Impact of grief delivered via media technology

Advances in media technology have had a significant impact on our daily lives, in terms of how we conduct business and leisure. Recent events have also had significant emotional impact and we wish to highlight the potential health impact. The grief experienced following the death of a loved one can be one of the greatest stressors for those surviving — spouse and/or relatives. It is not only the emotional strain but also physiological changes in the immediate period after bereavement1,2 that affect health.

Bereavement may also affect non-relatives, which was only captured by these two patients referred independently for ambulatory blood pressure (ABP) monitoring as part of their clinical management. Both watched the televised broadcast of funeral proceedings for Australian cricketer Phillip Hughes. Although neither was a relative of Phillip Hughes and neither had met him, they both reported an emotional response to the broadcast.

Panel A in the Box shows the ABP recording for a woman who was taking an angiotensin II receptor antagonist. The recording shows that she had an increase in systolic blood pressure (25 mmHg) while she was sitting watching the funeral that was comparable with her responses to physical activity.

The ABP recording for the second woman is shown in Panel B in the Box; her antihypertensive therapy included β-blockade. There was a 25 mmHg increase in systolic blood pressure while she sat watching the broadcast of the funeral. The increase was comparable with that for people with mild hypertension receiving mental stressor tests3 and may have been greater in the absence of β-blockade.

Such increases in blood pressure reflect overall changes in the cardiovascular system at the time of emotional stress and are associated with heightened cardiovascular risk.4,5 We therefore need to be aware of the significant impact that media technology may have on our health and consider preventive treatment strategies.

1
Ambulatory blood pressure recordings for two patients who watched a televised funeral*

*Neither patient was related to the deceased.

[Correspondence] Infective endocarditis and antibiotic prophylaxis

Mark Dayer and colleagues1 outline an increased incidence of infective endocarditis since cessation of antibiotic prophylaxis for dental procedures in the UK. However, as the authors clearly point out, they are unable to show a causal association. The increase might be ascribed to several factors, such as improved coding of infective endocarditis, which was incomplete before 2008. Since 2009, infective endocarditis has almost become a notifiable disease, with reporting of cases to the National Institute for Cardiovascular Outcomes Research (NICOR) by all UK congenital cardiac centres.

[Correspondence] Infective endocarditis and antibiotic prophylaxis – Authors’ reply

John Chambers and Jonathan Sandoe raise concerns that our data are limited by scarcity of microbiological information. We agree, and are pursuing this further. Data from Public Health England, the most robust data available, suggest a decline in staphylococcal bacteraemia and septicaemia between 2003 and 2012 and a corresponding increase in streptococcal bacteraemias (appendix). Furthermore, US studies have identified a concerning increase in streptococcal infective endocarditis since modification of the American College of Cardiology (ACC) and American Heart Association (AHA) guidelines in 2007.

[Editorial] Focusing on angina

The 2015 Congress of the European Society of Cardiology will take place from Aug 29, to Sept 2, in London, UK. One focus will be on angina—the most common manifestation of coronary artery disease, a leading cause of death worldwide. Angina doubles the risk of major cardiovascular events, and the greater its severity, the greater the risk of myocardial infarction or death. Evidence to guide the management of angina is therefore important.

Better Cardiac Care measures for Aboriginal and Torres Strait Islander people: first national report 2015

This is the first national report on the 21 Better Cardiac Care measures for Aboriginal and Torres Strait Islander people. It shows that: the age-standardised death rate due to cardiac conditions for Indigenous people was 1.6 times that for non-Indigenous people; mortality from cardiac conditions for Indigenous Australians decreased by 41% between 1998 and 2012, while access to cardiac care has improved over time.

Splenic infarction after reversal of warfarin using Prothrombinex-VF in a patient with a mechanical aortic valve

Clinical record

A 55-year-old man presented to the emergency department with a 1-day history of upper abdominal pain, haematemesis and malaena on a background of aortic valve replacement and three-vessel coronary artery bypass graft surgery. At the time of admission, his medications included warfarin (target international normalised ratio [INR], 2–3), metformin, gliclazide, ezetimibe, fenofibrate, carvedilol, ramipril, aspirin, omeprazole, duloxetine and tramadol.

Examination revealed tenderness in the right hypochondrium and epigastric regions with dark blood and malaena in the rectum. Results of biochemical investigations showed an INR of 3.2, haemoglobin level of 124 g/L (reference interval [RI], 130–170 g/L) and urea level of 10.3 mmol/L (RI, 2.5–7.3 mmol/L]. The patient had a history of chronic anaemia, with haemoglobin levels ranging from 120 g/L to 125 g/L during previous admissions in the same year. This presentation was attributed to an episode of acute upper gastrointestinal bleeding (proximal to the ligament of Treitz) exacerbated by warfarin and aspirin. Box 1 summarises the patient’s investigation results during his inpatient stay.

