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Clinical trials require participation of numerous patients, enormous research resources and substantial public funding. Time-consuming trials lead to delayed implementation of beneficial interventions and to reduced benefit to patients. This manuscript discusses two methods for the allocation of research resources and reviews a framework for prioritisation and design of clinical trials. The traditional error-driven approach of clinical trial design controls for type I and II errors. However, controlling for those statistical errors has limited relevance to policy makers. Therefore, this error-driven approach can be inefficient, waste research resources and lead to research with limited impact on daily practice. The novel value-driven approach assesses the currently available evidence and focuses on designing clinical trials that directly inform policy and treatment decisions. Estimating the net value of collecting further information, prior to undertaking a trial, informs a decision maker whether a clinical or health policy decision can be made with current information or if collection of extra evidence is justified. Additionally, estimating the net value of new information guides study design, data collection choices, and sample size estimation. The value-driven approach ensures the efficient use of research resources, reduces unnecessary burden to trial participants, and accelerates implementation of beneficial healthcare interventions.

Exome sequencing and genome sequencing have the potential to improve clinical utility for patients undergoing genetic investigations. However, evidence of clinical utility is limited to pediatric populations; we aimed to fill this gap by conducting a systematic review of the literature on the clinical utility of exome/genome sequencing across disease indications in pediatric and adult populations. MEDLINE, EMBASE and Cochrane Library were searched between 2016 and 2020. Quantitative studies evaluating diagnostic yield were included; other measures of clinical utility such as changes to clinical management were documented if reported. Two reviewers screened, extracted data, and appraised risk of bias. Fifty studies met our inclusion criteria. All studies reported diagnostic yield, which ranged from 3 to 70%, with higher range of yields reported for neurological indications and acute illness ranging from 22 to 68% and 37–70%, respectively. Diagnoses triggered a range of clinical management changes including surveillance, reproductive-risk counseling, and identifying at-risk relatives in 4–100% of patients, with higher frequencies reported for acute illness ranging from 67 to 95%. The frequency of variants of uncertain significance ranged from 5 to 85% across studies with a potential trend of decreasing frequency over time and higher rates identified in patients of non-European ancestry. This review provides evidence for a higher range of diagnostic yield of exome/genome sequencing compared to standard genetic tests, particularly in neurological and acute indications. However, we identified significant heterogeneity in study procedures and outcomes, precluding a meaningful meta-analysis and certainty in the evidence available for decision-making. Future research that incorporates a comprehensive and consistent approach in capturing clinical utility of exome/genome sequencing across broader ancestral groups is necessary to improve diagnostic accuracy and yield and allow for analysis of trends over time. Prospero registration CRD42019094101.

To assess the association between time of birth and mortality among preterm infants. Population-based study of infants born 22–36 weeks gestation (GA) in Canada from 2010 to 2015 (n = 173 789). Multivariable logistic regression models assessed associations between timing of birth and mortality. Among infants 22–27 weeks GA, evening birth was associated with higher mortality than daytime birth (adjusted odds ratio [AOR] 1.14, 95% CI 1.01–1.29). Among infants 28–32 weeks GA and 33–36 weeks GA, night birth was associated with lower mortality than daytime birth (AOR 0.75, 95% CI 0.59–0.95; AOR 0.78, 95% CI 0.62–0.99, respectively). Sensitivity analysis excluding infants with major congenital anomaly revealed that associations between hour of birth and mortality among infants born 28–32 and 33–36 weeks GA decreased or were not statistically significant. Higher mortality among extremely preterm infants during off-peak hours may suggest variations in available resources based on time of day.

Aim: To assess the sensitivity and specificity of automated movement recognition in predicting motor impairment in high-risk infants. Method: We searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Scopus databases and identified additional studies from the references of relevant studies. We included studies that evaluated automated movement recognition in high-risk infants to predict motor impairment, including cerebral palsy (CP) and non-CP motor impairments. Two authors independently assessed studies for inclusion, extracted data, and assessed methodological quality using the Quality Assessment of Diagnostic Accuracy Studies-2. Meta-analyses were performed using hierarchical summary receiver operating characteristic models. Results: Of 6536 articles, 13 articles assessing 59 movement variables in 1248 infants under 5months corrected age were included. Of these, 143 infants had CP. The overall sensitivity and specificity for motor impairment were 0.73 (95% confidence interval [CI] 0.68–0.77) and 0.70 (95% CI 0.65–0.75) respectively. Comparatively, clinical General Movements Assessment (GMA) was found to have sensitivity and specificity of 98% (95% CI 74–100) and 91% (95% CI 83–93) respectively. Sensor-based technologies had higher specificity (0.88, 95% CI 0.80–0.93). Interpretation: Automated movement recognition technology remains inferior to clinical GMA. The strength of this study is its meta-analysis to summarize performance, although generalizability of these results is limited by study heterogeneity.

Background/Aims: Combinations of treatments that have already received regulatory approval can offer additional benefit over Each of the treatments individually. However, trials of these combinations are lower priority than those that develop novel therapies, which can restrict funding, timelines and patient availability. This article develops a novel trial design to facilitate the evaluation of New combination therapies. This trial design combines elements of phase II and phase III trials to reduce the burden of evaluating combination therapies, while also maintaining a feasible sample size. This design was developed for a randomised trial that compares the properties of three combination doses of ketamine and dexmedetomidine, given intranasally, to ketamine delivered intravenously for children undergoing a closed reduction for a fracture or dislocation. Methods: This trial design uses response-adaptive randomisation to evaluate different dose combinations and increase the information collected for successful novel drug combinations. The design then uses Bayesian dose-response modelling to undertake a comparative effectiveness analysis for the most successful dose combination against a relevant comparator. We used simulation methods determine the thresholds for adapting the trial and making conclusions. We also used simulations to evaluate the probability of selecting the dose combination with the highest true effectiveness the operating characteristics of the design and its Bayesian predictive power. Results: With 410 participants, five interim updates of the randomisation ratio and a probability of effectiveness of 0.93, 0.88 and 0.83 for the three dose combinations, we have an 83% chance of randomising the largest number of patients to the drug with the highest probability of effectiveness. Based on this adaptive randomisation procedure, the comparative effectiveness analysis has a type I error of less than 5% and a 93% chance of correcting concluding non-inferiority, when the probability of effectiveness for the optimal combination therapy is 0.9. In this case, the trial has a greater than 77% chance of meeting its dual aims of dose-finding and comparative effectiveness. Finally, the Bayesian predictive power of the trial is over 90%. Conclusions: By simultaneously determining the optimal dose and collecting data on the relative effectiveness of an intervention, we can minimise administrative burden and recruitment time for a trial. This will minimise the time required to get effective, safe combination therapies to patients quickly. The proposed trial has high potential to meet the dual study objectives within a feasible overall sample size.

Objective To evaluate the changes in the associations of antenatal corticosteroids (ACS) with neonatal mortality and severe neurological injury over time (2003-17). Design National, population-representative, retrospective cohort study. Setting Level III neonatal intensive care units participating in the Canadian Neonatal Network. Population All infants born at 230/7 -336/7 weeks of gestation (n = 43 456). Methods We estimated the associations between exposure to ACS and neonatal outcomes by year of birth. Year of birth was considered both continuously and categorically as three consecutive epochs. Main outcome measure Neonatal mortality and severe neurological injury. Results The absolute rates of neonatal mortality and severe neurological injury decreased during the study period in both the ACS and No ACS groups. For infants born at 230/7 -306/7 weeks of gestation, ACS was associated with similar reductions in neonatal mortality across the three epochs (9.0% versus 18.1%, adjusted relative risk [aRR] 0.54, 95% CI 0.47-0.61 in 2003-09; 7.6% versus 19.6%, aRR 0.51, 95% CI 0.44-0.59 in 2010-13; and 7.3% versus 14.5%, aRR 0.56, 95% CI 0.46-0.68 in 2014-17) and in severe neurological injury (13.2% versus 25.8%, aRR 0.57, 95% CI 0.50-0.64 in 2003-09; 7.4% versus 17.4%, aRR 0.53, 95% CI 0.43-0.66 in 2010-14; and 7.2% versus 14.8%, aRR 0.59, 95% CI 0.48-0.74 in 2014-17). Conclusion Despite the ongoing improvements in neonatal care of preterm infants, as reflected by the gradual decrease in the absolute rates of neonatal mortality and severe neurological injury, the association of ACS treatment with neonatal mortality and severe neurological injury among extremely preterm infants born at 23-30 weeks of gestation has remained stable throughout the study period of 15 years. Tweetable abstract Despite the gradual decrease in the rates of neonatal mortality and severe neurological injury, antenatal corticosteroids remain an important intervention in the current era of neonatal care.

