ABSTRACT
BACKGROUND: Infective endocarditis (IE) following cardiac valve surgery is associated with high morbidity and mortality. Data on the impact of iatrogenic healthcare exposures on this risk are sparse. This study aimed to investigate risk factors including healthcare exposures for post open-heart cardiac valve surgery endocarditis (PVE). METHODS: In this population-linkage cohort study, 23,720 patients who had their first cardiac valve surgery between 2001 and 2017 were identified from an Australian state-wide hospital-admission database and followed-up to 31 December 2018. Risk factors for PVE were identified from multivariable Cox regression analysis and verified using a case-crossover design sensitivity analysis. RESULTS: In 23,720 study participants (median age 73, 63% male), the cumulative incidence of PVE 15 years after cardiac valve surgery was 7.8% (95% CI 7.3-8.3%). Thirty-seven percent of PVE was healthcare-associated, which included red cell transfusions (16% of healthcare exposures) and coronary angiograms (7%). The risk of PVE was elevated for 90 days after red cell transfusion (HR = 3.4, 95% CI 2.1-5.4), coronary angiogram (HR = 4.0, 95% CI 2.3-7.0), and healthcare exposures in general (HR = 4.0, 95% CI 3.3-4.8) (all p < 0.001). Sensitivity analysis confirmed red cell transfusion (odds ratio [OR] = 3.9, 95% CI 1.8-8.1) and coronary angiogram (OR = 2.6, 95% CI 1.5-4.6) (both p < 0.001) were associated with PVE. Six-month mortality after PVE was 24% and was higher for healthcare-associated PVE than for non-healthcare-associated PVE (HR = 1.3, 95% CI 1.1-1.5, p = 0.002). CONCLUSIONS: The risk of PVE is significantly higher for 90 days after healthcare exposures and associated with high mortality.
Subject(s)
Endocarditis , Heart Valve Prosthesis , Prosthesis-Related Infections , Humans , Male , Aged , Female , Cohort Studies , Heart Valve Prosthesis/adverse effects , Australia/epidemiology , Heart Valves , Endocarditis/epidemiology , Endocarditis/etiology , Prosthesis-Related Infections/surgeryABSTRACT
BACKGROUND: Coronary heart disease (CHD) is the leading cause of deaths and disability worldwide. Cardiac rehabilitation (CR) effectively reduces the risk of future cardiac events and is strongly recommended in international clinical guidelines. However, CR program quality is highly variable with divergent data systems, which, when combined, potentially contribute to persistently low completion rates. The QUality Improvement in Cardiac Rehabilitation (QUICR) trial aims to determine whether a data-driven collaborative quality improvement intervention delivered at the program level over 12 months: (1) increases CR program completion in eligible patients with CHD (primary outcome), (2) reduces hospital admissions, emergency department presentations and deaths, and costs, (3) improves the proportion of patients receiving guideline-indicated CR according to national and international benchmarks, and (4) is feasible and sustainable for CR staff to implement routinely. METHODS: QUICR is a multi-centre, type-2, hybrid effectiveness-implementation cluster-randomized controlled trial (cRCT) with 12-month follow-up. Eligible CR programs (n = 40) and the individual patient data within them (n ~ 2,000) recruited from two Australian states (New South Wales and Victoria) are randomized 1:1 to the intervention (collaborative quality improvement intervention that uses data to identify and manage gaps in care) or control (usual care with data collection only). This sample size is required to achieve 80% power to detect a difference in completion rate of 22%. Outcomes will be assessed using intention-to-treat principles. Mixed-effects linear and logistic regression models accounting for clusters within allocated groupings will be applied to analyse primary and secondary outcomes. DISCUSSION: Addressing poor participation in CR by patients with CHD has been a longstanding challenge that needs innovative strategies to change the status-quo. This trial will harness the collaborative power of CR programs working simultaneously on common problem areas and using local data to drive performance. The use of data linkage for collection of outcomes offers an efficient way to evaluate this intervention and support the improvement of health service delivery. ETHICS: Primary ethical approval was obtained from the Northern Sydney Local Health District Human Research Ethics Committee (2023/ETH01093), along with site-specific governance approvals. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12623001239651 (30/11/2023) ( https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386540&isReview=true ).