A second episode of perirectal bleeding while the patient was in the emergency department led to the decision to transfuse one unit of packed red cells and reverse warfarin. The method for reversal was decided using clinical acumen (discussed below) and practice guidelines (Box 2), and treatment comprised administering prothrombin complex concentrate (PCC; brand name, Prothrombinex-VF) at 50 IU/kg (patient weight, 100 kg) and 1 mg of vitamin K intravenously.

After a third episode of malaena (haemoglobin, 80 g/L), the patient was taken urgently, in spite of poor bowel preparation, for endoscopy to identify any reversible source of bleeding. The findings of the colonoscopy were indefinite and upper gastrointestinal endoscopy did not show any active source of bleeding, so we presumed that the haemorrhage was arising from the small bowel or colon.

Three hours after the endoscopy, still within the first 24 hours of his admission, the patient developed chest pain and was found to have new ST-segment changes in leads V4–V6 and elevated serial troponins (peaking at 19 ug/L [RI, < 0.04 ug/L). Subsequent angiography revealed native triple vessel disease and graft vessel disease; however, no definite culprit lesion or thrombus were identified, so angioplasty was not considered. The likely explanation for this event was a Type 2 myocardial infarction (secondary to ischaemic imbalance due to acute bleeding) rather than an acute coronary event secondary to plaque rupture.

At this stage, we felt that the benefit of introducing antithrombotic therapy to prevent further thrombotic complications outweighed the risk of any significant gastrointestinal bleeding. Aspirin was recommenced, and heparin was commenced as bridging therapy with a target activated partial thromboplastin time (APTT) of 70 seconds.

Three days after admission, the patient developed left flank pain with a distended abdomen and guarding in the left upper quadrant. An urgent contrast computed tomography scan showed a wedge-shaped, hypodense area with absent perfusion in the lower pole of the spleen, consistent with an infarction (Figures A–C). A thrombus was identified in a small branch of the splenic artery supplying the lower pole of the spleen (Figure B). No source of the thrombus was found on transthoracic echocardiography (TTE) or transoesophageal echocardiography (TOE), and results of thrombophilia screening were negative. Although the patient received intravenous heparin anticoagulation therapy during this time, his APTT was subtherapeutic (32 s). The infarction was mananged conservatively.

After the patient’s symptoms resolved and there was no further bleeding, warfarin was recommenced on Day 12 of admission. The patient was discharged on Day 15 of admission after no further cardiovascular or gastrointestinal complication.

This case highlights the difficulty of managing patients with a mechanical valve replacement who sustain acute major bleeding. In these patients, continuing anticoagulation exacerbates bleeding, but reversing or discontinuing it poses the risk of embolic complications from a mechanical prosthesis, some of which were seen in this patient. Current recommendations for these patients dictate the use of prothrombin complex concentrate (PCC), but this is unproven and based only on scant evidence and a series of case reports.1

This patient had two infarctions (myocardial and splenic) that could be attributed to either an embolic source from the mechanical aortic valve in the setting of subtherapeutic anticoagulation or the procoagulant effects of Prothrombinex-VF.

If the mechanical valve was the source of the emboli, then, irrespective of coagulation status, a thrombus in one of the left cardiac chambers or on the mechanical valve would be expected to be seen on echocardiogram. However, both TTE and TOE did not show this. Furthermore, while anticoagulation was subtherapeutic at the time of the splenic infarction, anticoagulation with heparin had been commenced according to Queensland Health protocols. Therefore, it is unlikely that either one of the infarctions was secondary to a thrombus from the mechanical aortic valve.

The non-ST-segment myocardial infarction could potentially be attributed to several alternative factors, including a significant history of cardiovascular disease, anaemia, sympathetic stress secondary to bleeding, or coronary embolisation. However, the splenic infarction is very unlikely to have occurred spontaneously in the absence of Prothrombinex-VF.

Current guidelines for active bleeding requiring emergency reversal recommend Prothrombinex-VF, and it is preferred over fresh frozen plasma owing to the immediacy of reversal2,3 which has been well documented in selected case reports.4 Prothrombinex-VF has been shown to be a safe gold standard in warfarin-related bleeding episodes.2,3,5,6

However, there is no consensus regarding treatment in patients with mechanical heart valves who require emergency anticoagulation reversal. Most case reports recommend weighing up the bleeding risk of warfarin with the thromboembolic risks of anticoagulation reversal with Prothrombinex-VF. A number of case reports have shown significant reported mortality and morbidity associated with warfarin-induced bleeding, a mortality rate of 9.5%–13.4%, and a one in 12 chance of rebleeding,7 which is why we made the decision to reverse warfarin in this patient.

Guidelines recommend vitamin K to sustain the long-term effect of warfarin reversal, but its clinical use is inconsistent. The concern with using a large dose of vitamin K (5–10 mg) is a period of warfarin reversal that outlasts the period of acute bleeding, thereby placing the patient at risk of subtherapeutic anticoagulation. For this reason, we only administered 1 mg of vitamin K. Despite this level of caution, the patient still sustained two infarctions that may have arisen from subtherapeutic anticoagulation. This suggests that further investigation is needed in administering vitamin K to patients with mechanical heart valves.

