Selected state of the art research in internal medicine, 2017

In late 2017, the specialty editors of the Internal Medicine Journal (IMJ) were tasked with providing a summary of their particular discipline of internal medicine. The result was a summary of selected ‘state of the art’ papers for 10 disciplines of relevance to this journal. General internal medicine is a discipline that deals with the ‘big picture’ of clinical care, both from the perspective of total care of individual patients, especially those with multi-organ disease, and the system of care in regards to quality, safety and efficiency. One notable paper in recent years provided, for the first time, an evidence-based rate for compliance with the National Emergency Access (4 h) Target (NEAT).1 Prior to this study, the conventional wisdom was that the greater the proportion of patients who exited hospital emergency departments (EDs) within 4 h of presentation, the better the patient outcomes, with target rates of 90% or more being promulgated. Data were collected from 59 hospitals throughout Australia on 12.5 million ED episodes of care and million in-patient episodes of care between 1 July 2010 and 30 June 2014. A highly significant (P < 0.001) linear, inverse relationship between hospital standardised mortality ratio for emergency patients (eHSMR) and total and admitted NEAT compliance rates was found. The eHSMR declined to a nadir of 73 (i.e. observed risk-adjusted in-patient mortality 27% less than that expected) as total and admitted NEAT compliance rates rose to 83% and 65%, respectively. Further decrease in eHSMR with higher compliance rates could not be demonstrated. These findings caused Queensland Health and other State Health Departments to revise their nominated targets to be more in line with the evidence-based rates. The same research group also defined which types of patients benefited most from compliance with NEAT, with older patients, those admitted after hours and those with time-sensitive acute cardiorespiratory illness demonstrating significantly lower mortality following introduction of NEAT. Other articles that have had impact included new clinical practice guidelines on care of patients with acute coronary syndromes which, for the first time in Australia, met all criteria of high-quality, trustworthy guidelines set by the US Institute of Medicine.2 Deprescribing inappropriate medications in older people subject to polypharmacy was shown to be safe and effective, and indeed reduced mortality.3 Cognitive biases that may predispose to clinical decisions that result in low value care were introduced to clinical audiences in an article, which attracted considerable professional and media interest, and was circulated within college circles.4 Research in the field of cardiac arrhythmias embodies the concept of translational medicine – from bench to bedside, from genetics to animal models to clinical trials. Australian and New Zealand researchers continued to be at the forefront of all aspects of translational research in 2017. Starting with genetics, the team at the Centenary Institute in Sydney characterised the genotype and phenotype of Australian patients with hypertrophic cardiomyopathy and found a much less malignant phenotype in those with non-familial subtype and proposed a revised clinical pathway for follow up and management.5 Moving to a basic science level, the team at the Centre for Heart Rhythm Disorders, University of Adelaide, examined the development of arrhythmogenic substrates for atrial fibrillation in a rat model of hypertension with and without obesity, increasing our understanding of the mechanisms behind developing an atrial fibrillation (AF) phenotype.6 This adds to their impressive collection of work on AF mechanisms and the importance of obesity and the metabolic syndrome in the development of AF again from a mechanistic level. The Westmead group in Sydney examined the effect of intra-myocardial adipose tissue on scar in an ovine model of infarction.7 Their novel findings have implications on how we measure scar and how intra-myocardial adiposity might affect electrophysiological properties of scar and the risk of arrhythmia and sudden death. On the subject of scar and sudden death, the Flinders group in South Australia published a methods paper for cardiac magnetic resonance (CMR) guide, a large multinational, multicentre study of CMR-guided therapy in mild to moderate heart failure, where patients with scar defined on CMR will be randomised to implantable defibrillator or loop recorder.8 This trial has the potential to alter guidelines significantly and should report in a few years. Staying with clinical trials, the team led by the Baker Institute and the Alfred Hospital in Melbourne published the results of a randomised controlled trial of catheter ablation versus rate control in patients with AF and left ventricular systolic dysfunction – the CAMERA-AF trial.9 They demonstrated significant improvement in left ventricular ejection fraction in those undergoing ablation, especially in the group without scar on CMR, challenging the paradigm that rate control strategy is the appropriate strategy in this group. One of the most heated controversies in the field of public health in the last few years has been the safety and desirability of electronic cigarettes (e-cigarettes) containing nicotine. The technical term is electronic nicotine delivery systems (ENDS) and their use is popularly referred to as ‘vaping’. On the one hand, advocates for their use cite the potential reduction in the immense burden of tobacco-related death and disease if the use of e-cigarettes were to replace tobacco to any extent.10 However, few soundly performed clinical trials of e-cigarettes as quitting aids have yet been published and the evidence of their effectiveness is currently uncertain.11 On the other hand are those who argue that, whatever the theoretical benefits, their manufacture and marketing is being