Subject(s)
Cardiac Rehabilitation , Multicenter Studies as Topic , Quality Improvement , Quality Indicators, Health Care , Randomized Controlled Trials as Topic , Humans , Quality Improvement/standards , Cardiac Rehabilitation/standards , Treatment Outcome , Time Factors , Quality Indicators, Health Care/standards , New South Wales , Cooperative Behavior , Victoria , Coronary Disease/rehabilitation , Coronary Disease/diagnosis , Guideline Adherence/standards , Health Care CostsABSTRACT
BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death globally, accounting for almost 18 million deaths annually. People with CVDs have a five times greater chance of suffering a recurrent cardiovascular event than people without known CVDs. Although drug interventions have been shown to be cost-effective in reducing the risk of recurrent cardiovascular events, adherence to medication remains suboptimal. As a scalable and cost-effective approach, mobile phone text messaging presents an opportunity to convey health information, deliver electronic reminders, and encourage behaviour change. However, it is uncertain whether text messaging can improve medication adherence and clinical outcomes. This is an update of a Cochrane review published in 2017. OBJECTIVES: To evaluate the benefits and harms of mobile phone text messaging for improving medication adherence in people with CVDs compared to usual care. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, four other databases, and two trial registers. We also checked the reference lists of all primary included studies and relevant systematic reviews and meta-analyses. The date of the latest search was 30 August 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with participants with established arterial occlusive events. We included trials investigating interventions using short message service (SMS) or multimedia messaging service (MMS) with the aim of improving adherence to medication for the secondary prevention of cardiovascular events. The comparator was usual care. We excluded cluster-RCTs and quasi-RCTs. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were medication adherence, fatal cardiovascular events, non-fatal cardiovascular events, and combined CVD event. Secondary outcomes were low-density lipoprotein cholesterol for the effect of statins, blood pressure for antihypertensive drugs, heart rate for the effect of beta-blockers, urinary 11-dehydrothromboxane B2 for the antiplatelet effects of aspirin, adverse effects, and patient-reported experience. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 18 RCTs involving a total of 8136 participants with CVDs. We identified 11 new studies in the review update and seven studies in the previous version of the review. Participants had various CVDs including acute coronary syndrome, coronary heart disease, stroke, myocardial infarction, and angina. All studies were conducted in middle- and high-income countries, with no studies conducted in low-income countries. The mean age of participants was 53 to 64 years. Participants were recruited from hospitals or cardiac rehabilitation facilities. Follow-up ranged from one to 12 months. There was variation in the characteristics of text messages amongst studies (e.g. delivery method, frequency, theoretical grounding, content used, personalisation, and directionality). The content of text messages varied across studies, but generally included medication reminders and healthy lifestyle information such as diet, physical activity, and weight loss. Text messages offered advice, motivation, social support, and health education to promote behaviour changes and regular medication-taking. We assessed risk of bias for all studies as high, as all studies had at least one domain at unclear or high risk of bias. Medication adherence Due to different evaluation score systems and inconsistent definitions applied for the measurement of medication adherence, we did not conduct meta-analysis for medication adherence. Ten out of 18 studies showed a beneficial effect of mobile phone text messaging for medication adherence compared to usual care, whereas the other eight studies showed either a reduction or no difference in medication adherence with text messaging compared to usual care. Overall, the evidence is very uncertain about the effects of mobile phone text messaging for medication adherence when