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Background Observational burden of illness studies are used in pharmacoepidemiology to address a variety of objectives, including contextualizing the current treatment setting, identifying important treatment gaps, and providing estimates to parameterize economic models. Methodologies such as retrospective chart review may be utilized in settings for which existing datasets are not available or do not include sufficient clinical detail. While specifying the number of charts to be extracted and/or determining whether the number that can feasibly extracted will be clinically meaningful is an important study design consideration, there is a lack of rigorous methods available for sample size calculation in this setting. The objective of this study was to develop recommended sample size calculations for use in such studies. Methods Calculations for identifying the optimal feasible sample size calculations were derived, for studies characterizing treatment patterns and medical costs, based on the ability to comprehensively observe treatments and maximize precision of resulting 95% confidence intervals. For cost outcomes, if the standard deviation is not known, the coefficient of variation cv can be used as an alternative. A case study of a chart review of advanced melanoma (MELODY) was used to characterize plausible values for cv in a real-world example. Results Across sample sizes, any treatment given with greater than 1% frequency has a high likelihood of being observed. For a sample of size 200, and a treatment given to 5% of the population, the precision of a 95% confidence interval (CI) is expected to be ±0.03. For cost outcomes, for the median cv value observed in the MELODY study (0.72), a sample size of approximately 200 would be required to generate a 95% CI precise to within ±10% of the mean. Conclusion This study presents a formal guidance on sample size calculations for retrospective burden of illness studies. The approach presented here is methodologically rigorous and designed for practical application in real-world retrospective chart review studies.

In October 2019, cannabis edibles were legalized for sale in Canada for non-medical use. This move was intended to improve public safety by regulating contents (including a maximum 10 mg tetrahydrocannabinol (THC) per package) and packaging to prevent accidental ingestion or over consumption. This study aimed to explore consumer preferences for cannabis edibles to inform cannabis policy. We explored the relative importance and trade-offs consumers make for attributes of cannabis edibles using a discrete choice experiment. Attributes included type of edible, price, THC content, cannabis taste, package information, product consistency, product recommendations, and Health Canada regulation. Participants lived in Canada, were 19 years of age or older, and purchased a cannabis edible in the last 12 months. A multinomial logit (MNL) model was used for the base model, and latent class analysis to assess preference sub-groups. This study was approved by the institutional ethics committee. Among 684 participants, the MNL model showed that potency was the most relevant attribute, followed by edible type. A two-group latent class model revealed two very distinct preference patterns. Preferences for group 1 (~65% of sample) were driven primarily by edible type, while for group 2 (~35% of sample) were driven almost entirely by THC potency. This study found that consumer preferences for ~65% of consumers of cannabis edibles are being met through regulated channels. The remaining ~35% are driven by THC potency at levels that are not currently available on the licensed market. Attracting this market segment will require reviewing the risks and benefits of restricting THC package content.

Surgical site infection (SSI) complicates 2-5% of surgeries in the United States. Severity of SSI ranges from superficial skin infection to life-threatening conditions such as severe sepsis, and SSIs are responsible for increased morbidity, mortality, and economic burden associated with surgery. Staphylococcus aureus (S. aureus) is a commonly-isolated organism for SSI, and methicillin-resistant S. aureus SSI incidence is increasing globally. The objective of this systematic review was to characterize risk factors for SSI within observational studies describing incidence of SSI in a real-world setting. An initial search identified 328 titles published in 2002-2012; 57 were identified as relevant for data extraction. Extracted information included study design and methodology, reported cumulative incidence and post-surgical time until onset of SSI, and odds ratios and associated variability for all factors considered in univariate and/or multivariable analyses. Median SSI incidence was 3.7%, ranging from 0.1% to 50.4%. Incidence of overall SSI and S. aureus SSI were both highest in tumor-related and transplant surgeries. Median time until SSI onset was 17.0 days, with longer time-to-onset for orthopedic and transplant surgeries. Risk factors consistently identified as associated with SSI included co-morbidities, advanced age, risk indices, patient frailty, and surgery complexity. Thirteen studies considered diabetes as a risk factor in multivariable analysis; 85% found a significant association with SSI, with odds ratios ranging from 1.5-24.3. Longer surgeries were associated with increased SSI risk, with a median odds ratio of 2.3 across 11 studies reporting significant results. In a broad review of published literature, risk factors for SSI were characterized as describing reduced fitness, patient frailty, surgery duration, and complexity. Recognition of risk factors frequently associated with SSI allows for identification of such patients with the greatest need for optimal preventive measures to be identified and pre-treatment prior to surgery.