Background Adhesive small bowel obstruction (aSBO) is a potentially recurrent disease. Although non‐operative management is often successful, it is associated with greater risk of recurrence than operative intervention, and may have greater downstream morbidity and costs. This study aimed to compare the current standard of care, trial of non‐operative management (TNOM), and early operative management (EOM) for aSBO. Methods Patients admitted to hospital between 2005 and 2014 in Ontario, Canada, with their first episode of aSBO were identified and propensity‐matched on their likelihood to receive EOM for a cost–utility analysis using population‐based administrative data. Patients were followed for 5 years to determine survival, recurrences, adverse events and inpatient costs to the healthcare system. Utility scores were attributed to aSBO‐related events. Cost–utility was presented as the incremental cost‐effectiveness ratio (ICER), expressed as Canadian dollars per quality‐adjusted life‐year (QALY). Results Some 25 150 patients were admitted for aSBO and 3174 (12·6 per cent) were managed by EOM. Patients managed by TNOM were more likely to experience recurrence of aSBO (20·9 per cent versus 13·2 per cent for EOM; P, This population‐based cost–utility analysis compared early operative management (EOM) for adhesive small bowel obstruction (SBO) to the current standard of care of a trial of non‐operative management. Although EOM was more costly, it was associated with a significantly lower risk of recurrence and reduced exposure to the morbidity and costs associated with multiple admissions for adhesive SBO. With longer follow‐up, EOM becomes increasingly cost‐effective, and crosses published willingness‐to‐pay thresholds within 5 years of the first admission. Early operative management in small bowel occlusion

Background Pediatric musculoskeletal injuries cause moderate to severe pain, which should ideally be addressed upon arrival to the emergency department (ED). Despite extensive research in ED-based pediatric pain treatment, recent studies confirm that pain management in this setting remains suboptimal. The No OUCH study consist of two complementary, randomized, placebo-controlled trials that will run simultaneously for patients presenting to the ED with an acute limb injury and a self-reported pain score of at least 5/10, measured via a verbal numerical rating scale (vNRS). Caregiver/parent choice will determine whether patients are randomized to the two-arm or three-arm trial. In the two-arm trial, patients will be randomized to receive either ibuprofen alone or ibuprofen in combination with acetaminophen. In the three-arm trial, patients can also be randomized to a third arm where they would receive ibuprofen in combination with hydromorphone. This article details the statistical analysis plan for the No OUCH study and was submitted before the trial outcomes were available for analysis. Methods/design The primary endpoint of the No OUCH study is self-reported pain at 60 min, recorded using a vNRS. The principal safety outcome is the presence of any adverse event related to study drug administration. Secondary effectiveness endpoints include pain measurements using the Faces Pain Scale-Revised and the visual analog scale, time to effective analgesia, requirement of a rescue analgesic, missed fractures, and observed pain reduction using different definitions of successful analgesia. Secondary safety outcomes include sedation measured using the Ramsay Sedation Score and serious adverse events. Finally, the No OUCH study investigates the reasons given by the caregiver for selecting the two-arm (Non-Opioid) or three-arm (Opioid) trial, caregiver satisfaction, physician preferences for analgesics, and caregiver comfort with at-home pain management. Discussion The No OUCH study will inform the relative effectiveness of acetaminophen and hydromorphone, in combination with ibuprofen, and ibuprofen alone as analgesic agents for patients presenting to the ED with an acute musculoskeletal injury. The data from these trials will be analyzed in accordance with this statistical analysis plan. This will reduce the risk of producing data-driven results and bias in our reported outcomes. Trial registration ClinicalTrials.gov NCT03767933. Registered on December 7, 2018.

Chronic hepatitis C (CHC) is among the most burdensome infectious diseases in the world. Health utilities are a valuable tool for quantifying this burden and conducting cost-utility analysis.Our study summarizes the available data on utilities in CHC patients. This will facilitate analyses of CHC treatment and elimination strategies.We searched MEDLINE, Embase, and the Cochrane Library for studies measuring utilities in CHC patients. Utilities were pooled by health state and utility instrument using meta-analysis. A further analysis used meta-regression to adjust for the effects of clinical status and methodological variation.Fifty-one clinical studies comprising 15 053 patients were included. Based on the meta-regression, patients' utilities were lower for more severe health states (predicted mean EuroQol-5D-3L utility for mild/moderate CHC: 0.751; compensated cirrhosis: 0.671; hepatocellular carcinoma: 0.662; decompensated cirrhosis: 0.602). Patients receiving interferon-based treatment had lower utilities than those on interferon-free treatment (0.647 vs 0.733). Patients who achieved sustained virologic response (0.786) had higher utilities than those with mild to moderate CHC. Utilities were substantially higher for patients in experimental studies compared to observational studies (coefficient: +0.074, P.05). The time tradeoff instrument was associated with the highest utilities, and the Health Utilities Index 3 was associated with the lowest utilities.Chronic hepatitis C is associated with a significant impairment in global health status, as measured by health utility instruments. Impairment is greater in advanced disease. Experimental study designs yield higher utilities-an effect not previously documented. Curative therapy can alleviate the burden of CHC, although further research is needed in certain areas, such as the long-term impacts of treatment on utilities.

Background Adhesive small-bowel obstruction (aSBO) is among the most common reasons for admission to a surgical service. While operative intervention for aSBO is associated with a lower risk of recurrence, current guidelines continue to advocate a trial of nonoperative management. The impact of the increased risk for recurrence on long-term survival is unknown. We sought to explore the potential for improved survival with operative management through the prevention of admissions for recurrence of aSBO and the associated risks. Methods This is a population-based retrospective cohort study using administrative data. We identified patients admitted to hospital for their first episode of aSBO from 2005 to 2014 and created a propensity-matched cohort to compare survival of patients managed operatively with those managed nonoperatively. To test whether survival differences were mediated by recurrence prevention, a competing risk regression was used to model the subdistribution hazard of death when accounting for the risk of recurrence. An instrumental variable approach was used as a secondary analysis to compare survival while accounting for unmeasured confounding. Results There were 27,904 patients admitted for their first episode of aSBO between 2005 and 2014. The mean age was 61.2 years (std dev, 13.6), and 51% were female. Operative management was associated with a significantly lower risk of death (hazard ratio, 0.80; 95% confidence interval, 0.75-0.86), which was robust to instrumental variable analyses, and a lower risk of recurrence (hazard ratio, 0.59; 95% confidence interval, 0.54-0.65). When adjusting for the risk of recurrence, operative intervention was not associated with improved survival, suggesting that the survival benefit is mediated through prevention of recurrences of aSBO. Conclusion In patients admitted for their first episode of aSBO, operative intervention is associated with a significant long-term survival benefit. This survival benefit appears to be mediated through the prevention of recurrences of aSBO. Study type Retrospective cohort study. Level of evidence Therapeutic study, Level II.

Background Adolescent women treated for Hodgkin lymphoma (HL) are at increased risk of breast cancer (BC). We evaluate the cost-utility of eight high-risk BC surveillance strategies for this population, including the Children’s Oncology Group guideline of same-day annual mammography and magnetic resonance imaging (MRI) beginning at age 25 years. Methods A discrete event simulation model was used to simulate the life histories of a cohort of 500 000 25-year-old women treated for HL at age 15 years. We estimated BC incidence and mortality, life expectancy, quality-adjusted life-years (QALYs), health-care costs, and the relative cost-utility (incremental cost-utility ratio [ICUR]) under the eight assessed surveillance strategies. One-way sensitivity analysis enabled modeling of uncertainty evaluation. A publicly funded health-care payer perspective was adopted. Results Costs across the eight screening strategies ranged from $32 643 to $43 739, whereas QALYs ranged from 24.419 to 24.480. In an incremental cost-effectiveness analysis, annual mammography beginning at age 25 years was associated with an ICUR of $43 000/QALY gained, annual MRI beginning at age 25 years with a switch to annual mammography at age 50 years had an ICUR of $148 000/QALY, and annual MRI beginning at age 25 years had an ICUR of $227 222/QALY. Among all assessed surveillance strategies, the differences in life expectancy were small. Conclusions Current high-risk BC surveillance guidelines do not reflect the most cost-effective strategy in survivors of adolescent HL. The results suggest that groups at high risk of BC may require high-risk surveillance guidelines that reflect their specific risk profile.

This systematic review and meta-analysis updates evidence pertaining to deficient response inhibition in obsessive-compulsive disorder (OCD) as measured by the stop-signal task (SST). We conducted a meta-analysis of the literature to compare response inhibition in patients with OCD and healthy controls, meta-regressions to determine relative influences of age and sex on response inhibition impairment, and a risk of bias assessment for included studies using the Newcastle-Ottawa Scale (NOS). Stop-signal reaction time (SSRT), which estimates the latency of the stopping process deficit, was significantly longer in OCD samples than in controls, reflecting inferior inhibitory control (Raw mean difference = 23.43ms; p = General Scientific SummaryDifficulty inhibiting responses is an hypothesized deficit in Obsessive-Compulsive Disorder (OCD). The results of this systematic review and meta-analysis of studies using the Stop Signal Task support the notion of deficient response inhibition in OCD and indicate that older individuals with OCD show greater impairments than younger ones.