compared to usual care. Fatal cardiovascular events Text messaging may have little to no effect on fatal cardiovascular events compared to usual care (odds ratio 0.83, 95% confidence interval (CI) 0.47 to 1.45; 4 studies, 1654 participants; low-certainty evidence). Non-fatal cardiovascular events We found very low-certainty evidence that text messaging may have little to no effect on non-fatal cardiovascular events. Two studies reported non-fatal cardiovascular events, neither of which found evidence of a difference between groups. Combined CVD events We found very low-certainty evidence that text messaging may have little to no effect on combined CVD events. Only one study reported combined CVD events, and did not find evidence of a difference between groups. Low-density lipoprotein cholesterol Text messaging may have little to no effect on low-density lipoprotein cholesterol compared to usual care (mean difference (MD) -1.79 mg/dL, 95% CI -4.71 to 1.12; 8 studies, 4983 participants; very low-certainty evidence). Blood pressure Text messaging may have little to no effect on systolic blood pressure (MD -0.93 mmHg, 95% CI -3.55 to 1.69; 8 studies, 5173 participants; very low-certainty evidence) and diastolic blood pressure (MD -1.00 mmHg, 95% CI -2.49 to 0.50; 5 studies, 3137 participants; very low-certainty evidence) when compared to usual care. Heart rate Text messaging may have little to no effect on heart rate compared to usual care (MD -0.46 beats per minute, 95% CI -1.74 to 0.82; 4 studies, 2946 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Due to limited evidence, we are uncertain if text messaging reduces medication adherence, fatal and non-fatal cardiovascular events, and combined cardiovascular events in people with cardiovascular diseases when compared to usual care. Furthermore, text messaging may result in little or no effect on low-density lipoprotein cholesterol, blood pressure, and heart rate compared to usual care. The included studies were of low methodological quality, and no studies assessed the effects of text messaging in low-income countries or beyond the 12-month follow-up. Long-term and high-quality randomised trials are needed, particularly in low-income countries.
Subject(s)
Cardiovascular Diseases , Cell Phone , Medication Adherence , Randomized Controlled Trials as Topic , Secondary Prevention , Text Messaging , Humans , Secondary Prevention/methods , Cardiovascular Diseases/prevention & control , Reminder Systems , Bias , Middle Aged , Stroke/prevention & control , Myocardial Infarction/prevention & controlABSTRACT
BACKGROUND: Adults <55 years of age comprise a quarter of all acute coronary syndromes (ACS) hospitalisations. There is a paucity of data characterising this group, particularly sex differences. This study aimed to compare the clinical and risk profile of patients with ACS aged <55 years with older counterparts, and measure short-term outcomes by age and sex. METHOD: The study population comprised patients with ACS enrolled in the AUS-Global Registry of Acute Coronary Events (GRACE), Cooperative National Registry of Acute Coronary Syndrome Care (CONCORDANCE) and SNAPSHOT ACS registries. We compared clinical features and combinations of major modifiable risk factors (hypertension, smoking, dyslipidaemia, and diabetes) by sex and age group (20-54, 55-74, 75-94 years). All-cause mortality and major adverse events were identified in-hospital and at 6-months. RESULTS: There were 16,658 patients included (22.3% aged 20-54 years). Among them, 20-54 year olds had the highest proportion of ST-elevation myocardial infarction compared with sex-matched older age groups. Half of 20-54 year olds were current smokers, compared with a quarter of 55-74 year olds, and had the highest prevalence of no major modifiable risk factors (14.2% women, 12.7% men) and of single risk factors (27.6% women, 29.0% men), driven by smoking. Conversely, this age group had the highest proportion of all four modifiable risk factors (6.6% women, 4.7% men). Mortality at 6 months in 20-54 year olds was similar between men (2.3%) and women (1.7%), although lower than in older age groups. CONCLUSIONS: Younger adults with ACS are more likely to have either no risk factor, a single risk factor, or all four modifiable risk factors, than older patients. Targeted risk factor prevention and management is warranted in this age group.