ObjectiveTo estimate the association between the use of sodium glucose co-transporter-2 (SGLT2) inhibitors and postmarket harms as identified by drug regulatory agencies.DesignWe conducted a systematic review and meta-analysis of randomised controlled trials (RCT). Six large databases were searched from inception to May 2018. Random effects models were used to estimate pooled relative risks (RRs).InterventionSGLT2 inhibitors, compared with placebo or active comparators.Primary outcomesAcute kidney injury (AKI), diabetic ketoacidosis (DKA), urinary tract infections (UTI), bone fractures and lower limb amputations.ResultsWe screened 2418 citations of which 109 were included. Most studies included one of four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin and ipragliflozin. When compared with placebo, SGLT2 inhibitors were found to be significantly protective against AKI (RR=0.59; 95% CI 0.39 to 0.89; I2=0.0%), while no difference was found for DKA (RR 0.66; 95% CI 0.30 to 1.45, I2=0.0%), UTI (RR 1.02; 95% CI 0.95 to 1.09, I2=0.0%) or bone fracture (RR 0.87; 95% CI 0.69 to 1.09, I2=1.3%). Three studies reported on amputation, with one finding a significant increase risk. No increased risk for either outcome was found when compared with active controls. Subgroup analysis did show an increased risk of UTI with dapagliflozin only (RR 1.21; 95% CI 1.02 to 1.43, I2=0.0%), but no other analysis supported an increased risk of AKI, DKA, UTI or fracture.ConclusionsCurrent evidence from RCTs does not suggest an increased risk of harm with SGLT2 inhibitors as a class over placebo or active comparators with respect to AKI, DKA, UTI or fracture. However, wide CIs for many comparisons suggest limited precision, and therefore clinically important adverse events cannot be ruled out. Dapagliflozin, appears to independently increase the risk of UTI, although the mechanism for this intraclass variation in risk is unclear.PROSPERO registration numberCRD42016038715.

To provide a national estimate of the incidence of hospitalizations due to osteoporotic fractures (OFs) in women; compare this with the incidence of myocardial infarction (MI), stroke, and breast cancer; and assess temporal trends in the incidence and length of hospitalizations. The study included all women 55 years and older at the time of admission, admitted to a hospital participating in the US Nationwide Inpatient Sample for an outcome of interest. We performed a retrospective analysis of hospitalizations for OFs (hip, forearm, spine, pelvis, distal femur, wrist, and humerus), MI, stroke, or breast cancer, using the US Nationwide Inpatient Sample, 2000-2011. From 2000 to 2011, there were 4.9 million hospitalizations for OF, 2.9 million for MI, 3.0 million for stroke, and 0.7 million for breast cancer. Osteoporotic fractures accounted for more than 40% of the hospitalizations in these 4 outcomes, with an age-adjusted rate of 1124 admissions per 100,000 person-years. In comparison, MI, stroke, and breast cancer had age-adjusted incidence rates of 668, 687, and 151 admissions per 100,000 person-years, respectively. The annual total population facility-related hospital cost was highest for hospitalizations due to OFs ($5.1 billion), followed by MI ($4.3 billion), stroke ($3.0 billion), and breast cancer ($0.5 billion). These data provide evidence that in US women 55 years and older, the hospitalization burden of OFs and population facility-related hospital cost is greater than that of MI, stroke, or breast cancer. Prioritization of bone health and supporting programs such as fracture liaison services is needed to reduce this substantial burden.

