, is commonly performed in patients with stable coronary artery disease but is a double-edged sword. In the presence of ischaemia, revascularisation improves outcomes; in its absence, outcomes are worsened. In current practice, the decision of whether to revascularise is mainly made on the basis of the angiographic appearance of the coronary lesion in question. Physiological assessment of coronary lesions by the use of a pressure wire and measurement of fractional flow reserve (FFR) often shows that lesions thought to be sufficiently severe to warrant stenting or bypass do not cause ischaemia. A recent randomised study has shown that using FFR measurements to guide coronary stenting resulted in a lower use of stents, decreased costs and superior outcomes at 2 years, compared with traditional angiographic assessment alone. We believe that changes to the methods of health reimbursement are needed in both the public and private health systems, to facilitate greater use of FFR measurement.

Richard W Harper MB BS, FRACP, FACC · Brian S Ko MB BS, FRACP

CorrectionsIncorrect criterion for timely reperfusion in figure legend: In “Reperfusion therapy in the acute management of ST-segment-elevation myocardial infarction in Australia: findings from the ACACIA Registry” in the 1 November 2010 issue of the Journal (Med J Aust 2010; 193: 496-501), there was an error in Box 2 (page 498) in the legend of the second (“Door-to-balloon time”) graph. The criterion for timely reperfusion given as 30 min should have been 90 min. The html and pdf versions of this article were corrected on 30 Nov 2010.

Luan T Huynh · Jamie M Rankin · Phil Tideman · David B Brieger · Matthew Erickson · Andrew J Markwick · Carolyn Astley · David J Kelaher · Derek P B Chew

Reports of adverse events related to calcium supplementation should be supported by rigorous evidence Calcium is an essential nutrient, not only because of its major role in bone, where 99% of it is stored, but because of its central role in neuromuscular function. It is this latter role that explains why ionised calcium in the blood and tissue fluids is one of the most tightly controlled analytes of those that are commonly measured.1 However, maintenance of the calcium level in tissue fluids carries with it the penalty of continuous loss of calcium through the kidneys, bowel and skin, even on a low calcium intake, which is why the recommended daily calcium allowance for adults is relatively high, at 1000 mg.2 Nutritional deficiencies of other minerals, such as magnesium and phosphate, are rare because their tissue fluid levels are not tightly controlled but vary with intake and, therefore, so does their excretion. Calcium is different; reducing calcium intake has a marginal effect on extracellular calcium (and therefore on calcium excretion) because bone is mobilised to maintain the calcium level, which leads sooner or later to the development of osteoporosis. This is the case in laboratory animals3 and, by implication, in humans. Osteoporosis is therefore the index disease for calcium deficiency,4 just as rickets and osteomalacia are the index diseases for vitamin D deficiency; however, there is some overlap between them because the secondary hyperparathyroidism associated with hypovitaminosis D5 increases bone resorption. This is not to suggest that all adult osteoporosis is due to calcium deficiency, but simply to point out that the increase in bone resorption which follows menopause6 can be largely or wholly explained by the fall in calcium absorption and rise in obligatory calcium excretion which occur at this time,7 and also occur in oophorectomised animals.8,9 (The loss of a direct antiresorptive action of oestrogen on bone at menopause cannot be excluded but is probably quantitatively much less important.) For these reasons, it has become standard practice to recommend calcium supplementation to postmenopausal women, increasingly with vitamin D, to prevent or delay bone loss and reduce fracture risk. In the largest meta-analyses, calcium with vitamin D in adequate dosage reduces fracture risk by 25% or more, but vitamin D alone is not effective.10,11 Until very recently, calcium supplementation was not thought to cause any significant side effects. However, a New Zealand team recently reported an increase in the mean rate of mainly self-reported myocardial infarction in participants who were allocated to receive calcium supplements in five prospective trials for which patient-level information was available.12 Although the effect was not significant in any of the trials individually, it was significant at the 5% level in the whole series and has attracted sufficient media attention to endanger the use of calcium in the prevention of osteoporosis in postmenopausal women. An extension of this case against calcium recently appeared in this Journal, in a position statement on fracture prevention in aged-care facilities that was co-authored by one member of the New Zealand team.13 The article not only ignores the seminal work of Chapuy and colleagues on fracture prevention with vitamin D and calcium in aged care homes,14 but specifically opposes the general use of calcium supplementation on four separate grounds, none of which are directly referenced. The first is that long-term compliance with calcium supplementation is very poor, whereas in most trials it is not significantly different from compliance with placebo.15 The second is that the anti-fracture efficacy of calcium is marginal, despite overwhelming evidence to the contrary in the largest meta-analyses.10,11 The third is a bizarre claim that calcium could increase the rate of hip fracture; this is only supported by one trial (by one of the co-authors of the position statement) in which the adverse effect was not remotely significant in participants who complied with calcium supplementation,15 which is widely regarded as an anomaly and is contradicted by a later meta-analysis.16 The final is that calcium supplementation could increase the risk of myocardial infarction, which is highly contentious and negated by the latest meta-analysis of 17 trials.17 These negative statements about calcium (which are not reflected in the article’s abstract) are coupled with the promotion of bisphosphonates — particularly the intravenous variety — despite the fact that virtually all the bisphosphonate trials have incorporated calcium supplements. It may therefore be relevant that this article arose from a meeting financed by a pharmaceutical company that happens to market an intravenous bisphosphonate and gave some form of assistance to six of the 10 authors.13 Since it is clearly stated that this meeting was endorsed by the Royal Australian College of General Practitioners, the Australian and New Zealand Bone and Mineral Society and Osteoporosis Australia, there is a strong implication that these bodies also support the article itself. It is questionable whether such public bodies should lend their authority to a position statement of uneven quality and which runs the risk of being seen as commercially driven.