Subject(s)
Acute Coronary Syndrome , Diabetes Mellitus , Adult , Humans , Male , Female , Aged , Middle Aged , Acute Coronary Syndrome/epidemiology , Risk Factors , Smoking/epidemiology , Age Factors , Registries , Hospital Mortality , Treatment OutcomeABSTRACT
BACKGROUND: Global trends in mitral valve surgery (MVSx) suggest increasing repair compared with replacement, especially in the United States and European countries. The relative use, and outcomes of, MV repair and replacement in Australia are unknown. METHODS: New South Wales residents who underwent isolated MVSx between 2001 and 2017 were identified from the Admitted-Patient-Data-Collection database. Mortality outcomes were tracked to 31 Dec 2018 and adjusted based on age, sex, urgency of operation, and comorbidity status. RESULTS: The study cohort comprised 5,693 patients: 2020 (35%) underwent repair (MVr), 1,656 (29%) underwent mechanical replacement (mech.MVR), and 2017 (35%) underwent bioprosthetic replacement (bio.MVR). Respective median ages [interquartile range] were 67 yo [59-75 yo], 64 yo [55-71 yo], and 75 yo [68-80 yo] (p<0.001 across groups). Between 2001 and 2017, total MVSx increased steadily with population growth. Whereas the relative use of MVr remained static (34% to 38%), that for bio.MVR (22% to 50%) and mech.MVR (45% to 13%) changed significantly. MVr had the best outcome with 1.2% in-hospital, 2.5% 1-year, and 21.6% total cumulative mortality during a median follow-up of 6.5 years. Compared to MVr, the adjusted hazard ratio (aHR) for mech.MVR and bio.MVR for long-term mortality were 1.41 (95% confidence interval [CI]=1.24-1.61) and 1.73 (95% CI=1.53-1.95), respectively. Heart failure and sepsis were the main cardiovascular and noncardiovascular causes of death in all groups. CONCLUSION: In this statewide Australian cohort examined over 17 years, MVr is potentially underutilised despite having superior outcomes to MVR. Access to quality dataset which provides the indication for MVSx and quantitative clinical factors is critical to further improve MVr coverage and outcome MVSx.
Subject(s)
Heart Valve Prosthesis Implantation , Mitral Valve Insufficiency , Humans , United States , Mitral Valve/surgery , Treatment Outcome , Australia/epidemiology , Mitral Valve Insufficiency/surgery , Retrospective StudiesABSTRACT
BACKGROUND: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among cancer survivors. Mental health is considered an important risk factor affecting the treatment of cardiovascular disease. However, little is known about the use of secondary prevention strategies for CVD in patients with both cancer and CVD. This study aimed to compare the utilisation of primary care chronic disease management plans, mental health care and guideline-indicated cardioprotective medications among CVD patients with and without cancer. METHODS: Retrospective cross-sectional study utilising clinical data of patients with CVD from 50 Australian primary care practices. Outcomes included the use of chronic disease management plans, mental health care, guideline-indicated cardioprotective medications and influenza vaccination. Logistic regression, accounting for demographic and clinical covariates and clustering effects by practices, was used to compare the two groups. RESULTS: Of the 15,040 patients with CVD, 1,486 patients (9.9%) concurrently had cancer. Patients with cancer, compared to those without, were older (77.6 vs 71.8 years, p<0.001), more likely to drink alcohol (62.6% vs 55.7%, p<0.001), have lower systolic (130.3±17.8 vs 132.5±21.1 mmHg, p<0.001) and diastolic (72.2±11 vs 75.3±34 mmHg, p<0.001) blood pressure. Although suboptimal for both groups, patients with cancer were significantly more likely to have general practice management plans (GPMPs) (51.4% vs 43.2%, p<0.001), coordination of team care arrangements (TCAs) (46.2% vs 37.0%, p<0.001), have a review of either GPMP or TCA (42.8% vs 34.7%, p<0.001), have a mental health treatment consultation (15.4% vs 10.5%, p=0.004) and be prescribed blood pressure-lowering medications (70.1% vs 66.0%, p=0.002). However, there were no statistical differences in the prescription of lipid-lowering or antiplatelet medications. After adjustments for covariates and multiple testing, patients with cancer did not show a difference in GPMPs, TCAs, and a review of either, but were more likely to receive mental health treatment consultations than those without cancer (odds ratio 1.76; 95% confidence interval 1.42-2.19). CONCLUSIONS: Less than half of patients with CVD had a GPMP, TCA or review of either. Although those patients with cancer were more likely to receive these interventions, still around half the patients did not. Medicare-funded GPMPs, TCAs and a review of either GPMP or TCA were underutilised, and future studies should seek to identify ways of improving access to these services.