BACKGROUND Therapy for childhood acute lymphoblastic leukemia (ALL) is associated with substantial health care utilization and burden on families. Little is known about health care utilization during specific treatment phases. PROCEDURES We identified children with ALL diagnosed during 2002-2012 in Ontario, Canada and treated according to Children's Oncology Group (COG) protocols. Disease and treatment data were chart abstracted. Population-based health care databases identified all outpatient visits, emergency department (ED) visits, and hospitalizations. In addition to comparing standard and intensified versions of treatment phases, we compared patients receiving different steroids (dexamethasone vs. prednisone) and different versions of interim maintenance (IM) (Capizzi vs. high-dose methotrexate [HD-MTX]). RESULTS Six hundred thirty-seven children met inclusion criteria. During intensified consolidation, 76.2% of patients were hospitalized at least once, compared to only 32.3% of patients receiving standard consolidation (p

Although different treatment protocols for childhood acute lymphoblastic leukaemia (ALL) all achieve high cure rates, their health care utilisation and costs have not been rigorously compared.Disease, treatment, and outcome data were chart abstracted for all children with ALL in Ontario, Canada, diagnosed 2002-2012. Linkage to population-based databases identified health care utilisation. Utilisation-associated costs were determined through validated algorithms. Chemotherapy-associated costs were calculated separately. Health care utilisation and costs were compared between patients receiving Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI)-based treatment.Of 802 patients, 146 (18.2%) were treated on DFCI-based protocols. COG patients experienced significantly higher rates of emergency department (ED) visits (adjusted rate ratio [aRR]: 1.3, 95% confidence interval [CI]: 1.1-1.5; p = 0·01), whereas outpatient visit rates were 60% higher among DFCI patients (aRR: 1.6, 95% CI: 1.5-1.7, p 0.0001). In adjusted analyses, DFCI-associated cost intensity was 70% higher (aRR: 1.7, 95% CI: 1.5-1.9; p 0.0001), mainly attributable to outpatient visit costs. Total chemotherapy costs were higher among COG-treated patients ($39,400 ± $1100 versus $33,400 ± $2800; p = 0.02). Among PEG-ASNase-treated patients, total chemotherapy costs were highest among DFCI patients (median $54,200 ± $7400; p = 0.003 versus COG patients).COG and DFCI treatments were associated with higher ED visit rates and higher outpatient visit rates, respectively. Overall utilisation-associated costs were increased in DFCI-treated patients. Administration of some intravenous chemotherapy at home and decreases in PEG-ASNase cost would decrease health care utilisation and costs for all patients and mitigate differences between COG and DFCI protocols.C

Background Acute gastroenteritis is a leading cause of emergency department visits and hospitalizations among children in North America. Oral-rehydration therapy is recommended for children with mild-to-moderate dehydration, but children who present with vomiting are frequently offered intravenous rehydration in the emergency department (ED). Recent studies have demonstrated that the anti-emetic ondansetron can reduce vomiting, intravenous rehydration, and hospitalization when administered in the ED to children with dehydration. However, there is little evidence of additional benefit from prescribing ondansetron beyond the initial ED dose. Moreover, repeat dosing may increase the frequency of diarrhea. Despite the lack of evidence and potential adverse side effects, many physicians across North America provide multiple doses of ondansetron to be taken following ED disposition. Thus, the Multi-Dose Oral Ondansetron for Pediatric Gastroenteritis (DOSE-AGE) trial will evaluate the effectiveness of prescribing multiple doses of ondansetron to treat acute gastroenteritis-associated vomiting. This article specifies the statistical analysis plan (SAP) for the DOSE-AGE trial and was submitted before the outcomes of the study were available for analysis. Methods/design The DOSE-AGE study is a phase III, 6-center, placebo-controlled, double-blind, parallel design randomized controlled trial designed to determine whether participants who are prescribed multiple doses of oral ondansetron to administer, as needed, following their ED visit have a lower incidence of experiencing moderate-to-severe gastroenteritis, as measured by the Modified Vesikari Scale score, compared with a placebo. To assess safety, the DOSE-AGE trial will investigate the frequency and maximum number of diarrheal episodes following ED disposition, and the occurrence of palpitations, pre-syncope/syncope, chest pain, arrhythmias, and serious adverse events. For the secondary outcomes, the DOSE-AGE trial will investigate the individual elements of the Modified Vesikari Scale score and caregiver satisfaction with the therapy. Discussion The DOSE-AGE trial will provide evidence on the effectiveness of multiple doses of oral ondansetron, taken as needed, following an initial ED dose in children with acute gastroenteritis-associated vomiting. The data from the DOSE-AGE trial will be analyzed using this SAP. This will reduce the risk of producing data-driven results and bias in our reported outcomes. The DOSE-AGE study was registered on ClinicalTrials.gov on February 22, 2019. Trial registration ClinicalTrials.gov NCT03851835. Registered on 22 February 2019.

Background/Aims Non-inferiority trials investigate whether a novel intervention, which typically has other benefits (i.e., cheaper or safer), has similar clinical effectiveness to currently available treatments. In situations where interim evidence in a non-inferiority trial suggests that the novel treatment is truly inferior, ethical concerns with continuing randomisation to the “inferior” intervention are raised. Thus, if interim data indicate that concluding non-inferiority at the end of the trial is unlikely, stopping for futility should be considered. To date, limited examples are available to guide the development of stopping rules for non-inferiority trials. Methods We used a Bayesian predictive power approach to develop a stopping rule for futility for a trial collecting binary outcomes. We evaluated the frequentist operating characteristics of the stopping rule to ensure control of the Type I and Type II error. Our case study is the Intranasal Ketamine for Procedural Sedation trial (INK trial), a non-inferiority trial designed to assess the sedative properties of ketamine administered using two alternative routes. Results We considered implementing our stopping rule after the INK trial enrols 140 patients out of 560. The trial would be stopped if 12 more patients experience a failure on the novel treatment compared to standard care. This trial has a type I error rate of 2.2% and a power of 80%. Conclusions Stopping for futility in non-inferiority trials reduces exposure to ineffective treatments and preserves resources for alternative research questions. Futility stopping rules based on Bayesian predictive power are easy to implement and align with trial aims. Trial registration ClinicalTrials.gov NCT02828566 July 11, 2016., Highlights • It is important to consider stopping for futility in non-inferiority trials. • We develop a rule to stop a non-inferiority trial using Bayesian predictive power. • We provide code and an online application to implement this method. • We reduce the complexity of developing stopping rules in non-inferiority trials.

In patients with adhesive small bowel obstruction (aSBO), the decision to operate as well as the timing and technique of surgery have significant impacts on clinical outcomes. Trends in the management of aSBO have not been described at the population level and guideline adherence is unknown. We sought to evaluate the secular trends in the management of aSBO in a large North American population. We used administrative data to identify patients admitted to hospital for their first episode of aSBO over 2005–2014. We evaluated temporal trends in admission for aSBO and in management practices using Cochran-Armitage tests. Multivariable logistic regressions were used to assess trends when controlling for potential confounders. Patients (40,800) were admitted with their first episode of aSBO. The mean age was 68.5 years and 55% of patients were female. The population-based rate of admission for aSBO decreased over the study period, from 39.1 to 38.1 per 100,000 persons per year. There was a significant increase in the proportion of patients who underwent surgery for aSBO (19 to 23%, p

Background Preterm birth (birth before 37 wk of gestation) occurs in about 8% of pregnancies in Canada and is associated with high mortality and morbidity rates that substantially affect infants, their families and the health care system. Our overall goal is to create a transdisciplinary platform, the Canadian Preterm Birth Network (CPTBN), where investigators, stakeholders and families will work together to improve childhood outcomes of preterm neonates. Methods Our national cohort will include 24 maternal-fetal/obstetrical units, 31 neonatal intensive care units and 26 neonatal follow-up programs across Canada with planned linkages to provincial health information systems. Three broad clusters of projects will be undertaken. Cluster 1 will focus on quality-improvement efforts that use the Evidence-based Practice for Improving Quality method to evaluate information from the CPTBN database and review the current literature, then identify potentially better health care practices and implement identified strategies. Cluster 2 will assess the impact of current practices and practice changes in maternal, perinatal and neonatal care on maternal, neonatal and neurodevelopmental outcomes. Cluster 3 will evaluate the effect of preterm birth on babies, their families and the health care system by integrating CPTBN data, parent feedback, and national and provincial database information in order to identify areas where more parental support is needed, and also generate robust estimates of resource use, cost and cost-effectiveness around preterm neonatal care. Interpretation These collaborative efforts will create a flexible, transdisciplinary, evaluable and informative research and quality-improvement platform that supports programs, projects and partnerships focused on improving outcomes of preterm neonates.

Microsimulation models are becoming increasingly common in the field of decision modeling for health. Because microsimulation models are computationally more demanding than traditional Markov cohort models, the use of computer programming languages in their development has become more common. R is a programming language that has gained recognition within the field of decision modeling. It has the capacity to perform microsimulation models more efficiently than software commonly used for decision modeling, incorporate statistical analyses within decision models, and produce more transparent models and reproducible results. However, no clear guidance for the implementation of microsimulation models in R exists. In this tutorial, we provide a step-by-step guide to build microsimulation models in R and illustrate the use of this guide on a simple, but transferable, hypothetical decision problem. We guide the reader through the necessary steps and provide generic R code that is flexible and can be adapted for other models. We also show how this code can be extended to address more complex model structures and provide an efficient microsimulation approach that relies on vectorization solutions.

To examine rates and determinants of mother's own milk (MOM) feeding at hospital discharge in a cohort of infants born very preterm within the Canadian Neonatal Network (CNN).This was a population-based cohort study of infants born at33 weeks of gestation and admitted to neonatal intensive care units (NICUs) participating in the CNN between January 1, 2015, and December 31, 2018. We examined the rates and determinants of MOM use at discharge home among the participating NICUs. We used multivariable logistic regression analysis to identify independent determinants of MOM feeding.Among the 6404 infants born very preterm and discharged home during the study period, 4457 (70%) received MOM or MOM supplemented with formula. Rates of MOM feeding at discharge varied from 49% to 87% across NICUs. Determinants associated with MOM feeding at discharge were gestational age 29-32 weeks compared with26 weeks (aOR 1.56, 95% CI 1.25-1.93), primipara mothers (aOR 2.12, 95% CI 1.86-2.42), maternal diabetes (aOR 0.79, 95% CI 0.66-0.93), and maternal smoking (aOR 0.27, 95% CI 0.19-0.38). Receipt of MOM by day 3 of age was the major predictor of breast milk feeding at discharge (aOR 3.61, 95% CI 3.17-4.12).Approximately two-thirds of infants born very preterm received MOM at hospital discharge, and rates varied across NICUs. Supporting mothers to provide breast milk in the first 3 days after birth may be associated with improved MOM feeding rates at discharge.

