Restoring microvascular circulation with diagnostic ultrasound and contrast agent: rationale and design of the REDUCE trial.

OBJECTIVES: This study aims to evaluate the efficacy and cost-effectiveness of sonothrombolysis delivered pre and post primary percutaneous coronary intervention (pPCI) on infarct size assessed by cardiac MRI, in patients presenting with STEMI, when compared against sham procedure. BACKGROUND: More than a half of patients with successful pPCI have significant microvascular obstruction and residual infarction. Sonothrombolysis is a therapeutic use of ultrasound with contrast enhancement that may improve microcirculation and infarct size. The benefits and real time physiological effects of sonothrombolysis in a multicentre setting are unclear. METHODS: The REDUCE (Restoring microvascular circulation with diagnostic ultrasound and contrast agent) trial is a prospective, multicentre, patient and outcome blinded, sham-controlled trial. Patients presenting with STEMI will be randomized to one of 2 treatment arms, to receive either sonothrombolysis treatment or sham echocardiography before and after pPCI. This tailored design is based on preliminary pilot data from our centre, showing that sonothrombolysis can be safely delivered, without prolonging door to balloon time. Our primary endpoint will be infarct size assessed on day 4±2 on Cardiac Magnetic Resonance (CMR). Patients will be followed up for 6 months post pPCI to assess secondary endpoints. Sample size calculations indicate we will need 150 patients recruited in total. CONCLUSIONS: This multicentre trial will test whether sonothrombolysis delivered pre and post primary PCI can improve patient outcomes and is cost-effective, when compared with sham ultrasound delivered with primary PCI. The results from this trial may provide evidence for the utilization of sonothrombolysis as an adjunct therapy to pPCI to improve cardiovascular outcomes in STEMI. ANZ Clinical Trial Registration number: ACTRN 12620000807954.

Cost-effectiveness of Accepting Kidneys From Deceased Donors With Common Cancers-A Modeling Study.

BACKGROUND: The disparity between the demand for and supply of kidney transplants has resulted in prolonged waiting times for patients with kidney failure. A potential approach to address this shortage is to consider kidneys from donors with a history of common cancers, such as breast, prostate, and colorectal cancers. METHODS: We used a patient-level Markov model to evaluate the outcomes of accepting kidneys from deceased donors with a perceived history of breast, prostate, or colorectal cancer characterized by minimal to intermediate transmission risk. Data from the Australian transplant registry were used in this analysis. The study compared the costs and quality-adjusted life years (QALYs) from the perspective of the Australian healthcare system between the proposed practice of accepting these donors and the conservative practice of declining them. The model simulated outcomes for 1500 individuals waitlisted for a deceased donor kidney transplant for a 25-y horizon. RESULTS: Under the proposed practice, when an additional 15 donors with minimal to intermediate cancer transmission risk were accepted, QALY gains ranged from 7.32 to 20.12. This translates to an approximate increase of 7 to 20 additional years of perfect health. The shift in practice also led to substantial cost savings, ranging between $1.06 and $2.3 million. CONCLUSIONS: The proposed practice of accepting kidneys from deceased donors with a history of common cancers with minimal to intermediate transmission risk offers a promising solution to bridge the gap between demand and supply. This approach likely results in QALY gains for recipients and significant cost savings for the health system.

Feasibility of Symptom monitoring WIth Feedback Trial (SWIFT) for adults on hemodialysis: a registry-based cluster randomized pilot trial.