Lessons from practice

Caution needs to be exercised whenever prothrombin complex concentrate (PCC) is used in any acute setting for correction of warfarin-induced bleeding, particularly in the context of mechanical valves
Further studies are needed to assess the safety of PCC and vitamin K use in the patients with mechanical heart valves.
We suggest that complications such as the one described in this case report are rare and not substantial enough to contraindicate PCC.

Figure

A:
Contrast medium entering the inferior branch of the splenic artery, with absent perfusion in the lower pole of the spleen.

B:
A visible thrombus in the inferior branch of the splenic artery.

C:
Splenic infarction, seen as a wedge-shaped, hypodense area.

1
A summary of investigations during the patient’s inpatient admission

Event	Day of admission	INR (TR, 2.0–3.0; normal, 1.0)	APTT (target, 70 s; normal, < 40 s)	Hb (RI, 130–170 g/L)

Admission	0	3.2	n/a	124
Endoscopy	0 (about 2 h after warfarin reversed)	1.5	n/a	80
Myocardial infarction	0 (about 3 h after endoscopy completed)	n/d	n/a	88
Heparin commenced	2	1.3	29 (initially)	88
Splenic infarction	3	1.3	32	93

INR = international normalised ratio. TR = therapeutic range. RI = reference interval. APTT = activated partial thromboplastin time. Hb = haemoglobin. n/a = not applicable. n/d = not done.

2
Australasian Society of Thrombosis and Haemostasis guidelines for warfarin reversal*

*Reproduced from the Medical Journal of Australia.
2

Nation pays high price for unnecessary tests, unproven treatments

Cracking down on inefficient and clinically unnecessary practices like over-ordering diagnostic tests, prescribing inappropriate medications and using unproven or speculative treatments could save the health system more than $15 billion a year, a leading epidemiologist has said.

In a provocative speech to the AMA National Conference in which he called for a transformation in the way in care is conceived and delivered, Associate Professor Ian Scott said up to 30 per cent of health spending was wasteful or went on procedures and treatments that were of little benefit or could actually be harmful.

A/Professor Scott, who is director of Internal Medicine and Clinical Epidemiology at Brisbane’s Princess Alexandra Hospital, said while some interventions and treatments, like vaccination programs, public health campaigns, chemotherapy, renal dialysis and some cancer screening programs were effective uses of scarce health funds, the pay-off from many other practices was more questionable.

He questioned the bias in the medical profession to provide intensive care, including “heroic interventions”, for very ill patients – 30 per cent of health funds are spent on health care in the last year of life, including $2.4 billion on providing hospital care to the elderly – and suggested a more conservative approach involving a shift in focus away from treatments that do not improve survival beyond six months or enhance quality of life.

One of the oft-cited sources of inefficiency and cost blow-outs in the health system is in the area of diagnosis, including the tendency to over-prescribe diagnostic tests.

Much of this has been attributed to the rise of “defensive medicine”, which MDA National Manager of Medico-legal and Advisory Services, Dr Sara Bird, defined as the ordering of treatments, tests and procedures “primarily to help protect the doctor from liability”, rather than to substantially advance patient diagnosis or treatment.

Dr Bird, who addressed the same AMA National Conference policy session as A/Professor Scott, said that although the incidence of defensive medicine was difficult to measure, evidence suggested it was widespread.

In the United States, 96 per cent of specialists practising in fields at high risk of litigation confessed to practising defensively, including 43 per cent who reported ordering unnecessary diagnostic imaging tests.

Dr Bird said the situation appeared to be similar in the United Kingdom, where almost 80 per cent of hospital-based doctors said they practised defensive medicine, including 60 per cent who admitted ordering unnecessary tests and 55 per cent who said they made unnecessary referrals.

In Australia, research indicates that doctors who have been the subject of legal action are much more likely to practise defensively – 55 per cent ordered more tests and 43 per cent made more referrals than was considered usual.

A/Professor Scott said that in addition to unnecessary tests, often clinicians provided treatments that were of little or no value.

He lauded the National Prescribing Service’s Choosing Wisely initiative, under which so far more than 200 routinely used treatments have been placed under scrutiny.

The Federal Government has also commissioned a review of Medicare Benefit Schedule items, led by Sydney Medical School Dean Professor Bruce Robinson, to scrutinise and assess the appropriateness of more than 5500 listed services.

AMA President Professor Brian Owler has cautiously welcomed the reviews.

Professor Owler said that although it was important to rigorously assess the value and appropriateness of procedures and treatments, it was vital the process was not driven primarily a search for savings, and that it had the support and involvement of medical colleges and societies.

A/Professor Scott warned of “indication creep”, where a treatment proved to be of benefit to one group of patients is uncritically applied more broadly , such as cardioverter defibrillators, cardiac resynchronisation pacemakers and transcatheter aortic valves.