taken over by tobacco manufacturers who see widespread and visible use of e-cigarettes as a way of re-normalising the use of the conventional tobacco product.12 An important concern is emerging evidence that use of ENDS by adolescents and adults, the prevalence of which is rising steeply in some countries, is associated with subsequent cigarette smoking, although a cause and effect relationship has not been fully established.13 While it is very likely that the use of ENDS leads to lower exposure to toxins than does tobacco smoking, concerns remain about fire risk, passive exposure to toxins and child poisoning through access to nicotine liquids. In Australia, the sale of the nicotine is banned by Commonwealth legislation but e-cigarettes (without the nicotine liquid) are freely available; after a period of uncertainty, all Australian states and territories have regulated the sale of e-cigarettes to prevent their sale to minors, to limit advertising and to ban their use in tobacco smoke-free areas. This is a rapidly evolving issue, and many of the uncertainties regarding risks and benefits are likely to be resolved in the next few years. While regulation is essential to prevent initiation by minors and re-normalisation of cigarette smoking, flexibility is required in the event that properly controlled trials demonstrate the value of e-cigarettes in smoking cessation. As always it is both the best and the worst of times in infectious diseases with great advances, including the possibility of disease elimination with new medications and the use of new diagnostics including whole-genome sequencing of infectious organisms being matched by rapid development of resistance organisms in bacteria that may render anti-bacterial therapies redundant. Hepatitis C virus now has pan-genomic therapy requiring as little as 8 weeks of therapy, and there is hope that no more new drugs may be needed for global elimination. Individuals on human immunodeficiency virus (HIV) therapy with an undetectable viral load can now safely have condomless sex without fear of transmitting the retrovirus. In a study using CRISPR (clustered regularly interspaced short palindromic repeats) technology, Yin and colleagues demonstrated the ability to first infect humanised mouse models with HIV and then excise the HIV using single-guided RNAs. The study demonstrates the possibility of manipulating the genome not only for cure of genetic diseases but also for the elimination of communicable diseases without the use of vaccines or anti-microbials, though many steps are required before clinical use of this technology for this purpose.14 Meanwhile tuberculosis, the great plague of the 19th century, is now the number one single infectious killer again surpassing both HIV and hepatitis C virus. The major recent advance in the management of type 2 diabetes is the finding that new therapeutic options that improve glycaemic control also reduce cardiovascular risk. In 2016, the glucagon-like peptide 1 (GLP 1) analogue liraglutide was reported to reduce major adverse cardiovascular events in high-risk patients compared to usual care (hazard ratio = 0.87; 95% confidence interval (CI) 0.78–0.97, P = 0.01 for superiority).15 GLP 1 analogues join sodium glucose transporter 2 inhibitors as glucose-lowering agents that have been reported to reduce cardiovascular risk. Liraglutide is not funded for use in Australia on the Pharmaceutical Benefit Scheme. Once-weekly exenatide is a GLP 1 analogue that is funded on the Pharmaceutical Benefit Scheme. Patients randomised to once-weekly exenatide had a 9% lower rate of cardiovascular events, but this difference did not reach statistical significance (hazard ratio = 0.91; 95% CI 0.83–1.00, P = 0.06 for superiority).16 An upcoming Clinical Perspectives article in the IMJ will place these findings in the Australian clinical context. Media outlets across the globe reported on an article from the IMJ published in May 2017.17 The finding that a myocardial infarction can be triggered by a respiratory infection garnered global attention. People both in and out of medicine might have initially expected that a cold or the flu can cause a heart attack. Previous studies had suggested an association but this landmark paper in the IMJ provides the best scientific proof to date. Working in Sydney, Tofler and colleagues used a stringent case – crossover methodology. They studied 578 patients admitted to the Royal North Shore Hospital with confirmed myocardial infarction. All completed a questionnaire and underwent coronary angiography. The relative risk for myocardial infarction occurring within 1–7 days following respiratory infection symptoms was found to be 17. This is a large magnitude effect. The research area is not one that will be open to a direct randomised control trial of viral or respiratory infection, and therefore the paper should stand for considerable time as a major work in the field. As such it truly did merit the global attention it received and it is now ranked in the top 5% of research outputs scored by Almetric. It also nicely illustrates the global impact that the IMJ can have. Emergency medicine continues to be buffeted by rising demand for healthcare and higher acuity in rapidly ageing and chronically sick patients. ED congestion around the world has compelled administrators and policymakers to understand better the complexity of front-end hospital services and the deleterious impact congestion has on clinical outcomes, staff morale and retention. Observational studies, historical cohort and time-trend studies abundantly demonstrate increased ED demand, reduced ED throughput and delays to hospital admission are harmful to patients and stressful for ED staff. There are tantalising hints of single or bundled process of care interventions and mandates (such as the 4-h NEAT) hold promise in improving ED care. Elder et al.18 gathered widely scattered evidence in assessing strategies to improve ED delays in a