Subject(s)
Cardiovascular Diseases , Neoplasms , Primary Health Care , Humans , Cross-Sectional Studies , Male , Neoplasms/complications , Neoplasms/drug therapy , Female , Retrospective Studies , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/epidemiology , Aged , Chronic Disease , Australia/epidemiology , Mental Health Services/statistics & numerical data , Cardiotonic Agents/therapeutic use , Middle Aged , Disease ManagementABSTRACT
BACKGROUND: Multidisciplinary collaborative care has been widely recommended as an effective strategy for managing diabetes; however, the cardiovascular risk factors of patients with diabetes are often inadequately managed in primary care settings. This study aimed to assess the effect of multidisciplinary collaboration on cardiovascular risk factors among patients with diabetes in primary care settings. METHODS: Five databases (i.e., Medline, Embase, CINAHL, SCOPUS and CENTRAL) were systematically searched to retrieve randomised controlled trials. Studies were eligible for inclusion if the interventions included a multidisciplinary team with professionals from at least three health disciplines and focused on patients with diabetes in primary care settings. A random-effects model was used to calculate the pooled effects. RESULTS: In total, 19 studies comprising 6538 patients were included in the meta-analysis. The results showed that compared with usual care, multidisciplinary collaborative care significantly reduced cardiovascular risk factors, including mean systolic blood pressure (-3.27â¯mm Hg, 95â¯% confidence interval [CI]: -4.72 to -1.82, p < 0.01), diastolic blood pressure (-1.4â¯mm Hg, 95â¯% CI: -2.32 to -0.47, p < 0.01), glycated haemoglobin (-0.42â¯%, 95â¯% CI: -0.59 to -0.25, p < 0.01), low-density lipoprotein (-0.16â¯mmol/L, 95â¯% CI: -0.26 to -0.06, p < 0.01) and high-density lipoprotein (0.06â¯mmol/L, 95â¯% CI: 0.00-0.12, p < 0.05). The subgroup analysis showed multidisciplinary collaboration was more effective in reducing cardiovascular risk factors when it comprised team members from a number of different disciplines, combined pharmacological and non-pharmacological components, included both face-to-face and remote interactions and was implemented in high-income countries. CONCLUSION: Multidisciplinary collaborative care is associated with reduced cardiovascular risk factors among patients with diabetes in primary care. Further studies need to be conducted to determine the optimal team composition.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Heart Disease Risk Factors , Patient Care Team , Primary Health Care , Humans , Cardiovascular Diseases/prevention & control , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/therapy , Diabetes Mellitus/therapy , Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Male , Middle Aged , Female , Treatment Outcome , Aged , Delivery of Health Care, Integrated , Risk Assessment , Adult , Cooperative Behavior , Interdisciplinary Communication , Risk FactorsABSTRACT
Background: Haemorrhagic stroke (HS) is an important cardiovascular cause of mortality worldwide. Trends in admission rates and outcomes, and predictors of outcomes, post-HS in Australia remain unclear. Methods: All New South Wales residents, Australia, hospitalized with HS from 2002 to 2017 were identified from the Admitted-Patient-Data-Collection database. Admission rates were adjusted to population size by sex, age-groups and calendar-year. Mortality was tracked from the death registry to 31-Dec-2018 and adjusted for admission calendar-year, age, gender, referral source, surgical evacuation following HS and comorbidities. Results: The cohort comprised 35,433 patients (51.1% males). Overall age-adjusted mean(±SD) admission rates were higher for males (63.6 ± 6.2 vs 49.9 ± 4.4 admissions-per-100,000-persons-per-annum). Annual admission rates declined for both sexes from 2002 to 2017 especially in those ≥60yo. In-hospital and 1-year mortality rates were higher for females than males (25.0% vs 20.0% and 40.6% vs 35.9% respectively, all p < 0.001). Adjusted in-hospital and 1-year mortality declined for men and women, overall decreasing by 45% (odds ratio 0.55, 95% confidence interval [CI] = 0.47-0.64), and 31% (hazard ratio 0.69,95%CI = 0.63-0.76) respectively between 2002 and 2017. Independent predictors of increased in-hospital and 1-year mortality included increasing age and Charlson comorbidity index, while male sex, a history of hyperlipidaemia and current smoking, and surgical evacuation following HS were associated with reduced mortality (all p < 0.001). Conclusion: HS incidence increases markedly with age. Although age-adjusted HS admission rates and post HS mortality have fallen, HS remains associated with high early and 1-year mortality, with females consistently associated with worse outcomes. Strategies to improve outcomes of these patients remain a clinical priority.