He urged a much more considered and cautious approach to the use of new interventions until there was rigorous evaluation of their safety and effectiveness.

A/Professor Scott said told the conference that clinical guidelines should take into account cost-effectiveness in recommending interventions.

He said often less intensive and cheaper management regimes for conditions such as bleeding peptic ulcers and urinary tract infections in children were just as safe and effective as higher-intensity regimens.

A/Professor Scott recommended that analyses of the comparative cost effectiveness be an integral part of the assessment of each new service or intervention.

He told the conference this cost-effectiveness approach should also inform the selection of patients for a particular treatment.

The epidemiologist said interventions should be targeted to those who would derive greatest benefit.

Adrian Rollins

Signs not good for flu season

The nation’s top medical officer has issued an urgent call for people, particularly vulnerable groups including pregnant women, the elderly and those with chronic illnesses, to get vaccinated against the flu amid signs the nation is headed for its worst season on record.

Official figures show that so far this year more than 14,124 have caught the flu – double the long-term average for the period – and a third higher than for the same time last year.

In a worrying sign that the flu season is gathering momentum, figures compiled through the National Notifiable Diseases Surveillance System show that in in just one month, from 5 June to 6 July, an extra 4911 laboratory-confirmed cases were reported, including almost 2000 in the first week of July.

Underlining the seriousness of the illness, the Health Department said it had so far been notified of 36 deaths associated with influenza since the beginning of the year, with the likelihood that number will rise sharply as the rate of infection accelerates.

Commonwealth Chief Medical Officer Professor Chris Baggoley specifically urged people considered to be at risk, including those aged 65 years and older, Indigenous Australians, pregnant women, and those with cardiac disease and chronic respiratory conditions and illnesses, to take advantage of the free vaccine provided by the Government.

“Flu is highly contagious and spreads easily from person to person, through the air, and on the hands,” Professor Baggoley said. “We need to get higher uptake [of the vaccine] among these groups.”

The Chief Medical Officer emphasised the importance of doctors and other health professionals in helping ensure people were vaccinated against the disease.

“Immunisation is still the best form of protection from influenza, and health care professionals play an essential role in ensuring high uptake,” he said.

The National Seasonal Influenza Immunisation Program began late this year because of a rare double strain change in the vaccine to cover two new strains of the virus – one of which caused havoc in the northern hemisphere.

In the US alone, around 100 children were reported to have died from the flu during the northern flu season, and there was also widespread illness among the elderly.

For the first time under the national immunisation program, Australians have access to single-dose vaccines covering the four most common flu viruses, including three quadrivalent formulations.

The World Health Organisation and the Australian Influenza Vaccine Committee have recommended that vaccines this year cover one existing and two new strains – the California H1N1-like virus that has been in circulation since 2010, the Switzerland H3N2-like virus and the Phuket 2013-like virus.

There have been claims that the delay to the vaccination program has contributed to the strong start to the flu season by leaving a large number of people unprotected, and Professor Robert Booy of the Influenza Specialist Group told the Herald Sun fewer people had been vaccinated that “we would have liked”.

But Health Minister Sussan Ley said the Government was ahead of where it was last year in acquiring vaccine doses.

Ms Ley said that so far in 2015 4.5 million doses had been bought under the National Immunisation Program, 200,000 more than were distributed in 2014.

She did not say how many of these doses had been administered.

Ms Ley said the flu season usually peaked in August and September which, given that it usually takes around three weeks following vaccination to develop immunity, meant people needed to get themselves vaccinated as soon as possible.

Promisingly, early figures suggest vaccinations are helping to reduce the number and severity of infections.

The pilot Flu Tracking surveillance system, a joint University of Newcastle, Hunter New England Area Health Service and Hunter Medical Research initiative that collects data from a weekly online survey, has so far identified only low levels of influenza infection.

But it found that 3.4 per cent of those not vaccinated against the flu suffered fevers and coughs, and 2.1 per cent had to take time off work, while among those vaccinated, 2.7 per cent had coughs and fevers and 1.6 per cent reported having to take sick leave.

The results underline calls from AMA Vice President Dr Stephen Parnis for people, particularly elderly and vulnerable patients and health professionals, to make sure they are vaccinated against the flu.

Dr Parnis said it was important for doctors, nurses and other health workers to get the flu vaccine, for the sake of their own health as well as that of their patients.

Adrian Rollins

Determinants of variations in initial treatment strategies for stable ischemic heart disease [Research]

Background:

The ratio of revascularization to medical therapy (referred to herein as the revascularization ratio) for the initial treatment of stable ischemic heart disease varies considerably across hospitals. We conducted a comprehensive study to identify patient, physician and hospital factors associated with variations in the revascularization ratio across 18 cardiac centres in the province of Ontario. We also explored whether clinical outcomes differed between hospitals with high, medium and low ratios.