BACKGROUND: Patients with kidney failure on hemodialysis (HD) experience considerable symptom burden and poor health-related quality of life (HRQoL). There is limited use of patient reported outcome measures (PROMs) in facility HD units to direct immediate care, with response rates in other studies between 36 to 70%. The aim of this pilot study was to evaluate feasibility of electronic PROMs (e-PROMs) in HD participants, with feedback 3-monthly to the participants' treating team, for severe or worsening symptoms as identified by the Integrated Palliative Outcome Scale (IPOS-Renal), with linkage to the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, compared with usual care. METHODS: This is a registry-based cluster-randomized controlled pilot trial involving all adults receiving HD in 4 satellite units in Australia over a 6-month period. HD units were cluster randomized 1:1 to the control (HRQoL data collection only) or intervention arm (symptom monitoring with feedback to treating team every 3 months). Feasibility was assessed by participant response rate (percentage of eligible HD participants, including new incident participants, who completed the questionnaire at each time point); retention rate (percentage of participants who completed the baseline questionnaire and all subsequent measures); and completion time. HRQoL and symptom burden scores are described. RESULTS: There were 226 unique participants who completed the e-PROMs (mean age 62 years, 69% males, 78% White-European, median dialysis vintage 1.62 years). At 6 months, response rate and retention rate for the intervention arm were 54% and 68%, respectively, and 89% and 97% in the control arm. Median time to complete IPOS-Renal was 6.6 min (5.3, 10.1) at 3 months, and when combined with the outcome measure (EQ-5D-5L), the median time was 9.4 min (6.9, 13.6) at 6 months. CONCLUSIONS: Electronic symptom monitoring among HD participants with feedback to clinicians is feasible. Variations in response and retention rates could be potentially explained by the lengthier questionnaire, and higher frequency of data collection time points for participants in the intervention arm. A definitive national RCT is underway. TRIAL REGISTRATION: ACTRN12618001976279 (07/12/2018).

Cost-effectiveness of Kidney Transplantation From Donors at Increased Risk of Blood-borne Virus Infection Transmission.

BACKGROUND: Demand for donor kidneys outstrips supply. Using kidneys from selected donors with an increased risk of blood-borne virus (BBV) transmission (hepatitis B virus and hepatitis C virus [HCV], human immunodeficiency virus) may expand the donor pool, but cost-effectiveness of this strategy is uncertain. METHODS: A Markov model was developed using real-world evidence to compare healthcare costs and quality-adjusted life years (QALYs) of accepting kidneys from deceased donors with potential increased risk of BBV transmission, because of increased risk behaviors and/or history of HCV, versus declining these kidneys. Model simulations were run over a 20-y time horizon. Parameter uncertainty was assessed through deterministic and probabilistic sensitivity analyses. RESULTS: Accepting kidneys from donors at increased risk of BBVs (2% from donors with increased-risk behaviors and 5% from donors with active or past HCV infection) incurred total costs of 311 303 Australian dollars with a gain of 8.53 QALYs. Foregoing kidneys from these donors incurred total costs of $330 517 and a gain of 8.44 QALYs. A cost-saving of $19 214 and additional 0.09 QALYs (~33 d in full health) per person would be generated compared with declining these donors. Increasing the availability of kidneys with increased risk by 15% led to further cost-savings of $57 425 and additional 0.23 QALY gains (~84 d in full health). Probabilistic sensitivity analysis using 10 000 iterations showed accepting kidneys from donors at increased risk led to lower costs and higher QALY gains. CONCLUSIONS: Shifting clinical practice to accept increased BBV risk donors would likely produce lower costs and higher QALYs for health systems.

Cost Effectiveness of Ambulatory Blood Pressure Monitoring Compared with Home or Clinic Blood Pressure Monitoring for Diagnosing Hypertension in Australia.

OBJECTIVES: The aim of this study was to evaluate the cost effectiveness of ambulatory blood pressure monitoring (ABPM) compared with home blood pressure monitoring (HBPM) and clinic blood pressure monitoring (CBPM) in diagnosing hypertension in Australia. METHODS: A cohort-based Markov model was built from the Payer's perspective (Australian government) comparing lifetime costs and effectiveness of ABPM, HBPM and CBPM in people aged ≥ 35 years with suspected hypertension who have a CBPM between ≥ 140/90 mmHg and ≤ 180/110 mmHg using a sphygmomanometer and have not yet commenced antihypertensive treatment. The main outcome measures were incremental cost-effectiveness ratio (ICER) assessing cost per quality-adjusted life-year (QALY) and life-years (LYs) gained by ABPM versus HBPM and CBPM. Cost was measured in Australian dollars (A$). RESULTS: Over a lifetime model, ABPM had lower total costs (A$8,491) compared with HBPM (A$9,648) and CBPM (A$10,206) per person. ABPM was associated with a small but significant improvement in the quality and quantity of life for people with suspected hypertension with 12.872 QALYs and 17.449 LYs compared with 12.857 QALYs and 17.433 LYs with HBPM, and 12.850 QALYs and 17.425 LYs with CBPM. In the base-case analysis, ABPM dominated HBPM and CBPM. In scenario analyses, at 100% specificity of HBPM, ABPM no longer remained cost effective at a A$50,000/QALY threshold. However, in probabilistic sensitivity analysis, over 10,000 iterations, ABPM remained dominant. CONCLUSION: ABPM was the dominant strategy for confirming the diagnosis of hypertension among Australian adults aged ≥ 35 years old with suspected hypertension. The findings of this study are important for reimbursement decision makers to support policy change and for clinicians to make practice changes consistent with ABPM recommendations in primary care.