ABSTRACT
BACKGROUND: People living with cardiac and respiratory disease require improved post-hospital support that is readily available and efficient. OBJECTIVES: To 1) test the effectiveness of an automated, semi-personalised text message support program on clinical and lifestyle outcomes amongst people attending cardiac and pulmonary rehabilitation. Also, 2) to evaluate the program's acceptability and utility using patient-reported outcome and experience measures. METHODS: Multicentre randomised controlled trial (3:1, intervention:control) amongst cardiac and pulmonary rehabilitation attendees. Control received usual care (no message program). Intervention also received a 6-month text message lifestyle and support program. Primary outcome was 6-minute walk distance (6MWD). Secondary outcomes included clinical measures, lifestyle, patient-reported outcome and experience measures, medication adherence and rehabilitation attendance. RESULTS: A total of 316 participants were recruited. They had a mean age of 66.7 (SD 10.1) years. Sixty percent were male (190/316) and 156 were cardiac rehabilitation participants. The cohort's mean baseline 6MWD was higher in the intervention than the control group. At 6 months, 6MWD improved in both groups; it was significantly greater amongst intervention than control participants (unadjusted mean difference of 43.4 m, 95 % CI 4.3 to 82.4; P = 0.0296). After adjustment for baseline values, there was no significant difference between intervention and control groups for 6MWD (adjusted mean difference 2.2 m, -21.2 to 25.6; P = 0·85), medication adherence, or cardiovascular risk factors. At 6-month follow-up, intervention participants reported significantly lower depression scores (adjusted mean difference -1.3, 95 % CI -2.2 to -0.3; P = 0.0124) and CAT scores (adjusted mean difference -3.9, 95 % CI -6.6 to -1.3; P = 0.0038), and significantly lower anxiety (adjusted mean difference -1.1, 95 %CI -2.1 to 0; P = 0.0456). Most participants (86 %) read most of their messages and strongly/agreed that the intervention was easy to understand (99 %) and useful (86 %). CONCLUSIONS: An educational and supportive text message program for cardiac and pulmonary rehabilitation attendees improved anxiety and depression plus program attendance. The program was acceptable to, and useful for, participants and would be suitable for implementation alongside rehabilitation programs. TRIAL REGISTRATION NUMBER: ACTRN12616001167459.
Subject(s)
Text Messaging , Aged , Female , Humans , Male , Anxiety , Life Style , Medication Adherence , Quality of Life , Middle AgedABSTRACT
BACKGROUND: This study evaluates primary care practices' engagement with various features of a quality improvement (QI) intervention for patients with coronary heart disease (CHD) in four Australian states. METHODS: Twenty-seven practices participated in the QI intervention from November 2019 -November 2020. A combination of surveys, semi-structured interviews and other materials within the QUality improvement in primary care to prevent hospitalisations and improve Effectiveness and efficiency of care for people Living with heart disease (QUEL) study were used in the process evaluation. Data were summarised using descriptive statistical and thematic analyses for 26 practices. RESULTS: Sixty-four practice team members and Primary Health Networks staff provided feedback, and nine of the 63 participants participated in the interviews. Seventy-eight percent (40/54) were either general practitioners or practice managers. Although 69% of the practices self-reported improvement in their management of heart disease, engagement with the intervention varied. Forty-two percent (11/26) of the practices attended five or more learning workshops, 69% (18/26) used Plan-Do-Study-Act cycles, and the median (Interquartile intervals) visits per practice to the online SharePoint site were 170 (146-252) visits. Qualitative data identified learning workshops and monthly feedback reports as the key features of the intervention. CONCLUSION: Practice engagement in a multi-featured data-driven QI intervention was common, with learning workshops and monthly feedback reports identified as the most useful features. A better understanding of these features will help influence future implementation of similar interventions. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12619001790134.