Methods:

We identified all patients in Ontario who had stable ischemic heart disease documented by index angiography performed between Oct. 1, 2008, and Sept. 30, 2011, at any of the 18 cardiac centres in the province. We classified patients by initial treatment strategy (medical therapy or revascularization). Hospitals were classified into equal tertiles based on their revascularization ratio. The primary outcome was all-cause mortality. Patient follow-up was until Dec. 31, 2012. Hierarchical logistic regression models identified predictors of revascularization. Multivariable Cox proportional hazards models, with a time-varying covariate for actual treatment received, were used to evaluate the impact of the revascularization ratio on clinical outcomes.

Results:

Variation in revascularization ratios was twofold across the hospitals. Patient factors accounted for 67.4% of the variation in revascularization ratios. Physician and hospital factors were not significantly associated with the variation. Significant patient-level predictors of revascularization were history of smoking, multivessel disease, high-risk findings on noninvasive stress testing and more severe symptoms of angina (v. no symptoms). Treatment at hospitals with a high revascularization ratio was associated with increased mortality compared with treatment at hospitals with a low ratio (hazard ratio 1.12, 95% confidence interval 1.03–1.21).

Interpretation:

Most of the variation in revascularization ratios across hospitals was warranted, in that it was driven by patient factors. Nonetheless, the variation was associated with potentially important differences in mortality.

Australian clinical trial activity and burden of disease: an analysis of registered trials in National Health Priority Areas

To improve Australia’s health, clinical research programs should devote substantial activity to advancing practice in areas of high clinical need. Clinical trials are designed to provide high-quality evidence of the effectiveness of new interventions to establish best clinical practice. However, few studies have examined the extent to which Australian clinical trials address priority areas of clinical need.

The Australian Institute of Health and Welfare (AIHW) National Health Priority Areas (NHPAs) were introduced to encourage appropriate targeting of health services and clinical research to improve health. Currently, there are nine NHPAs: cancer control, cardiovascular health, mental health, injury prevention and control, diabetes mellitus, obesity, arthritis and musculoskeletal conditions, dementia and asthma. These NHPAs account for approximately three-quarters of the total estimated burden of disease in Australia (1 915 600 of 2 632 800 disability-adjusted life-years [DALYs]).1

Previous studies have reported a disparity between the level of National Health and Medical Research Council (NHMRC) grant funding for studies investigating NHPA conditions relative to their disease burden.2,3 The founding of clinical trial registries, including the Australian New Zealand Clinical Trial Registry (ANZCTR) in 2005, provides the first opportunity to examine how well clinical trial activity in Australia is targeted to NHPAs.

Methods

We conducted a retrospective analysis using ANZCTR and ClinicalTrials.gov (CT.gov) data to report on Australian trial activity and characteristics for NHPAs; and to compare the level of trial activity to the relative burden of disease for each NHPA.

Ethics approval was not required for this analysis of publicly available trial data.

Data sources

Trial registration is voluntary in Australia.4

The ANZCTR is an online public registry of clinical trials maintained by the NHMRC Clinical Trials Centre, the University of Sydney. It collects information about trial interventions, investigated health conditions, planned recruitment, outcomes, funding and sponsorship using the World Health Organization-defined 20-item minimum dataset.5 Health conditions are coded using the United Kingdom Clinical Research Collaboration Health Research Classification System (http://www.hrcsonline.net). Additional data are collected about trial design, including randomisation and blinding. The ANZCTR 2011 Data Quality and Completeness Audit reported that, on average, at least 93 of 94 data fields for 148 trials were complete.6

CT.gov is an online public registry of clinical trials maintained by the United States National Library of Medicine (https://clinicaltrials.gov). It records similar data items to the ANZCTR.

Trial sample and characteristics

The trial sample included all trials of health-related interventions registered on the ANZCTR or CT.gov between 1 January 2008 and 31 December 2012 that included Australia as a country of recruitment. To avoid entering duplicate trial data, trials that listed a CT.gov or ANZCTR registration number as a secondary identifier were only included in the ANZCTR trial list.

Condition categories and codes were used to classify individual trials as addressing one or more NHPA conditions, or other, non-NHPA conditions. For each trial, we extracted information for: purpose of intervention (treatment, prevention, diagnosis, education/counselling/training, other/missing); allocation of intervention (randomised, non-randomised); trial phase (I–IV, not applicable, missing), blinding (blinded, open, other/missing), planned recruitment (reported as target sample size, and classified as < 100, 100–1000, > 1000 participants); participant age range (< 18 years, 18–69 years, ≥ 70 years); and countries of recruitment (Australia only, Australia and overseas).