Notifiable Infectious Diseases Among Organ Transplant Recipients: A Data-Linked Cohort Study, 2000-2015.

Background: Infections, including common communicable infections such as influenza, frequently cause disease after organ transplantation, although the quantitative extent of infection and disease remains uncertain. Methods: A cohort study was conducted to define the burden of notifiable infectious diseases among all solid organ recipients transplanted in New South Wales, Australia, 2000-2015. Data linkage was used to connect transplant registers to hospital admissions, notifiable diseases, and the death register. Standardized incidence ratios (SIRs) were calculated relative to general population notification rates, accounting for age, sex, and calendar year. Infection-related hospitalizations and deaths were identified. Results: Among 4858 solid organ recipients followed for 39 183 person-years (PY), there were 792 notifications. Influenza was the most common infection (532 cases; incidence, 1358 [95% CI, 1247-1478] per 100 000 PY), highest within 3 months posttransplant. Next most common was salmonellosis (46 cases; incidence, 117 [95% CI, 87-156] per 100 000 PY), then pertussis (38 cases; incidence, 97 [95% CI, 71-133] per 100 000 PY). Influenza and invasive pneumococcal disease (IPD) showed significant excess cases compared with the general population (influenza SIR, 8.5 [95% CI, 7.8-9.2]; IPD SIR, 9.8 [95% CI, 6.9-13.9]), with high hospitalization rates (47% influenza cases, 68% IPD cases) and some mortality (4 influenza and 1 IPD deaths). By 10 years posttransplant, cumulative incidence of any vaccine-preventable disease was 12%, generally similar by transplanted organ, except higher among lung recipients. Gastrointestinal diseases, tuberculosis, and legionellosis had excess cases among transplant recipients, although there were few sexually transmitted infections and vector-borne diseases. Conclusions: There is potential to avoid preventable infections among transplant recipients with improved vaccination programs, health education, and pretransplant donor and recipient screening.

Transcatheter Aortic Valve Implantation (TAVI) Versus Surgical Aortic Valve Replacement for Aortic Stenosis (SAVR): A Cost-Comparison Study.

BACKGROUND: Comparative costing studies using real-world data stratified by patient case-mix, are valuable to decision makers for making reimbursement decisions of new interventions. This study evaluated real-world hospital admissions and short-term costs of transcatheter aortic valve implantation (TAVI) and isolated surgical aortic valve replacement (SAVR) for patients with aortic stenosis, stratified by the Society of Thoracic Surgeons (STS) risk scores. METHODS: Retrospective analysis of consecutive patients with a principal diagnosis of aortic stenosis who underwent isolated valve replacement at a single tertiary hospital, January 2012-December 2017. Patients were followed-up for 30 days post-procedure or until hospital discharge if index hospitalisation was greater than 30 days. Intensive care unit (ICU) and hospital length of stay (days), and costs in 2018 Australian dollars for the index procedure and 30-day follow-up were assessed. Multivariable generalised linear and two-part models with gamma distribution and log link function adjusting for Society of Thoracic Surgeons (STS) risk group and key sociodemographic characteristics were used. RESULTS: Of 488 patients, 61% males, median age 78 years (IQR 14 years), 221 (45%) received transcatheter aortic valve replacement (TAVI) and 267 (55%) received surgical aortic valve replacement (SAVR). STS risk scores were low (28%), intermediate (46%) and high (26%) for TAVI patients, and low (85%), intermediate (12%) and high (3%) for SAVR patients. When adjusted, TAVI length of stay was 57% shorter than SAVR (95% CI 31-83%, p<0.001) for intensive care unit (ICU) admission, and 64% shorter (95% CI 47-81%, p<0.001) for hospital admissions. TAVI costs were 13% lower than SAVR (95% CI 4-22%, p=0.005). CONCLUSION: This data suggests short-term health care costs are lower for patients with aortic stenosis undergoing TAVI than SAVR. A further roll-out of the TAVI program in hospitals across Australia may result in savings to the health system.