B E Christopher Nordin MD, FRACP, DSc

To the Editor: I am writing about important errors contained in a letter of reply by Hamilton-Craig.1 In his response to a letter by Montgomery,2 he states: 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 [cardiovascular disease] events in the ezetimibe group (P = 0.02; number needed to treat, 23), driven by a reduced need for coronary artery bypass grafting. However, in the SEAS trial, patients were treated with statin plus ezetimibe or with placebo, not with statin plus placebo. Therefore, the reduction in ischaemic events in the statin/ezetimibe group cannot be attributed to ezetimibe, as it could have been caused by the effect of simvastatin alone (or by the combined effect of the two drugs). I note also that the absolute reduction in ischaemic events over the course of the trial was 4.4% (15.7% v 20.1%), not 4.7%.3 With respect to the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial, Hamilton-Craig states: As no placebo group was included, neither lack of benefit nor harm from ezetimibe therapy can be inferred.1 In the ENHANCE trial, patients with familial hypercholesterolaemia were treated with simvastatin plus ezetimibe or simvastatin plus placebo. There was no significant difference in progression of mean carotid intima media thickness (CIMT) between the two groups (0.0058 mm in the simvastatin/placebo group v 0.0111 mm in the simvastatin/ezetimibe group [P = 0.29]).4 Therefore, contrary to Hamilton-Craig’s statement, there was a placebo group, and a lack of benefit from ezetimibe was shown in the trial. Thus, the SEAS trial was unable to confirm a benefit of ezetimibe, as the active treatment arm included both a statin and ezetimibe, while the ENHANCE trial showed no additional benefit of ezetimibe on the surrogate endpoint of CIMT progression in patients taking a statin. Author’s note: The United States Securities and Exchange Commission disclaims responsibility for any private publication or statement of any Commission employee or Commissioner. This letter expresses my views and does not necessarily reflect those of the Commission, the Commissioners, or other members of the Commission staff.

Marilyn K Mann

To the Editor: I would like to endorse the letter by Montgomery1 questioning the efficacy of ezetimibe. As yet there are no data to support its use in clinical trials using carotid intima media thickness (CIMT) as a measure of treatment effectiveness, and there is also some evidence to suggest it could be harmful. A randomised trial conducted by Berneis et al2 suggested that ezetimibe may induce an unfavourable pro-atherogenic low-density lipoprotein (LDL) subfraction profile by increasing small, dense LDLs. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial3 compared simvastatin/ezetimibe 40/10 mg daily with placebo, so any benefit from that treatment may have been from either the ezetimibe or the simvastatin. It tells us nothing about the effectiveness of ezetimibe alone. Until the results of clinical trials are available, I believe ezetimibe should be used with much reluctance and only considered as a last resort. I agree with Hamilton-Craig4 that it is a matter of concern that slow-release niacin, which is effective and safe, is not available under the Pharmaceutical Benefits Scheme in Australia. Searching for supplies of this drug in Australia or overseas seems the best option for treating patients whose levels of LDL cholesterol are inadequately controlled with statin therapy.

Brett H Forge