Androgen-deprivation therapy (ADT) is an effective treatment for men with advanced prostate cancer, but loss of bone mineral density (BMD) is a major risk factor for fractures. This review compared the efficacy of available treatments to provide prescribing guidance to healthcare professionals. This is the first review to compare the effectiveness of different osteoporotic treatments (bisphosphonates, denosumab, toremifene, and raloxifene) on BMD in patients with non-metastatic prostate cancer on ADT using network meta-analysis. Results suggest that all evaluated treatments are effective in improving BMD compared to placebo. Zoledronic acid (ZA) was found to have a greater improvement in BMD compared to other active treatments at all three studied sites, except for risedronate, which had better BMD improvement compared to ZA at the femoral neck site in one small study. Our study did not identify evidence that one drug is unequivocally more effective than another. All drugs appeared to be effective in reducing the rate of bone loss. Healthcare professionals should also consider patient preference, costs, and local availability as part of the decision process.

Purpose To use patient-level microsimulation models to evaluate the comparative cost-effectiveness of early corneal cross-linking (CXL) and conventional management with penetrating keratoplasty (PKP) when indicated in managing keratoconus in Canada. Design Cost-utility analysis using individual-based, state–transition microsimulation models. Participants Simulated cohorts of 100 000 individuals with keratoconus who entered each treatment arm at 25 years of age. Fellow eyes were modeled separately. Simulated individuals lived up to a maximum of 110 years. Methods We developed 2 state–transition microsimulation models to reflect the natural history of keratoconus progression and the impact of conventional management with PKP versus CXL. We collected data from the published literature to inform model parameters. We used realistic parameters that maximized the potential costs and complications of CXL, while minimizing those associated with PKP. In each treatment arm, we allowed simulated individuals to move through health states in monthly cycles from diagnosis until death. Main Outcome Measures For each treatment strategy, we calculated the total cost and number of quality-adjusted life years (QALYs) gained. Costs were measured in Canadian dollars. Costs and QALYs were discounted at 5%, converting future costs and QALYs into present values. We used an incremental cost-effectiveness ratio (ICER = difference in lifetime costs/difference in lifetime health outcomes) to compare the cost-effectiveness of CXL versus conventional management with PKP. Results Lifetime costs and QALYs for CXL were estimated to be Can$5530 (Can$4512, discounted) and 50.12 QALYs (16.42 QALYs, discounted). Lifetime costs and QALYs for conventional management with PKP were Can$2675 (Can$1508, discounted) and 48.93 QALYs (16.09 QALYs, discounted). The discounted ICER comparing CXL to conventional management was Can$9090/QALY gained. Sensitivity analyses revealed that in general, parameter variations did not influence the cost-effectiveness of CXL. Conclusions CXL is cost-effective compared with conventional management with PKP in the treatment of keratoconus. Our ICER of Can$9090/QALY falls well below the range of Can$20 000 to Can$100 000/QALY and below US$50 000/QALY, thresholds generally used to evaluate the cost-effectiveness of health interventions in Canada and the United States. This study provides strong economic evidence for the cost-effectiveness of early CXL in keratoconus.

The volume and technical complexity of both academic and commercial research using decision analytic modelling has increased rapidly over the last two decades. The range of software programs used for their implementation has also increased, but it remains true that a small number of programs account for the vast majority of cost-effectiveness modelling work. We report a comparison of four software programs: TreeAge Pro, Microsoft Excel, R and MATLAB. Our focus is on software commonly used for building Markov models and decision trees to conduct cohort simulations, given their predominance in the published literature around cost-effectiveness modelling. Our comparison uses three qualitative criteria as proposed by Eddy et al.: "transparency and validation", "learning curve" and "capability". In addition, we introduce the quantitative criterion of processing speed. We also consider the cost of each program to academic users and commercial users. We rank the programs based on each of these criteria. We find that, whilst Microsoft Excel and TreeAge Pro are good programs for educational purposes and for producing the types of analyses typically required by health technology assessment agencies, the efficiency and transparency advantages of programming languages such as MATLAB and R become increasingly valuable when more complex analyses are required.

Background The identification of patients who require transfer from non-trauma centers to trauma centers (secondary triage) is complicated by high rates of undertriage and overtriage. The objective of this study was to evaluate variations in secondary triage accuracy across non-trauma centers and identify factors associated with highly accurate secondary triage. Methods We performed a population-based study of injured patients who presented to non-trauma centers in a large regional trauma system. Patients were categorized as undertriaged, overtriaged, or appropriately triaged based on transfer status and presence of a severe injury (Injury Severity Score >15, death within 24 hours, or critical injury as defined by the American College of Surgeons). Mixed-effect models, adjusted for case mix and hospital resource, were used to compare triage accuracy across hospitals and identify factors associated with high-performing centers. Results Among 118,973 patients identified at 182 non-trauma centers, 37,528 (31.5%) had severe injuries. The majority (76.9%) of severely injured patients were not transferred to a trauma center (undertriaged), while 9.6% of nonseverely injured patients were transferred to a trauma center (overtriaged). Mixed-effect models demonstrated that at the average hospital severely injured patients were 3.76 times more likely to be transferred than nonseverely injured patients (diagnostic odds ratio, 3.76; 95% confidence interval, 3.20-4.31). Despite significant variation in triage accuracy across hospitals, adjusted analyses suggested that local resources bore no relationship to triage accuracy. Conclusion Triage accuracy varies significantly across non-trauma centers, after adjusting for hospital resources. These findings suggest that other potentially modifiable factors play a key role in transfer decisions. Level of evidence Therapeutic/care management, level IV.

To develop and validate an itemized costing algorithm for in-patient neonatal intensive care unit (NICU) costs for infants born prematurely that can be used for quality improvement and health economic analyses.We sourced patient resource use data from the Canadian Neonatal Network database, with records from infants admitted to 30 tertiary NICUs in Canada. We sourced unit cost inputs from Ontario hospitals, schedules of benefits, and administrative sources. Costing estimates were generated by matching patient resource use data to the appropriate unit costs. All cost estimates were in 2017 Canadian dollars and assigned from the perspective of a provincial public payer. Results were validated using previous estimates of inpatient NICU costs and hospital case-cost estimates.We assigned costs to 27 742 infants born prematurely admitted from 2015 to 2017. Mean (SD) gestational age and birth weight of the cohort were 31.8 (3.5) weeks and 1843 (739) g, respectively. The median (IQR) cost of hospitalization before NICU discharge was estimated as $20 184 ($9739-51 314) for all infants; $11 810 ($6410-19 800) for infants born at gestational age of 33-36 weeks; $30 572 ($16 597-$51 857) at gestational age of 29-32 weeks; and $100 440 ($56 858-$159 3867) at gestational age of29 weeks. Cost estimates correlated with length of stay (r = 0.97) and gestational age (r = -0.65). The estimates were consistent with provincial resource estimates and previous estimates from Canada.NICU costs for infants with preterm birth increase as gestation decreases and length of stay increases. Our cost estimates are easily accessible, transparent, and congruent with previous cost estimates.

The use of open-source programming languages, such as R, in health decision sciences is growing and has the potential to facilitate model transparency, reproducibility, and shareability. However, realizing this potential can be challenging. Models are complex and primarily built to answer a research question, with model sharing and transparency relegated to being secondary goals. Consequently, code is often neither well documented nor systematically organized in a comprehensible and shareable approach. Moreover, many decision modelers are not formally trained in computer programming and may lack good coding practices, further compounding the problem of model transparency. To address these challenges, we propose a high-level framework for model-based decision and cost-effectiveness analyses (CEA) in R. The proposed framework consists of a conceptual, modular structure and coding recommendations for the implementation of model-based decision analyses in R. This framework defines a set of common decision model elements divided into five components: (1) model inputs, (2) decision model implementation, (3) model calibration, (4) model validation, and (5) analysis. The first four components form the model development phase. The analysis component is the application of the fully developed decision model to answer the policy or the research question of interest, assess decision uncertainty, and/or to determine the value of future research through value of information (VOI) analysis. In this framework, we also make recommendations for good coding practices specific to decision modeling, such as file organization and variable naming conventions. We showcase the framework through a fully functional, testbed decision model, which is hosted on GitHub for free download and easy adaptation to other applications. The use of this framework in decision modeling will improve code readability and model sharing, paving the way to an ideal, open-source world.

To assess health outcomes of parents caring for children with chronic illnesses compared with parents of healthy children.We searched OvidSP MEDLINE, EBM Reviews-Cochrane Central Register of Controlled Trials, EMBASE, and EBSCOHost CINAHL through September 2019. Included were English-language studies reporting health conditions or mortality of parents of affected children compared with healthy controls.Of 12 181 screened publications, 26 met inclusion criteria. Eight studies reported on anxiety, 23 on depression, 1 on mortality, and 1 on cardiovascular disease. Parents of chronically ill children had greater anxiety (standardized mean difference 0.42; 95% CI 0.24-0.60; P .001) and depression scores (standardized mean difference 0.35; 95% CI 0.26-0.45; P .001) than parents of healthy children. Thirty-five percent of parents of affected children met cut-offs for clinical depression, compared with 19% in the control (relative risk 1.75; 95% CI 1.55-1.97). Fifty-seven percent of such parents met cut-offs for anxiety, compared with 38% in the control (relative risk 1.40; 95% CI 1.18-1.67). One study of mothers of children with congenital anomalies reported a greater mortality risk than a comparison (adjusted hazard ratio 1.22; 95% CI 1.15-1.29), and another reported that these mothers experience an increased risk of cardiovascular disease (adjusted hazard ratio 1.15; 95% CI 1.07-1.23).Parents of chronically ill children experience poorer mental health (more anxiety and depression), and mothers of those with congenital anomalies may have greater risk of cardiovascular disease and mortality than parents of unaffected children. Our findings suggest a need for targeted interventions to attenuate adverse parental caregiver health outcomes.PROSPERO CRD42018094657 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=94657).