Analysis

To measure trial activity, we recorded the total number and planned recruitment of registered trials investigating NHPA conditions. To assess whether trial activity reflected the burden of disease for each NHPA, we compared the relative trial activity targeted to each NHPA, measured as a proportion of the total trial activity, with the “expected” distribution of trial activity estimated from the relative burden of disease for that NHPA. Burden of disease was estimated from published estimates of DALYs for each NHPA expressed as a percentage of the total burden of disease and injury in Australia (%DALY).1

To describe disparities in relative trial activity by NHPA, we identified NHPAs where the observed trial activity was less than 50% or more than 200% of expected values. The χ2 goodness-of-fit test was also used to test for statistically significant differences between observed and expected trial activity for each NHPA. For these analyses, a two-sided P < 0.006 was regarded as statistically significant using the Bonferroni adjustment for multiple comparisons (nine comparisons).

For assessment of trial recruitment across NHPA, we also conducted a sensitivity analysis to examine trial recruitment to NHPA from Australian sites, where Australian recruitment was estimated from the planned recruitment from all ANZCTR trials plus 10% of the planned recruitment from CT.gov trials that included at least one Australian site. The figure of 10% was estimated from a randomly selected sample of 100 CT.gov registered trials that included at least one Australian site and represents the number of Australian sites as a proportion of all sites for each trial.

We also calculated the frequency distribution of trial characteristics for each NHPA. SAS, version 9.3 (SAS Institute) was used for data analyses.

Results

There were 5143 intervention trials registered during 2008–2012 that planned to recruit in Australia (ANZCTR, 3379; CT.gov, 1764). Of these, 3032 (59%) related to NHPA conditions (ANZCTR, 1908; CT.gov, 1124). Total planned recruitment for the trial sample was 2 404 609 participants, including 1 532 064 (64%) for NHPA trials (ANZCTR, 670 832; CT.gov, 861 232).

Trial activity in NHPA

The three disease areas that contribute the largest %DALY — cancer, cardiovascular diseases and mental disorders — also attracted the largest number of trial registrations and the largest planned recruitment (Box 1; Box 2).

The proportions of registered trials that investigated dementia or injury interventions were less than half those expected from their %DALYs (65/185 [35%] and 137/360 [38%], respectively; Box 1). The proportions of obesity and asthma trials were also lower than expected (195/386 [51%] and 68/123 [55%], respectively). In contrast, the proportion of registered arthritis and musculoskeletal diseases trials was about twice as high as expected on the basis of the %DALY (Box 1).

The proportions of planned recruitment to trials investigating obesity and dementia were also substantially lower than expected from their %DALYs (33 948/180 346 [19%] and 24 248/86 566 [28%], respectively), and was also low for asthma (29 468/57 711 [51%]) (Box 1).

When this analysis was repeated using estimated recruitment from Australian sites only, a similar pattern was observed, with the exception of recruitment to diabetes trials. For diabetes trials, total trial planned recruitment was relatively high (185 929/132 253 [141%]) compared with Australian sites (44 201/66 607 [66%]).

Trial characteristics

Overall, 2335 of 3032 (77%) NHPA trials used a randomised design and 1509 (50%) planned recruitment of ≤ 100 participants (Box 3). Of the 2931 NHPA trials that reported information about blinding, 1504 (51%) reported using it (Box 3).

About three-quarters of NHPA intervention trials investigated treatments (2321 [76%]) and 397 (13%) investigated prevention interventions (Box 3). The ratio of treatment to prevention trials ranged from less than 2 : 1 for obesity trials to 14 : 1 for cancer trials.

Most NHPA trials excluded children, whereas 2252 (75%) specified a maximum participant age of ≥ 70 years, or did not specify a maximum age (Box 3). International recruitment sites were reported in 1081 (36%) of NHPA trials (169 ANZCTR trials, 912 CT.gov trials) and varied by condition (Box 3).

Discussion

This study provides the first overview of clinical trial activity in Australia. We found that more than half of Australian registered intervention trials and planned trial recruitment are targeted to NHPA conditions.

Trial activity for cancer, cardiovascular diseases and mental disorders was high relative to other NHPA conditions, consistent with their position as the three major contributors to disability and premature death in Australia. In contrast, trial activity for obesity and dementia interventions was substantially less than the level expected from their contribution to the total DALY.

To interpret these results, the number of trials can be considered to provide a proxy measure for the number of active research questions being investigated to identify more effective interventions in each area. Planned trial recruitment provides a measure of the number of patients actively participating in research to determine best practice in each area.

These findings suggest there is a need to further examine research activity for obesity, dementia and asthma to determine if and how clinical trials research in these areas should be increased. However, this study does not allow us to define the optimum level of trial activity for each condition. Clearly, not all important research questions for NHPAs are amenable to investigation through clinical trials. For conditions where trial activity is already high relative to other disease areas, further increases may still represent good value for money by improving health care. For example, if promising new interventions are available; or practice variations or controversies exist with gaps in evidence to guide best practice. Conversely, for some conditions where trial activity is currently low, research priorities may warrant other study designs, such as those used in translational research or behavioural science, to develop new interventions.