systematic review. Increased nursing scope of practice, physician-assisted triage and medical assessment units were all found to work. Rather than conduct more primary research, it is time to try to summarise the many single health system studies that have already been published about ED processes. Emergency medicine is not pre-occupied with just improved hospital and ED functioning at a systems level. A high-impact clinical trial assessing the reputed benefits of early goal-directed therapy (EGDT) for septic shock has finally put EGDT to bed. The PRISM Investigators,19 a collaborative patient-level meta-analysis conducted by ED and intensive care unit colleagues in Australia/New Zealand, the UK and the United States, found no mortality risk reduction from aggressive haemodynamic management in adults suffering severe sepsis. PRISM and the Australasian Resuscitation in Sepsis Evaluation (ARISE) progenitor study represent a clarion call for emergency medicine's aspiration to cross-disciplinary research with other specialties represented by IMJ. Over the past 25 years the emergence of evidence-based treatments for acute stroke has driven the development of systems of stroke care. The advent of stroke units, thrombolysis and, more recently, endovascular clot retrieval (ECR) has demanded that clinicians adapt practice to incorporate these new therapies to optimise delivery of care to patients. In 2015, several landmark clinical trials conclusively demonstrated the superiority of ECR in combination with thrombolysis over thrombolysis alone and have forever changed the landscape of stroke practice.20 Previously it had been considered that ECR was only available to patients fortunate to live close to major metropolitan stroke centres. Emerging data suggest that in carefully selected patients, the opportunity to benefit from ECR might extend to as long as 24 h after symptom onset. This is particularly relevant to rural and regional Australia, and demands that systems be developed to co-ordinate rapid patient assessment and transfer of stroke patients. In August 2017, Bray and colleagues21 described the development of a strategic framework to improve access to stroke treatment including ECR across Victoria. This includes the development of a clinical network and telemedicine. Other states are developing similar systems, so the future now looks greatly improved for long disadvantaged, rural stroke patients. The advocacy for cannabis, currently considered an ‘illegal’ drug, as a therapeutic agent contrasts starkly with the epidemic of addiction to the legal drug prescription, opioid analgesics. The evidence for cannabidiol for intractable childhood epilepsy in achieving seizure-free status was found this year to be still lacking.22 Similarly, calls for compassionate access to medicinal cannabis for the nausea and vomiting of terminal illness have to date not been found beneficial although most studies have compared medicinal cannabis with older anti-emetics and not the newer formulations.23 Systematic reviews of medicinal cannabis for a range of other medical conditions have highlighted the lack of standard research-based safety and effectiveness data that are normally required for a novel therapeutic agent.23 The issue has put physicians in a difficult position with calls from patients, community and some politicians, demanding access to medicinal cannabis for a range of conditions. At the same time, physicians face an epidemic of prescription opioids in the Western world. Australia has followed similar trends to the United States and Canada with substantial increases in prescription opioids prescribing over the past 20 years.24 These alarming trends have lead to unprecedented deaths and calls for universal precautions when prescribing these analgesics, re-scheduling of over-the-counter preparations of codeine by the Therapeutic Goods Association and other systems changes such as Real Time Prescription Monitoring in Australia. Such 21st century health issues impact on physicians and have been the topic of much public debate, requiring medical professionals to reflect on a completely new way of practising according to the adage ‘first do no harm’. Internationally, clinical pharmacology has had an active year with research including new drug development and repurposing of old drugs, understanding how the cannabis plant can be developed into a potential therapeutic product, problems and development with biosimilar agents and issues around pricing and reimbursement. The IMJ covered much of this, with a focus on individualised ways of using even very old drugs better, based on phenotypic, genetic and pharmacologic factors, for example on optimising intravenous iron dosing in pregnancy,25 use of gentamicin in pregnancy,26 in neonates and in the elderly, use of anti-cholinergic drugs in the elderly, interpretation of penicillin allergy documentations and the safety of benzbromazone in special populations. The IMJ received several submissions on drug toxicity. These included a review of life-threatening adverse events, specific adverse events of new drugs such as PUO (pyrexia of unknown origin) with rosuvastatin,27 autoimmune hepatitis and myositis with statins,28 drugs interactions with denosumab, toxic Chinese therapies, toxicity with complementary therapies including from ayurvedic plumbisms. Clinical effects from drugs of abuse (khat29 and cardiomyopathy), and management of patients with drug and alcohol problems and clinical comorbidities were commonly downloaded. The IMJ also followed international concerns about careers for clinical academics, and education and training in medicines, and career paths in clinical pharmacology. This potpourri of leading-edge clinical science from last year is indicative of the prominence of our editors in their respective disciplines. The Editorial Board welcomes comments and suggestions for future summaries such as this.

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