Quality of life among caregivers of people with end-stage kidney disease managed with dialysis or comprehensive conservative care.

BACKGROUND: To measure health-related and care-related quality of life among informal caregivers of older people with end-stage kidney disease (ESKD), and to determine the association between caregiver quality of life and care recipient's treatment type. METHODS: A prospective cross-sectional study was conducted. Three renal units in the UK and Australia were included. Informal caregivers of people aged ≥75 years with ESKD managed with dialysis or comprehensive conservative non-dialytic care (estimated glomerular filtration (eGFR) ≤10 mL/min/1.73m2) participated. Health-related quality of life (HRQoL) was assessed using Short-Form six dimensions (SF-6D, 0-1 scale) and care-related quality of life was assessed using the Carer Experience Scale (CES, 0-100 scale). Linear regression assessed associations between care-recipient treatment type, caregiver characteristics and the SF-6D utility index and CES scores. RESULTS: Of 63 caregivers, 49 (78%) were from Australia, 26 (41%) cared for an older person managed with dialysis, and 37 (59%) cared for an older person managed with comprehensive conservative care. Overall, 73% were females, and the median age of the entire cohort was 76 years [IQR 68-81]. When adjusted for caregiver sociodemographic characteristics, caregivers reported significantly worse carer experience (CES score 15.73, 95% CI 5.78 to 25.68) for those managing an older person on dialysis compared with conservative care. However, no significant difference observed for carer HRQoL (SF-6D utility index - 0.08, 95% CI - 0.18 to 0.01) for those managing an older person on dialysis compared with conservative care. CONCLUSIONS: Our data suggest informal caregivers of older people on dialysis have significantly worse care-related quality of life (and therefore greater need for support) than those managed with comprehensive conservative care. It is important to consider the impact on caregivers' quality of life when considering treatment choices for their care recipients.

Health-related quality of life and well-being in people over 75 years of age with end-stage kidney disease managed with dialysis or comprehensive conservative care: a cross-sectional study in the UK and Australia.

OBJECTIVE: To measure health-related quality of life (HRQoL) and well-being in older people with end-stage kidney disease (ESKD) and to determine the association between treatment type and sociodemographic characteristics on these outcome measures. In addition, to assess the convergent validity between the HRQoL and well-being measure and their feasibility and acceptability in this population. DESIGN: Prospective cross-sectional study. SETTING: Three renal units in the UK and Australia. PARTICIPANTS: 129 patients with ESKD managed with dialysis or with an estimated glomerular filtration ≤10 mL/min/1.73 m2 and managed with comprehensive conservative, non-dialytic care. OUTCOME MEASURES: HRQoL and well-being were assessed using Short-Form six dimensions (SF-6D, 0-1 scale); Kidney Disease Quality of Life (KDQOL-36) (0-100 scale) and Investigating Choice Experiments Capability Measure-Older people (ICECAP-O, 0-1 scale). Linear regression assessed associations between treatment, HRQoL and well-being. Pearson's correlation coefficient assessed convergent validity between instruments. RESULTS: Median age of 81 years (IQR 78-85), 65% males; 83 (64%) were managed with dialysis and 46 (36%) with conservative care. When adjusted for treatment type and sociodemographic variables, those managed on dialysis reported lower mean SF-6D utility (-0.05, 95% CI -0.12 to 0.01); lower KDQOL Physical Component Summary score (-3.17, 95% CI -7.61 to 1.27); lower Mental Component Summary score (-2.41, 95% CI -7.66 to 2.84); lower quality of life due to burden (-28.59, 95% CI -41.77 to -15.42); symptoms (-5.93, 95% CI -14.61 to 2.73) and effects of kidney disease (-16.49, 95% CI -25.98 to -6.99) and lower overall ICECAP-O well-being (-0.07, 95% CI -0.16 to 0.02) than those managed conservatively. Correlation between ICECAP-O well-being and SF-6D utility scores was strong overall, 0.65 (p<0.001), but weak to moderate at domain level. CONCLUSIONS: Older people on dialysis report significantly higher burden and effects of kidney disease than those on conservative care. Lower HRQoL and well-being may be associated with dialysis treatment and should inform shared decision-making about treatment options. TRIAL REGISTRATION NUMBER: UK (IRAS project ID: 134360andREC reference 14/LO/0291) and Australia (R20140203 HREC/14/RAH/36).