This study also provides the first opportunity to assess the extent to which Australian trials are designed to provide robust, high-quality evidence for guiding practice. The use of randomisation and blinding provides a measure of trial quality; trial size provides an indicator of study power. Trials enrolling more than 100 participants are generally required to assess clinically meaningful health outcomes and to weigh up the benefits and harms of the new strategy, whereas smaller trials are generally designed to assess surrogate outcomes. About three-quarters of Australian trials used a randomised design; however, only around half reported blinding, or planned recruitment of more than 100 participants. These findings are slightly more favourable than those of a recent analysis of 79 413 intervention trials registered on CT.gov between 2000 and 2010, which reported that 70% used a randomised design, 44% used a blinded design and 38% enrolled 100 or more participants.7

One commonly raised concern about clinical trials research is the applicability of trial data to routine clinical practice populations and settings. Our finding that more than two-thirds of trials in NHPA areas did not exclude participants aged 70 years or older is encouraging.

The main strength of our study is that it provides a unique, timely overview of Australian clinical trials to inform current debate on the achievements, limitations and future directions for clinical trials research in Australia. Clinical researchers can use the same methods to further explore gaps for conditions within specific disease areas, as has been performed for cancer trials.8

There are two main limitations to our study that could affect our estimates of trial activity in different directions. First, we relied on trial registrations to estimate trial activity. As trial registration is not compulsory in Australia, we may have underestimated trial activity. Additionally, we only included international trials registered on the ANZCTR or CT.gov. A search using the WHO International Clinical Trials Registry Platform Search Portal (http://www.who.int/ictrp/search/en) showed that 11 096 of 11 412 (97%) trials with Australian sites are registered on these two registries. The total number of registered trials may therefore be 3% higher than our study estimate.

Second, our estimates of trial participation may overestimate the number of Australians participating in clinical trials, because 1622 of 5143 trials (32%) included sites outside Australia. Nevertheless, by including Australian sites, these trial recruitment figures capture participation in trials that can be expected to provide evidence relevant to Australian practice.

Despite these limitations, we believe our findings are valuable in informing initiatives to increase clinical trial activity.9,10 It is well documented that trial research is often not available to guide many routine clinical decisions about selecting interventions.11 To guide practice, large trials with adequate long-term follow-up are needed to identify small incremental improvements in health outcomes and/or adverse events. Our findings on trial size suggest that further efforts are needed to promote and support the conduct of large trials, or support the conduct of small high-quality trials that can later contribute data to meta-analyses.

Overall, we demonstrate the feasibility and value of using publicly available trial registry data to examine the profile of trials research for particular conditions and identify gaps in trial activity to inform trial initiatives. The ANZCTR provides a valuable resource for researchers to ensure new studies build on, or contribute to, existing trials.

1 Number of registered Australian intervention trials and total planned recruitment in National Health Priority Areas, as a percentage of total trial activity, and comparison to the expected number based on %DALY, Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, 2008–2012

	DALY		Trials					Planned recruitment
National Health Priority Area	Rank	%	Rank	Observed no. (%)	Expected no.	Observed/ expected %	P*	Rank	Observed no. (%)	Expected no.	Observed/ expected %	P*

Cancer control	1	19.0%	1	871 (16.9%)	977	89%	0.007	2	427 188 (17.8%)	456 876	94%	< 0.001
Cardiovascular health	2	18.0%	3	646 (12.6%)	926	70%	< 0.001	1	577 178 (24.0%)	432 830	133%	< 0.001
Mental health	3	13.3%	2	693 (13.5%)	684	101%	0.82	3	196 826 (8.2%)	319 813	62%	< 0.001
Obesity	4	7.5%	6	195 (3.8%)	386	51%	< 0.001	7	33 948 (1.4%)	180 346	19%	< 0.001
Injury prevention and control	5	7.0%	7	137 (2.7%)	360	38%	< 0.001	5	125 256 (5.2%)	168 323	74%	< 0.001
Diabetes mellitus	6	5.5%	5	282 (5.5%)	283	100%	1.00	4	185 929 (7.7%)	132 253	141%	< 0.001
Arthritis and musculoskeletal conditions	7	4.0%	4	410 (8.0%)	206	199%	< 0.001	6	109 107 (4.5%)	96 184	113%	< 0.001
Dementia	8	3.6%	9	65 (1.3%)	185	35%	< 0.001	9	24 248 (1.0%)	86 566	28%	< 0.001
Asthma	9	2.4%	8	68 (1.3%)	123	55%	< 0.001	8	29 468 (1.2%)	57 711	51%	< 0.001

DALY = disability-adjusted life-years. %DALY = DALYs expressed as a proportion of the total burden of disease in Australia.1 Observed number of trials is expressed as a percentage of total 5143 registered intervention trials. Observed planned recruitment is expressed as a % of total 2 404 609 planned recruitment. Expected number of trials is calculated by applying %DALY to total 5143 registered intervention trials. Expected planned recruitment is calculated by applying %DALY to total 2 404 609 planned recruitment. * χ2 goodness-of-fit test for comparison of observed versus expected values.