Background Preterm birth is a major risk factor for morbidity and mortality among infants worldwide, and imposes considerable burden on health, education and social services, as well as on families and caregivers. Morbidity and mortality resulting from preterm birth is highest among early (< 28 weeks gestational age) and moderate (28–32 weeks) preterm infants, relative to late preterm infants (33–36 weeks). However, substantial societal burden is associated with late prematurity due to the larger number of late preterm infants relative to early and moderate preterm infants. Methods The aim in this study was to characterize the burden of premature birth in Canada for early, moderate, and late premature infants, including resource utilization, direct medical costs, parental out-of-pocket costs, education costs, and mortality, using a validated and published decision model from the UK, and adapting it to a Canadian setting based on analysis of administrative, population-based data from Québec. Results Two-year survival was estimated at 56.0% for early preterm infants, 92.8% for moderate preterm infants, and 98.4% for late preterm infants. Per infant resource utilization consistently decreased with age. For moderately preterm infants, hospital days ranged from 1.6 at age two to 0.09 at age ten. Cost per infant over the first ten years of life was estimated to be $67,467 for early preterm infants, $52,796 for moderate preterm infants, and $10,010 for late preterm infants. Based on population sizes this corresponds to total national costs of $123.3 million for early preterm infants, $255.6 million for moderate preterm infants, $208.2 million for late preterm infants, and $587.1 million for all infants. Conclusion Premature birth results in significant infant morbidity, mortality, healthcare utilization and costs in Canada. A comprehensive decision-model based on analysis of a Canadian population-based administrative data source suggested that the greatest national-level burden is associated with moderate preterm infants due to both a large cost per infant and population size while the highest individual-level burden is in early preterm infants and the largest total population size is in late preterm infants. Although the highest medical costs are incurred during the neonatal period, greater resource utilization and costs extend into childhood.

Introduction. Access to individual patient data (IPD) can be advantageous when conducting cost-effectiveness analyses or indirect treatment comparisons. While exact times of censoring are often marked on published Kaplan-Meier (KM) curves, an algorithm for reconstructing IPD from such curves that allows for their incorporation is presently unavailable. Methods. An algorithm capable of incorporating marked censoring times was developed to reconstruct IPD from KM curves, taking as additional inputs the total patient count and coordinates of the drops in survival. The reliability of the algorithm was evaluated via a simulation exercise, in which survival curves were simulated, digitized, and then reconstructed. To assess the reliability of the reconstructed curves, hazard ratios (HRs) and quantiles of survival were compared between the original and reconstructed curves, and the reconstructed curves were visually inspected. Results. No systematic differences were found in HRs and quantiles in the original versus reconstructed curves. Upon visual inspection, the reconstructed IPD provided a close fit to the digitized data from the published KM curves. Inherent to the algorithm, censoring times were incorporated into the reconstructed data exactly as specified. Conclusion. This new algorithm can reliably be used to reconstruct IPD from reported KM survival curves in the presence of extractable censoring times. Use of the algorithm will allow health researchers to reconstruct IPD more closely by incorporating censoring times exactly as marked, requiring as additional inputs the total patient count and coordinates of the drops in survival. Graphical Abstract This is a visual representation of the abstract.

Although brentuximab vedotin (BV) has changed the management of patients with relapsed or refractory Hodgkin lymphoma (RRHL), little information is available on routine clinical practice. We identified treatment patterns and costs of care among RRHL patients in the United States (US) treated with BV. A retrospective observational study of adults initiating BV for RRHL from 2011-2015, with ≥6 months of data prior to and following BV initiation, was conducted. Treatments were classified based on dispensations and chemotherapy administration. Median total and monthly costs were estimated based on all-cause healthcare resource use in 2015 US dollars (USD). The cohort comprised 289 patients (59% male; mean age at diagnosis, 42 years) with a mean follow-up of 250 weeks. Eleven percent had BV salvage therapy prior to ASCT, and 32% had BV for a relapse post-ASCT. 43% received treatment post-BV, most commonly allogeneic stem cell transplant (SCT) and bendamustine (both 10.2%). Median (IQR) total costs from BV initiation to censoring were 294,790 (142,110-483,360) USD; and were highest among those treated with BV prior to ASCT (up to 421,900 [300,940-778,970] USD). Median monthly costs were almost 20,000 USD per month, and up to 25,000 USD per month among those with BV and ASCT. Medications were the greatest driver of median monthly costs. Median total all-cause costs were almost 300,000 USD, and median monthly costs approximately 20,000 USD, per patient treated. Patients requiring treatment following BV continue to incur high costs, highlighting the economic burden associated with managing patients in the RRHL setting.