BackgroundIn-hospital medication review has been linked to improved outcomes after discharge, yet there is little evidence to support the use of community pharmacy-based interventions as part of transitional care.ObjectiveTo determine whether receipt of a postdischarge community pharmacy-based medication reconciliation and adherence review is associated with a reduced risk of death or re-admission.DesignPropensity score-matched cohort study.SettingOntario, CanadaParticipantsPatients over age 66 years discharged home from an acute care hospital from 1 April 2007 to 16 September 2016.ExposureMedsCheck, a publicly funded medication reconciliation and adherence review provided by community pharmacists.Main outcomeThe primary outcome was time to death or re-admission (defined as an emergency department visit or urgent rehospitalisation) up to 30 days. Secondary outcomes were the 30-day count of outpatient physician visits and time to adverse drug event.ResultsMedsCheck recipients had a lower risk of 30-day death or re-admission (23.4% vs 23.9%, HR 0.97, 95% CI 0.95 to 1.00, p=0.02), driven by a decreased risk of death (1.7% vs 2.1%, HR 0.79, 95% CI 0.73 to 0.86) and rehospitalisation (11.0% vs 11.4%, HR 0.96, 95% 0.93–0.99). In a post hoc sensitivity analysis with pharmacy random effects added to the propensity score model, these results were substantially attenuated. There was no significant difference in 30-day return to the emergency department (22.5% vs 22.8%, HR 0.99, 95% CI 0.96 to 1.01) or adverse drug events (1.5% vs 1.5%, HR 1.03, 95% CI 0.94 to 1.12). MedsCheck recipients had more outpatient visits (mean 2.11 vs 2.09, RR 1.01, 95% CI 1.00 to 1.02, p=0.02).Conclusions and relevanceAmong older adults, receipt of a community pharmacy-based medication reconciliation and adherence review was associated with a small reduced risk of short-term death or re-admission. Due to the possibility of unmeasured confounding, experimental studies are needed to clarify the relationship between postdischarge community pharmacy-based medication review and patient outcomes.

Small bowel obstruction due to adhesions (aSBO) is a common indication for admission to a surgical unit. Despite the prevalence of this condition, the short- and medium-term survival of this patient population has not been well described. The purpose of this study was to measure the short- and medium-term survival of patients admitted to hospital with aSBO.Linked administrative data were used to identify patients admitted to hospital in Ontario, Canada, for aSBO between 2005 and 2011. Patients were divided into two groups: those aged less than 65 years (younger group) and those aged 65 years and older (older group). Thirty-day, 90-day and 1-year mortality rates were estimated. One-year mortality was compared with that in the general population, adjusting for age and sex. The timing of deaths in relation to admission was assessed, as well as the proportion of patients discharged before experiencing short-term mortality.There were 22 197 patients admitted to hospital for aSBO for the first time in the study interval. Mean age was 64·5 years and 52·2 per cent of the patients were women. Overall, the 30-day, 90-day and 1-year mortality rates for the cohort were 5·7 (95 per cent c.i. 5·4 to 6·0), 8·7 (8·3 to 9·0) and 13·9 (13·4 to 14·3) per cent respectively. For both groups, the 1-year risk of death was significantly greater than that of the age-matched general population. The majority of deaths (62·5 per cent) occurred within 90 days of admission, with 36·4 per cent occurring after discharge from the aSBO admission.Patients admitted with aSBO have a high short-term mortality rate. Increased monitoring of patients in the early period after admission is advisable.La obstrucción del intestino delgado por adherencias (adhesive small bowel obstruction, aSBO) es una indicación frecuente de ingreso en una unidad quirúrgica. A pesar de la prevalencia de esta patología, la supervivencia de estos pacientes a corto y a medio plazo no ha sido bien descrita. El objetivo de este estudio fue determinar la supervivencia a corto y a medio plazo de pacientes con aSBO ingresados en el hospital. MÉTODOS: Utilizando el enlace de datos administrativos se identificaron a los pacientes ingresados por aSBO en Ontario, Canadá, entre 2005-2011. Los pacientes se dividieron en dos subgrupos: los menores de 65 años de edad (subgrupo joven) y los de 65 años o más (subgrupo mayor). Se estimó la mortalidad a los 30 días, 90 días y a 1 año. La mortalidad a 1 año se comparó con la de la población general, ajustando por edad y sexo. Se evaluó el momento del fallecimiento respecto al ingreso, así como la proporción de pacientes que fueron dados de alta antes de fallecer a los 30 días.Durante el periodo de estudio se ingresaron en el hospital 22.197 pacientes con aSBO por primera vez. La edad media de los pacientes era de 65 años y un 52% eran mujeres. La mortalidad global de la cohorte a los 30 días, a los 90 días y a 1 año fue del 5,7% (i.c. del 95%: 5,4-6,0%), 8,3% (i.c. del 95%: 8,3-9,0%) y 13% (i.c. del 95%: 12,9-15,0%), respectivamente. Para ambos subgrupos, el riesgo de mortalidad a 1 año fue significativamente mayor que en la población general emparejada por edad. La mayoría de los fallecimientos (59%) ocurrieron durante los 90 días del ingreso, con un 36% tras el alta después del ingreso por aSBO. CONCLUSIÓN: Los pacientes ingresados por aSBO presentan una alta mortalidad a corto plazo. Se recomienda incrementar la vigilancia de estos pacientes en el periodo temprano tras el alta hospitalaria.

Background One of the controversies in the management of twin gestations relates to mode of delivery, especially when the second twin is in a nonvertex presentation (Vertex/nonVertex pairs) and birth is imminent at extremely low gestation. Objective We hypothesized that, for Vertex/nonVertex twins born before 28 weeks’ gestation, cesarean delivery would be associated with a lower risk of adverse neonatal outcomes than trial of vaginal delivery. Our aim was to test this hypothesis by comparing the neonatal outcomes of Vertex/nonVertex twins born before 28 weeks’ gestation by mode of delivery using a large national cohort. Study Design This work is a retrospective cohort study of all twin infants born at 240/7 to 276/7 weeks’ gestation and admitted to level III neonatal intensive care units participating in the Canadian Neonatal Network (2010–2017). Exposure is defined a trial of vaginal delivery for Vertex/nonVertex twins. Nonexposed (control) groups are defined as cases where both twins were delivered by cesarean delivery, either in vertex or nonvertex presentation (control group 1) or owing to the nonvertex presentation of the first twin (control group 2). Outcome measures are defined as a composite of neonatal death, severe neurologic injury, or birth trauma. Results A total of 1082 twin infants (541 twin pairs) met the inclusion criteria: 220 Vertex/nonVertex pairs, of which 112 had a trial of vaginal delivery (study group) and 108 had cesarean delivery for both twins (control group 1); 170 pairs with the first twin in nonvertex presentation, all of which were born by cesarean delivery (control group 2); and 151 pairs with both twins in vertex presentation (vertex or nonvertex). In the study group, the rate of urgent cesarean delivery for the second twin was 30%. The rate of the primary outcome in the study group was 42%, which was not significantly different compared with control group 1 (37%; adjusted relative risk, 0.93; 95% confidence interval, 0.71–1.22) or control group 2 (34%; adjusted relative risk, 1.20; 95% confidence interval, 0.92–1.58). The findings remained similar when outcomes were analyzed separately for the first and second twins. Conclusion For preterm Vertex/nonVertex twins born at

Background Medication reviews have become part of pharmacy practice across developed countries. This study aimed to identify factors affecting the likelihood of eligible Ontario seniors receiving a pharmacy-led medication review called MedsCheck annual (MCA). Methods We designed a cohort study using a random sample of pharmacy claims for MCA-eligible Ontario seniors using linked administrative data from April 2012 to March 2013. Guided by a conceptual framework, we constructed a generalized-estimating-equations model to estimate the effect of patient, pharmacy and community factors on the likelihood of receiving MCA. Results Of the 2,878,958 eligible claim-dates, 65,605 included an MCA. Compared to eligible individuals who did not receive an MCA, recipients were more likely to have a prior MCA (OR = 3.03), receive a new medication on the claim-date (OR = 1.78), be hypertensive (OR = 1.18) or have a recent hospitalization (OR = 1.07). MCA recipients had fewer medications (e.g., OR = 0.44 for ≥12 medications versus 0–4 medications), and were less likely to receive an MCA in a rural (OR = 0.74) or high-volume pharmacy (OR = 0.65). Conclusions The most important determinant of receiving an MCA was having had a prior MCA. Overall, MCA recipients were healthier, younger, urban-dwelling, and taking fewer medications than non-recipients. Policies regarding current and future medication review programs may need to evolve to ensure that those at greatest need receive timely and comprehensive medication reviews.