Adaptive Radiotherapy for Head and Neck Cancer.

OBJECTIVE: To investigate the effects of adaptive radiotherapy on dosimetric, clinical, and toxicity outcomes for patients with head and neck cancer undergoing chemoradiotherapy with intensity-modulated radiotherapy. METHODS: Fifty-one patients with advanced head and neck cancer underwent definitive chemoradiotherapy with the original plan optimized to deliver 70.2 Gy. All patients were resimulated at a median dose of 37.8 Gy (range, 27.0-48.6 Gy) due to changes in tumor volume and/or patient weight loss (>15% from baseline). Thirty-four patients underwent adaptive replanning for their boost planning (21.6 Gy). The dosimetric effects of the adaptive plan were compared to the original plan and the original plan copied on rescan computed tomography. Acute and late toxicities and tumor local control were assessed. Gross tumor volume reduction rate was calculated. RESULTS: With adaptive replanning, the maximum dose to the spinal cord, brain stem, mean ipsilateral, and contralateral parotid had a median reduction of -4.5%, -3.0%, -6.2%, and -2.5%, respectively (median of 34 patients). Median gross tumor volume and boost planning target volume coverage improved by 0.8% and 0.5%, respectively. With a median follow-up time of 17.6 months, median disease-free survival and overall survival was 14.8 and 21.1 months, respectively. Median tumor volume reduction rate was 35.2%. For patients with tumor volume reduction rate ≤35.2%, median disease-free survival was 8.7 months, whereas it was 16.9 months for tumor volume reduction rate >35.2%. Four patients had residual disease after chemoradiotherapy, whereas 64.7% (20 of 34) of patients achieved locoregional control. CONCLUSION: Implementation of adaptive radiotherapy in head and neck cancer offers benefits including improvement in tumor coverage and decrease in dose to organs at risk. The tumor volume reduction rate during treatment was significantly correlated with disease-free survival and overall survival.

Decision Trees Predicting Tumor Shrinkage for Head and Neck Cancer: Implications for Adaptive Radiotherapy.

OBJECTIVE: To develop decision trees predicting for tumor volume reduction in patients with head and neck (H&N) cancer using pretreatment clinical and pathological parameters. METHODS: Forty-eight patients treated with definitive concurrent chemoradiotherapy for squamous cell carcinoma of the nasopharynx, oropharynx, oral cavity, or hypopharynx were retrospectively analyzed. These patients were rescanned at a median dose of 37.8 Gy and replanned to account for anatomical changes. The percentages of gross tumor volume (GTV) change from initial to rescan computed tomography (CT; %GTVΔ) were calculated. Two decision trees were generated to correlate %GTVΔ in primary and nodal volumes with 14 characteristics including age, gender, Karnofsky performance status (KPS), site, human papilloma virus (HPV) status, tumor grade, primary tumor growth pattern (endophytic/exophytic), tumor/nodal/group stages, chemotherapy regimen, and primary, nodal, and total GTV volumes in the initial CT scan. The C4.5 Decision Tree induction algorithm was implemented. RESULTS: The median %GTVΔ for primary, nodal, and total GTVs was 26.8%, 43.0%, and 31.2%, respectively. Type of chemotherapy, age, primary tumor growth pattern, site, KPS, and HPV status were the most predictive parameters for primary %GTVΔ decision tree, whereas for nodal %GTVΔ, KPS, site, age, primary tumor growth pattern, initial primary GTV, and total GTV volumes were predictive. Both decision trees had an accuracy of 88%. CONCLUSIONS: There can be significant changes in primary and nodal tumor volumes during the course of H&N chemoradiotherapy. Considering the proposed decision trees, radiation oncologists can select patients predicted to have high %GTVΔ, who would theoretically gain the most benefit from adaptive radiotherapy, in order to better use limited clinical resources.