BackgroundThe objective of this study was to describe patterns in monthly migraine days (MMD) and tablet utilization, and to estimate health-related quality of life (HRQoL) measures in patients treated as needed (PRN) with rimegepant 75 mg over 52-weeks.MethodsEligible subjects were adults with ≥1 year history of migraine and ≥ 6 MMD at baseline, who used rimegepant 75 mg up to once daily PRN (at their discretion) for up to 52-weeks in an open-label safety study (BHV3000–201; NCT03266588). Mean MMD were calculated at each 4-week period, along with mean monthly tablets taken. Migraine-specific quality of life (MSQv2) data were mapped to EQ-5D utilities and used to characterize HRQoL over time. A published network meta-analysis was used to characterize pain hours as well as time periods spent migraine free.ResultsOne thousand forty four subjects were included in this post-hoc analysis. Overall mean MMD were 10.9 at baseline and decreased to 8.9 by week 52. Tablet use remained stable over the follow-up period. A total of 0.08 incremental QALYs were associated with rimegepant use.ConclusionFor subjects with 6 or more MMD, acute treatment of migraine attacks with rimegepant 75 mg on a PRN basis over one-year of follow-up was found to be associated with reduced MMD frequency without an increase in monthly tablet utilization, and improved HRQoL. There was no evidence of medication-related increases in MMDs when rimegepant 75 mg was used as needed for the acute treatment of migraine over 52-weeks.Trial registrationClinicalTrials.gov identifier NCT03266588.

ObjectivesTo estimate the risk of subsequent exacerbations, in relation to history of exacerbations, in a cohort of older chronic obstructive pulmonary disease (COPD) patients in Canada.MethodsUsing provincial claims data from Ontario, Canada, patients with COPD aged≥65 years (identified between 2004 and 2018; followed up to 2020) were categorised into one of four mutually exclusive groups: no exacerbation; only one moderate; only one severe; or two or more exacerbations of any severity (moderate or severe) during the baseline period. The index date was the first documentation of a COPD diagnosis code; the subsequent 12 months served as the baseline period. Adjusted risks of subsequent exacerbations (any severity and severe exacerbation, separately) by the end of postbaseline year 1, 2 and 3 were estimated, accounting for differences in patient and disease characteristics and competing risk of death.ResultsA total of 591 686 patients were included. The majority (89.8%) had no exacerbation at baseline, 3.1% had one moderate exacerbation only, 3.6% had one severe exacerbation only and 3.6% had two or more exacerbations of any severity. Adjusted risks of a subsequent exacerbation of any severity by the end of year 3 were 28.6% (95% CI, 28.5% to 28.7%) with no baseline exacerbation; 56.6% (95% CI, 56.1% to 57.1%), one severe; 58.4% (95% CI, 58.0% to 58.8%), one moderate; and 77.5% (95% CI, 77.2% to 77.8%) two or more exacerbations. Adjusted risks of a subsequent severe exacerbation by the end of year 3 were 20.1% (95% CI, 20.0% to 20.2%) with no baseline exacerbation; 34.9% (95% CI, 34.5% to 35.4%), one moderate; 46.7% (95% CI, 46.2% to 47.2%), one severe; and 59.6% (95% CI, 59.3% to 60.0%) two or more exacerbations.ConclusionsHaving a history of a single severe or two or more exacerbations of any severity is associated with a higher risk of future exacerbations, with observed exacerbation rates and severity that are constant over time. Even one moderate exacerbation over a year is associated with poorer outcomes, compared with the absence of exacerbation, and moderate exacerbations should be managed accordingly.