Background:MedsCheck Annual (MCA) is an Ontario government-funded medication review service for individuals taking 3 or more prescription medications for chronic conditions.Methods:This cohort study analyzed linked administrative claims data from April 1, 2007, to March 31, 2013. Trends in MCA claims and recipient characteristics were examined.Results:A total of 1,498,440 Ontarians (55% seniors, 55% female) received an MCA. One-third (36%) had 2 or more MCAs within 6 years. Service provision increased over time, with a sharper increase from 2010 onward. Almost half of Ontario pharmacies made at least 1 MCA claim in the first month of the program. Hypertension, respiratory disease, diabetes, psychiatric conditions and arthritis were common comorbidities. Recipients older than 65 years were most commonly dispensed an antihypertensive and/or antihyperlipidemic drug in the prior year and received an average of 11 unique prescription medications. Thirty-eight percent of recipients visited an emergency department or were hospitalized in the year prior to their first MCA.Discussion:Over the first 6 years of the program, approximately 1 in 9 Ontarians received an MCA. There was rapid and widespread uptake of the service. Common chronic conditions were well represented among MCA recipients. Older MCA recipients had less emergency department use compared with population-based estimates.Conclusions:Medication reviews increased over time; however, the number of persons receiving the service more than once was low. Service delivery was generally consistent with program eligibility; however, there are some findings possibly consistent with delivery to less complex patients.

IMPORTANCE: Adhesive small-bowel obstruction (aSBO) is a potentially chronic, recurring surgical illness. Although guidelines suggest trials of nonoperative management, the long-term association of this approach with recurrence is poorly understood. OBJECTIVE: To compare the incidence of recurrence of aSBO in patients undergoing operative management at their first admission compared with nonoperative management. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal, propensity-matched, retrospective cohort study used health administrative data for the province of Ontario, Canada, for patients treated from April 1, 2005, through March 31, 2014. The study population included adults aged 18 to 80 years who were admitted for their first episode of aSBO. Patients with nonadhesive causes of SBO were excluded. A total of 27 904 patients were included and matched 1:1 by their propensity to undergo surgery. Factors used to calculate propensity included patient age, sex, comorbidity burden, socioeconomic status, and rurality of home residence. Data were analyzed from September 10, 2017, through October 4, 2018. EXPOSURES: Operative vs nonoperative management for aSBO. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of recurrence of aSBO among those with operative vs nonoperative management. Time-to-event analyses were used to estimate hazard ratios of recurrence while accounting for the competing risk of death. RESULTS: Of 27 904 patients admitted with their first episode of aSBO, 6186 (22.2%) underwent operative management. Mean (SD) patient age was 61.2 (13.6) years, and 51.1% (14 228 of 27 904) were female. Patients undergoing operative management were younger (mean [SD] age, 60.2 [14.3] vs 61.5 [13.4] years) with fewer comorbidities (low burden, 382 [6.2%] vs 912 [4.2%]). After matching, those with operative management had a lower risk of recurrence (13.0% vs 21.3%; hazard ratio, 0.62; 95% CI, 0.56-0.68; P

Importance Tisagenlecleucel, a chimeric antigen receptor T-cell therapy for relapsed or refractory pediatric acute lymphoblastic leukemia, has been approved for use in multiple jurisdictions. The public list price is US $475 000, or more than CaD $600 000. Assessing the cost-effectiveness of tisagenlecleucel is necessary to inform policy makers on the economic value of this treatment. Objective To assess the value for money of tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible pediatric patients with acute lymphoblastic leukemia under unknown long-term effectiveness. Design, Setting, and Participants A cost-utility analysis of tisagenlecleucel compared with current standard care using a Canadian population-based registry of pediatric patients with acute lymphoblastic leukemia was performed. Results from 3 pooled single-arm tisagenlecleucel clinical trials and a provincial pediatric cancer registry were combined to create treatment and control arms, respectively. The population-based control arm consisted of patients meeting clinical trial inclusion and exclusion criteria, starting at second relapse. Multistate and individual-level simulation modeling were combined to predict patient lifetime health trajectories by treatment strategy. Tisagenlecleucel efficacy was modeled across long-term cure rates, from 10% to 40%, to account for limited information on its long-term effectiveness. Uncertainty was tested with 1-way and probabilistic sensitivity analysis. Data were collected in September 2017, and analysis began in December 2017. Exposures Tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible patients. Main Outcomes and Measures Relative health care costs, survival gains, and quality-adjusted life-years (QALYs) between tisagenlecleucel and current standard care. Results The treatment and control arms were modeled on 192 and 118 patients, respectively. The mean (SD) age of control individuals was 10 (4.25) years, and the mean (SD) age of the pooled clinical trial sample was 11 (6) years. The control individuals had 78 boys (66%), and the pooled clinical trial sample had 102 boys (53%). Treatment with tisagenlecleucel was associated with an additional 2.14 to 9.85 life years or 1.68 to 6.61 QALYs, compared with current care. The average additional cost of tisagenlecleucel was CaD $470 013 (US $357 031). Accounting for the total discounted cost over the patient lifetime resulted in an incremental cost of CaD $71 000 (US $53 933) to CaD $281 000 (US $213 453) per QALY gain. Conclusions and Relevance To our knowledge, this study offers the first cost-effectiveness analysis of tisagenlecleucel compared with current standard care for pediatric patients with acute lymphoblastic leukemia using a constructed population-based control arm. At a willingness-to-pay threshold of $150 000/QALY, tisagenlecleucel had a 32% likelihood of being cost-effective. Tisagenlecleucel cost-effectiveness would fall below $50 000/QALY with a long-term cure rate of over 0.40 or a price discount of 49% at its currently known effectiveness.

Current guidelines for the management of adhesive small bowel obstruction suggest a limited trial of non-operative management, often of 3–5 days. A longer delay to operation may worsen post-operative outcomes in patients who ultimately require operation. Our objective was to evaluate the impact of time to operation on post-operative outcomes in patients who undergo operation following a trial of non-operative management for adhesive small bowel obstruction. We used health administrative data to identify patients with adhesive small bowel obstruction who underwent operative management following a trial of non-operative management from 2005 to 2014 in the province of Ontario, Canada. We used multivariable logistic regression to examine the relationship between the time from admission to operation with rates of 30-day mortality, serious complication, and bowel resection. Three thousand five hundred sixty-three patients underwent operation after a trial of non-operative management for adhesive small bowel obstruction. Older patients, patients with a high comorbidity burden, and patients with a lower socioeconomic status were more likely to experience a longer pre-operative period. After adjusting for covariates, each additional day from admission to operation increased odds of serious complication (OR = 1.07, 95% CI = 1.03–1.11) and bowel resection (OR = 1.06, 95% CI = 1.03–1.98). Longer times to operation were not associated with greater adjusted odds of 30-day mortality. Each additional day from admission to operation is associated with greater odds of adverse outcomes. Clinical practice guidelines should emphasize strategies that identify patients who will ultimately require operation.

Study objectives The objectives of this study were to evaluate (1) the accuracy of the clinical diagnosis of obstructive sleep apnea (OSA) informed by the home sleep study with a Type 4 portable monitor BresoDx® versus Type 1 polysomnography (PSG); and (2) agreement of the apnea-hypopnea index (AHI) compared between BresoDx and PSG. Material and methods This was a randomized, parallel, multicentre, single-blind, pragmatic controlled trial enrolling adults referred to three Ontario sleep clinics for suspected OSA. Participants were randomized to BresoDx followed by PSG (one-night apart) or PSG followed by BresoDx sleep testing sequence arms. The primary outcomes included the accuracy of clinical diagnosis and OSA severity measured by AHI between tests. Results In sum, 233 participants completed both sleep studies and 206 completed physician consultation visits. The agreement between clinical diagnosis informed by PSG versus BresoDx was fair (Cohen's kappa coefficient = 0.28). The sensitivity of BresoDx-informed clinical diagnosis against PSG was between 0.86 and 0.89, and the specificity between 0.38 and 0.44. For AHI cut-off of ≥5 events/hour the sensitivity, specificity and positive and negative predictive values were 0.85, 0.48, 0.81 and 0.54. Conclusions Home sleep apnea testing with BresoDx can be used in a referral population with a high pretest probability of OSA similar to other Type IV devices. This study complements the existing body of evidence suggesting that home testing with portable devices plays a valuable role for diagnosing of OSA in a variety of settings. SIESTA trial registration www.clinicaltrials.gov (Identifier: NCT02003729).

Background The clinical effectiveness of cardiac rehabilitation (CR) on health-related quality of life (HRQOL) is an area that has not been consistently explored. The objective of this systematic review was to evaluate the effectiveness of providing any core component of CR on HRQOL domains. Methods We performed a meta-analysis and meta-regression of randomized controlled trials (RCTs) on the core components of CR. RCTs included adult patients with diagnosed coronary artery disease via angiography, myocardial infarction, angina, or who had undergone coronary revascularization. The Cochrane Library, MEDLINE, EMBASE, CINAHL, SCI-EXPANDED, Psych INFO, and Web of Science were searched from inception to April 27, 2017. Outcomes included overall, physical, emotional, and social HRQOL. Outcomes were reported as standardized mean change (SMC) with 95% confidence intervals (CIs). Effect size changes of 0.2, 0.5, and 0.8 SD units reflect a small, moderate, and large effect, respectively. Results Forty-nine reports of 41 RCTs with 11,747 patients were included. Summary effect sizes were: overall HRQOL SMC, 0.28 (95% CI, 0.05-0.50), physical HRQOL SMC, 0.47 (95% CI, 0.13-0.81), emotional HRQOL SMC, 0.37 (95% CI, −0.02 to 0.77), and social HRQOL SMC, 0.13 (95% CI, −0.06 to 0.32). Meta-regression revealed type of CR intervention and year of publication as positive statistically significant treatment effect modifiers. Conclusions Receiving CR was shown to improve HRQOL, with exercise-, nonexercise-, and psychological-based interventions playing a vital role. Although these improvements in HRQOL were modest they still reflect an incremental benefit compared with receiving usual care.