2 Relationship between trial characteristics and %DALY for each NHPA, Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, 2008–2012

The diagonal line represents the line of equality where %DALY is equal to trial number as a percentage of total registered trials (A) or planned trial participation as % of total planned trial participation (B). Dots below the line show NHPAs where the variable falls below the %DALY. The size of dots corresponds to the size of planned trial participation (A) or number of trials (B) for the NHPA.

%DALY = disability-adjusted life-years expressed as a proportion of the total burden of disease in Australia.1 NHPA = National Health Priority Area.

3 Australian intervention trial characteristics, overall and by National Health Priority Area (NHPA),* Australian New Zealand Clinical Trials Registry and ClinicalTrials.gov, 2008–2012

Characteristic	All trials	NHPA trials	Cancer	Cardio- vascular	Mental health	Obesity	Injury	Diabetes	Arthritis/ musculoskeletal	Dementia	Asthma

Total	5143	3032	871	646	693	195	137	282	410	65	68
Randomisation
Yes	3990 (78%)	2335 (77%)	564 (65%)	494 (77%)	579 (84%)	163 (84%)	125 (91%)	253 (90%)	321 (78%)	53 (82%)	59 (87%)
No	1137 (22%)	691 (23%)	304 (35%)	150 (23%)	113 (16%)	31 (16%)	12 (9%)	28 (10%)	89 (22%)	12 (18%)	9 (13%)
Missing	16	6	3	2	1	1		1
Intervention type
Treatment	3834 (75%)	2321 (76%)	732 (84%)	444 (69%)	494 (71%)	108 (55%)	103 (75%)	210 (75%)	357 (87%)	50 (77%)	46 (68%)
Prevention	781 (15%)	397 (13%)	52 (6%)	131 (20%)	98 (14%)	67 (34%)	25 (18%)	46 (16%)	34 (8%)	5 (8%)	10 (15%)
Diagnosis	152 (3%)	78 (3%)	29 (3%)	26 (4%)	11 (2%)	3 (2%)	2 (2%)	8 (3%)	4 (1%)	4 (6%)	0
Educational/ counselling/training	263 (5%)	171 (6%)	39 (5%)	26 (4%)	73 (11%)	10 (5%)	4 (3%)	15 (5%)	9 (2%)	5 (8%)	7 (10%)
Other/missing	113 (2%)	65 (2%)	19 (2%)	19 (3%)	17 (2%)	7 (4%)	3 (2%)	3 (1%)	6 (2%)	1 (2%)	5 (7%)
Age group (years)
Minimum age < 18†	987 (19%)	490 (16%)	122 (14%)	60 (9%)	156 (23%)	29 (15%)	42 (31%)	28 (10%)	57 (14%)	7(11%)	26 (38%)
Missing	5	2	1							1
Maximum age ≥ 70†	3652 (71%)	2252 (75%)	774 (89%)	558 (87%)	397 (57%)	69 (36%)	98 (72%)	199 (71%)	316 (77%)	59 (94%)	41 (60%)
Missing	18	10	2	2		1			2	2
Blinding
Blinded	2639 (53%)	1504 (51%)	270 (31%)	347 (55%)	405 (61%)	93 (51%)	89 (67%)	141 (52%)	249 (64%)	47 (72%)	48 (72%)
Open	2322 (47%)	1427 (49%)	589 (69%)	281 (45%)	260 (39%)	91 (49%)	43 (33%)	129 (48%)	139 (36%)	18 (28%)	19 (28%)
Missing	182	101	12	18	28	11	5	12	22	0	1
Planned recruitment
1–100	2689 (52%)	1509 (50%)	361 (41%)	325 (50%)	361 (52%)	132 (68%)	66 (48%)	133 (47%)	228 (56%)	22 (35%)	33 (49%)
101–1000	2066 (40%)	1274 (42%)	427 (49%)	244 (38%)	300 (43%)	58 (30%)	61 (45%)	119 (42%)	161 (39%)	35 (55%)	31 (46%)
> 1000	383 (7%)	246 (8%)	83 (10%)	77 (12%)	30 (4%)	5 (2%)	10 (7%)	30 (11%)	21 (5%)	6 (10%)	3 (5%)
Missing	5	3	1		2					2	1
Country of recruitment
Australia only	3521 (68%)	1951 (64%)	349 (40%)	401 (62%)	578 (83%)	184 (94%)	113 (82%)	192 (68%)	286 (70%)	37 (57%)	47 (69%)
Australia and overseas	1622 (32%)	1081 (36%)	522 (60%)	245 (38%)	115 (17%)	11 (6%)	24 (18%)	90 (32%)	124 (30%)	28 (43%)	21 (31%)

Data are no. (%) unless otherwise specified. * Trials may be classified under more than one NHPA (eg, obesity and diabetes). † Includes trials that did not specify age limits.