This study aimed to explain a joint statistical procedure (two-part models and Cholesky decomposition) to incorporate second-order uncertainty from covariate adjusted mean utility functions in probabilistic cost-effectiveness models. First, two-part models were applied to obtain parameters for the utility function. Second, a new set of correlated parameters for each simulation was obtained by Cholesky decomposition. The procedure was applied to EuroQol5D-5L in the Spanish Health Survey (21,007 adults). An example for the first simulation showed that 71% of men aged 60 years, high social status and normal weight were in perfect health, and in those not in perfect health, the expected utility was 0.8474 (= 1 − 0.1526). Therefore, their estimated mean utility value was 0.9559. Mean utility values in the interval (− ∞1] were calculated and their associated uncertainty incorporated in the cost-effectiveness models, based on the uncertainty related to correlated parameters in the utilities function. Resumen: El objetivo de este estudio fue explicar el procedimiento estadístico conjunto (modelos en dos etapas y descomposición de Cholesky) para incorporar la incertidumbre de segundo orden asociada a la función de utilidad media ajustada por variables en los modelos probabilísticos de coste-efectividad. Primero se aplicaron los modelos en dos etapas para obtener los parámetros de la función de utilidad. Segundo, para cada simulación, se obtuvo un nuevo conjunto de parámetros correlacionados utilizando la descomposición de Cholesky. El procedimiento se aplicó al cuestionario EuroQol5D-5L de la Encuesta Nacional de Salud en España (21.007 adultos). El ejemplo de una primera simulación mostró que el 71% de los hombres de 60 años, con clase social alta y peso normal tenían una salud perfecta, y en aquellos que no tenían una salud perfecta la utilidad esperada fue de 0,8474 (= 1 − 0,1526). Por lo tanto, su utilidad media estimada fue de 0,9559. Se calcularon utilidades medias con valores comprendidos en el intervalo (-∞1] y se incorporó la incertidumbre asociada a ellos en los modelos de coste-efectividad, basándose en la incertidumbre correspondiente a los parámetros correlacionados de la función de utilidad. Keywords: Uncertainty, Cost-utility analysis, Decision modelling, Health-related quality of life, Patient reported outcomes, Health survey, Palabras clave: Incertidumbre, Análisis de coste-utilidad, Modelos de apoyo para la decisión, Calidad de vida relacionada con la salud, Resultados informados por el paciente, Encuesta de salud

Recent evidence suggests that less frequent repositioning of long-term care residents at moderate/high risk of developing pressure ulcers (PrUs) is non-inferior to current repositioning standards in preventing PrUs. However, the long-term health and economic consequences of less frequent repositioning have not been adequately estimated. Our objective is to estimate the cost-effectiveness of different repositioning strategies (2-, 3-, or 4-hour intervals). We conducted a cost-utility analysis using a lifetime horizon based on data from a randomized clinical trial and from the literature. We updated a published PrU decision model with resource utilization, unit costs, and epidemiological estimates from the literature and from a small observational study. The Ontario Ministry of Health and Long-Term Care perspective was taken. We estimated the reduction in costs at 3-hour vs 2- or 4-hour repositioning at CAN$5,425 (95% Credible Interval (CrI): $922 – $12,166), or CAN$3,296 (95%CrI: −$483 – $9,738) per resident across their lifetime respectively. The gain in the expected Quality Adjusted Life Years (QALYs) between 3-hour and 2- or 4-hour repositioning strategies were 0.008, (95% CrI: 0.005 – 0.016) and 0.009 (95%CrI: 0.007 – 0.018) respectively. Repositioning at 3-hour intervals was the dominant strategy with respect to the incremental cost-effectiveness ratio against both 2- and 4-hour strategies. Sensitivity analysis showed a 99% probability that the 3-hourly repositioning was a dominant strategy. We concluded that repositioning at 3-hour intervals for residents at moderate or high risk of PrUs and who were cared for on high-density foam mattresses appeared to be the most cost-effective strategy.

Aims Transoesophageal echocardiography (TOE) is the gold standard for identification of left atrial appendage (LAA) thrombi. However, TOE is semi-invasive and cannot be performed in certain patients. Left atrial appendage thrombi can also be identified by cardiac computed tomography (CCT) and cardiac magnetic resonance imaging (CMR); however, the diagnostic performance of these techniques vs. TOE is unclear. Methods and results We performed a systematic review and meta-analysis of 22 CCT and 4 CMR studies comparing diagnostic performance to TOE for identification of LAA thrombi. Meta-regression was performed to determine whether expected sensitivity and specificity differed between early and delayed image acquisition protocols for CCT vs. TOE and between CCT and CMR. Cardiac computed tomography demonstrated sensitivity and specificity of 0.99 [confidence interval (CI 0.93-1.00)] and 0.94 (CI 0.90-0.97) respectively vs. TOE. A subgroup analysis comparing early vs. delayed protocol CCT imaging was performed showing no significant differences in sensitivity (P-value = 0.17) however improved specificity of the delayed imaging protocols (P-value = 0.04). Cardiac magnetic resonance imaging demonstrated sensitivity and specificity of 0.80 (CI 0.63-0.91) and 0.98 (CI 0.97-0.99), respectively when compared to TOE. There was no significant difference in sensitivity or specificity between CMR and CCT (P-values 0.996 and 0.484, respectively). Conclusion Cardiac computed tomography and CMR had good to excellent sensitivity and specificity vs. TOE. Further, there was no significant difference in the sensitivity and specificity of CCT vs. CMR, suggesting that both modalities can be considered reasonable alternatives to TOE in the identification of LAA thrombi. Cardiac magnetic resonance imaging may be especially beneficial when TOE and CCT cannot be performed.

Efficacy of osteoporosis medication is not well-established among patients taking oral glucocorticoids. We assessed the efficacy of approved osteoporosis pharmacotherapies in preventing fracture by combining data from randomized controlled trials. Teriparatide, risedronate, and etidronate were associated with decreased vertebral fracture risk. Several osteoporosis drugs are approved for the prevention and treatment of glucocorticoid (GC)-induced osteoporosis. However, the efficacy of these treatments among oral GC users is still limited. We aimed to examine the comparative efficacy of osteoporosis treatments among oral GC users. We updated a systematic review through to March 2015 to identify all double-blinded randomized controlled trials (RCTs) that examined osteoporosis treatment among oral GC users. We used a network meta-analysis with informative priors to derive comparative risk ratios (RRs) and 95 % credible intervals (95 % CrI) for vertebral and non-vertebral fracture and mean differences in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD). Treatment ranking was estimated using the surface under the cumulative ranking curve (SUCRA) statistic. A meta-regression was completed to assess a subgroup effect between patients with prior GC exposures and GC initiators. We identified 27 eligible RCTs examining nine active comparators. Etidronate (RR, 0.41; 95%CrI = 0.17–0.90), risedronate (RR = 0.30, 95%CrI = 0.14–0.61), and teriparatide (RR = 0.07, 95%CrI = 0.001–0.48) showed greater efficacy than placebo in preventing vertebral fractures; yet, no treatment effects were statistically significant in reducing non-vertebral fractures. Alendronate, risedronate, and etidronate increased LS BMD while alendronate and raloxifene increased FN BMD. In preventing vertebral fractures, teriparatide was ranked as the best treatment (SUCRA: 77 %), followed by risedronate (77 %) and zoledronic acid (76 %). For non-vertebral fractures, teriparatide also had the highest SUCRA (69 %), followed by risedronate (64 %). No subgroup effect was identified with regards to prior GC exposure. Despite weak trial evidence available for fracture prevention among GC users, we identified several drugs that are likely to prevent osteoporotic fracture. Teriparatide, risedronate, and etidronate were associated with decreased vertebral fracture risk.

Little data exist on the frequency of fracture among oral glucocorticoid users. We examined the effect of oral glucocorticoids on fracture incidence using data from randomized controlled trials. Patients starting glucocorticoids had a higher probability of fracture and decline in bone mineral density compared to chronic glucocorticoid users. Oral glucocorticoids (GCs) are the leading cause of secondary osteoporosis. However, there have been few studies that quantify the rate of fracture among GC users. We sought to provide a pooled estimate of fracture risk from randomized controlled trials (RCTs) of GC-treated patients. We updated a MEDLINE search published by the American College of Rheumatology through to March 2015 and identified RCTs of osteoporosis therapies that reported fracture and bone mineral density (BMD) among oral GC users. We restricted the analysis to placebo or control arms. RCT arms were stratified by GC exposure at enrolment to GC initiators (≤6 months) and chronic GC users (>6 months). Bayesian meta-regression was used to estimate the annual probability of vertebral fracture (primary), non-vertebral fracture and percentage change in lumbar spine and femoral neck BMD. The annual incidence of vertebral and non-vertebral fracture was 5.1 % (95 % CrI = 2.8–8.2) and 2.5 % (95 % CrI = 1.2–-4.2) among GC initiators, and 3.2 % (95 % CrI = 1.8–5.0) and 3.0 % (95 % CrI = 0.8–5.9) among chronic GC users. Our meta-regression identified a non-significant effect of group-level variables (mean age, mean BMD, mean GC daily dose, patients with previous vertebral fractures, proportion of women and adjuvant used) on vertebral fracture rate. Our study found higher vertebral fracture incidence among GC initiators, yet a relative decline in fracture incidence with longer exposure. Our findings suggest that fracture incidence among oral GC users may be more common than previously estimated. Optimizing GC-induced osteoporosis management during early exposure to GC is essential to prevent fractures.

Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder. In-laboratory, overnight type I polysomnography (PSG) is the current “gold standard” for diagnosing OSA. Home sleep apnea testing (HSAT) using portable monitors (PMs) is an alternative testing method offering better comfort and lower costs. We aimed to systematically review the evidence on diagnostic ability of type IV PMs compared to PSG in diagnosing OSA. Participants: patients ≥16 years old with symptoms suggestive of OSA;intervention: type IV PMs (devices with

Background The objective of this study was to investigate the changes in blood pressure among patients enrolled in the Telehomecare programme in Ontario, Canada. Methods This observational study utilised a prospective longitudinal cohort design, including patients with heart failure and chronic obstructive pulmonary disease enrolled in the Ontario Telehomecare programme from July 2012 to July 2015. The outcome of interest was change in mean (biweekly) systolic and diastolic blood pressure levels over a six-month period. Patient data were extracted from the Ontario Telemedicine Network database, and analysed using generalised linear mixed model procedures. Results Overall, we analysed data for 3513 patients. Patients were on average 74.1 ± 11.4 years of age; almost half were men, 62% had heart failure, 55% chronic obstructive pulmonary disease and 29% diabetes. At baseline, the mean systolic and diastolic blood pressure levels were 130.4 ± 19.1 mmHg and 72.2 ± 12.5 mmHg for the total sample. At six months, the adjusted reduction in systolic and diastolic blood pressure values were 4.0 mmHg (95% confidence interval: −4.5 to −3.5) and 2.7 mmHg (95% confidence interval: −3.1 to −2.4), respectively. In a subgroup of 1220 patients with uncontrolled blood pressure at baseline (systolic/diastolic blood pressure of 150.7 ± 10.2 mmHg/80.2 ± 13.5 mmHg) the adjusted reduction in systolic blood pressure was 12.5 mmHg (95% confidence interval: −13.4 to −11.6) and in diastolic blood pressure was 7.1 mmHg (95% confidence interval: −7.8 to −6.5) over the six-month period. Conclusions Blood pressure levels were significantly reduced in patients enrolled in the Telehomecare programme, with changes being more pronounced in patients with uncontrolled blood pressure. The sustainability of decreased blood pressure on other clinical outcomes needs further evaluation.

BackgroundMRI-guided laser interstitial thermal therapy (MRgLITT) is a new minimally invasive treatment for temporal lobe epilepsy (TLE), with limited effectiveness data. It is unknown if the cost savings associated with shorter hospitalization could offset the high equipment cost of MRgLITT. We examined the cost-utility of MRgLITT versus surgery for TLE from healthcare payer perspective, and the value of additional research to inform policy decision on MRgLITT.MethodsWe developed a microsimulation model to evaluate quality adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER) of MRgLITT versus surgery in TLE, assuming life-time horizon and 1.5% discount rate. Model inputs were derived from the literature. We conducted threshold and sensitivity analyses to examine parameter uncertainties, and expected value of partial perfect information analyses to evaluate the expected monetary benefit of eliminating uncertainty on probabilities associated with MRgLITT.ResultsMRgLITT yielded 0.08 more QALYs and cost $7,821 higher than surgery, with ICER of $94,350/QALY. Influential parameters that could change model outcomes include probabilities of becoming seizure-free from disabling seizures state and returning to disabling seizures from seizure-free state 5 years after surgery and MRgLITT, cost of MRgLITT disposable equipment, and utilities of disabling seizures and seizure-free states of surgery and MRgLITT. The cost-effectiveness acceptability curve showed surgery was preferred in more than 50% of iterations. The expected monetary benefit of eliminating uncertainty for probabilities associated with MRgLITT was higher than for utilities associated with MRgLITT.ConclusionsMRgLITT resulted in more QALYs gained and higher costs compared to surgery in the base-case. The model was sensitive to variations in the cost of MRgLITT disposable equipment. There is value in conducting more research to reduce uncertainty on the probabilities and utilities of MRgLITT, but priority should be given to research focusing on improving the precision of estimates on effectiveness of MRgLITT.

Key Points Question What is the relative association of management strategies for adult patients with moderate to severe acute respiratory distress syndrome with mortality and barotrauma? Findings In this systematic review and network meta-analysis of 25 randomized clinical trials including 7743 patients, venovenous extracorporeal membrane oxygenation and prone positioning were associated with significantly lower 28-day mortality compared with lung protective ventilation alone. Moreover, venovenous extracorporeal membrane oxygenation was the highest-ranked intervention associated with a reduction in 28-day mortality among the 9 interventions evaluated. Meaning These findings support the use of prone positioning in patients with moderate to severe acute respiratory distress syndrome and venovenous extracorporeal membrane oxygenation in patients with severe acute respiratory distress syndrome., This systematic review and network meta-analysis compares and ranks different therapeutic strategies to identify the best intervention associated with a reduction in mortality in adult patients with moderate to severe acute respiratory distress syndrome (ARDS)., Importance A number of interventions are available to manage patients with moderate to severe acute respiratory distress syndrome (ARDS). However, the associations of currently available ventilatory strategies and adjunctive therapies with mortality are uncertain. Objectives To compare and rank different therapeutic strategies to identify the best intervention associated with a reduction in mortality in adult patients with moderate to severe ARDS. Data Sources An electronic search of MEDLINE, MEDLINE In-Process/ePubs Ahead of Print, Embase, Cochrane Controlled Clinical Trial Register (Central), PubMed, and CINAHL was conducted, from database inception to May 29, 2019. Study Selection Randomized clinical trials of interventions for adults with moderate to severe ARDS that used lung protective ventilation. No language restrictions were applied. Data Extraction and Synthesis Data were independently extracted by 2 reviewers and synthesized with Bayesian random-effects network meta-analyses. Main Outcomes and Measures The primary outcome was 28-day mortality. Barotrauma was a secondary outcome. Results Among 25 randomized clinical trials evaluating 9 interventions, 2686 of 7743 patients (34.6%) died within 28 days. Compared with lung protective ventilation alone, prone positioning and venovenous extracorporeal membrane oxygenation were associated with significantly lower 28-day mortality (prone positioning: risk ratio, 0.69; 95% credible interval, 0.48-0.99; low quality of evidence; venovenous extracorporeal membrane oxygenation: risk ratio, 0.60; 95% credible interval, 0.38-0.93; moderate quality of evidence). These 2 interventions had the highest ranking probabilities, although they were not significantly different from each other. Among 18 trials reporting on barotrauma, 448 of 6258 patients (7.2%) experienced this secondary outcome. No intervention was superior to any other in reducing barotrauma, and each represented low to very low quality of evidence. Conclusions and Relevance This network meta-analysis supports the use of prone positioning and venovenous extracorporeal membrane oxygenation in addition to lung protective ventilation in patients with ARDS. Moreover, venovenous extracorporeal membrane oxygenation may be considered as an early strategy for adults with severe ARDS receiving lung protective ventilation.

Data from clinical trials are needed to guide the safe and effective use of medicines in children. Clinical trials are challenging to design and implement in all populations, and children present additional considerations. Several regions including the UK, USA and Europe have established clinical trial infrastructure to capitalise on expertise and promote clinical trials enrolling children. Our objective is to describe the partnerships and operational considerations for the development of paediatric clinical trials infrastructure in Canada. We describe the design and conduct of four emergency room paediatric trials, with four separate sponsors, across four provinces in parallel. Operations discussed include multisite contract development, centralised risk-based data monitoring, ethical review and patient engagement. We conclude with lessons learnt, additional challenges and potential solutions to facilitate drug development for children in Canada.

As the complexity of health decision science applications increases, high-level programming languages are increasingly adopted for statistical analyses and numerical computations. These programming languages facilitate sophisticated modeling, model documentation, and analysis reproducibility. Among the high-level programming languages, the statistical programming framework R is gaining increased recognition. R is freely available, cross-platform compatible, and open source. A large community of users who have generated an extensive collection of well-documented packages and functions supports it. These functions facilitate applications of health decision science methodology as well as the visualization and communication of results. Although R’s popularity is increasing among health decision scientists, methodological extensions of R in the field of decision analysis remain isolated. The purpose of this article is to provide an overview of existing R functionality that is applicable to the various stages of decision analysis, including model design, input parameter estimation, and analysis of model outputs.

BackgroundThere are numerous health-related quality of life (HRQol) measurements used in coronary heart disease (CHD) in the literature. However, only values assessed with preference-based instruments can be directly applied in a cost-utility analysis (CUA).ObjectiveTo summarize and synthesize instrument-specific preference-based values in CHD and the underlying disease-subgroups, stable angina and post-acute coronary syndrome (post-ACS), for developed countries, while accounting for study-level characteristics, and within- and between-study correlation.MethodsA systematic review was conducted to identify studies reporting preference-based values in CHD. A multivariate meta-analysis was applied to synthesize the HRQoL values. Meta-regression analyses examined the effect of study level covariates age, publication year, prevalence of diabetes and gender.ResultsA total of 40 studies providing preference-based values were detected. Synthesized estimates of HRQoL in post-ACS ranged from 0.64 (Quality of Well-Being) to 0.92 (EuroQol European"tariff"), while in stable angina they ranged from 0.64 (Short form 6D) to 0.89 (Standard Gamble). Similar findings were observed in estimates applying to general CHD. No significant improvement in model fit was found after adjusting for study-level covariates. Large between-study heterogeneity was observed in all the models investigated.ConclusionsThe main finding of our study is the presence of large heterogeneity both within and between instrument-specific HRQoL values. Current economic models in CHD ignore this between-study heterogeneity. Multivariate meta-analysis can quantify this heterogeneity and offers the means for uncertainty around HRQoL values to be translated to uncertainty in CUAs.