White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: A meta-analysis, systematic review, and recommendations for future study harmonization.

INTRODUCTION: The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps. METHODS: A meta-analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke. RESULTS: Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post-stroke populations. Apolipoprotein E (APOE) genotype and domain-specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta-analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier. DISCUSSION: Recommendations and future directions for study of WMHs are provided to improve cross-study comparison and translation of research into consistent clinical interpretation.

Intravenous Thrombolysis After First-Ever Ischemic Stroke and Reduced Incident Dementia Rate.

BACKGROUND: The use of intravenous thrombolysis is associated with improved clinical outcomes. Whether thrombolysis is associated with reduced incidence of poststroke dementia remains uncertain. We sought to estimate if the use of thrombolysis following first-ever ischemic stroke was associated with a reduced rate of incident dementia using a pragmatic observational design. METHODS: We included first-ever ischemic stroke patients from the Ontario Stroke Registry who had not previously been diagnosed with dementia. The primary outcome was incident dementia ascertained by a validated diagnostic algorithm. We employed inverse probability of treatment-weighted Cox proportional hazard models to estimate the cause-specific hazard ratio for the association of thrombolysis and incident dementia at 1 and 5 years following stroke. RESULTS: From July 2003 to March 2013, 7072 patients with ischemic stroke were included, 3276 (46.3%) were female and mean age was 71.0 (SD, 12.8) years. Overall, 38.2% of the cohort (n=2705) received thrombolysis, 77.2% (n=2087) of which was administered within 3 hours of stroke onset. In the first year following stroke, thrombolysis administration was associated with a 24% relative reduction in the rate of developing dementia (cause-specific hazard ratio, 0.76 [95% CI, 0.58-0.97]). This association remained significant at 5 years (cause-specific hazard ratio, 0.79 [95% CI, 0.66-0.91]) and at the end of follow-up (median 6.3 years; cause-specific hazard ratio, 0.79 [95% CI, 0.68-0.89]). CONCLUSIONS: Thrombolysis administration following first-ever ischemic stroke was independently associated with a reduced rate of dementia. Incident dementia should be considered as a relevant outcome when evaluating risk/benefit of thrombolysis in ischemic stroke patients.

Impact of non-pharmaceutical interventions and vaccination on COVID-19 outbreaks in Nunavut, Canada: a Canadian Immunization Research Network (CIRN) study.

BACKGROUND: Nunavut, the northernmost Arctic territory of Canada, experienced three community outbreaks of the coronavirus disease 2019 (COVID-19) from early November 2020 to mid-June 2021. We sought to investigate how non-pharmaceutical interventions (NPIs) and vaccination affected the course of these outbreaks. METHODS: We used an agent-based model of disease transmission to simulate COVID-19 outbreaks in Nunavut. The model encapsulated demographics and household structure of the population, the effect of NPIs, and daily number of vaccine doses administered. We fitted the model to inferred, back-calculated infections from incidence data reported from October 2020 to June 2021. We then compared the fit of the scenario based on case count data with several counterfactual scenarios without the effect of NPIs, without vaccination, and with a hypothetical accelerated vaccination program whereby 98% of the vaccine supply was administered to eligible individuals. RESULTS: We found that, without a territory-wide lockdown during the first COVID-19 outbreak in November 2020, the peak of infections would have been 4.7 times higher with a total of 5,404 (95% CrI: 5,015-5,798) infections before the start of vaccination on January 6, 2021. Without effective NPIs, we estimated a total of 4,290 (95% CrI: 3,880-4,708) infections during the second outbreak under the pace of vaccination administered in Nunavut. In a hypothetical accelerated vaccine rollout, the total infections during the second Nunavut outbreak would have been 58% lower, to 1,812 (95% CrI: 1,593-2,039) infections. Vaccination was estimated to have the largest impact during the outbreak in April 2021, averting 15,196 (95% CrI: 14,798-15,591) infections if the disease had spread through Nunavut communities. Accelerated vaccination would have further reduced the total infections to 243 (95% CrI: 222-265) even in the absence of NPIs. CONCLUSIONS: NPIs have been essential in mitigating pandemic outbreaks in this large, geographically distanced and remote territory. While vaccination has the greatest impact to prevent infection and severe outcomes, public health implementation of NPIs play an essential role in the short term before attaining high levels of immunity in the population.

Multifaceted strategies for the control of COVID-19 outbreaks in long-term care facilities in Ontario, Canada.

The novel coronavirus disease 2019 (COVID-19) has caused severe outbreaks in Canadian long-term care facilities (LTCFs). In Canada, over 80% of COVID-19 deaths during the first pandemic wave occurred in LTCFs. We sought to evaluate the effect of mitigation measures in LTCFs including frequent testing of staff, and vaccination of staff and residents. We developed an agent-based transmission model and parameterized it with disease-specific estimates, temporal sensitivity of nasopharyngeal and saliva testing, results of vaccine efficacy trials, and data from initial COVID-19 outbreaks in LTCFs in Ontario, Canada. Characteristics of staff and residents, including contact patterns, were integrated into the model with age-dependent risk of hospitalization and death. Estimates of infection and outcomes were obtained and 95% credible intervals were generated using a bias-corrected and accelerated bootstrap method. Weekly routine testing of staff with 2-day turnaround time reduced infections among residents by at least 25.9% (95% CrI: 23.3%-28.3%), compared to baseline measures of mask-wearing, symptom screening, and staff cohorting alone. A similar reduction of hospitalizations and deaths was achieved in residents. Vaccination averted 2-4 times more infections in both staff and residents as compared to routine testing, and markedly reduced hospitalizations and deaths among residents by 95.9% (95% CrI: 95.4%-96.3%) and 95.8% (95% CrI: 95.5%-96.1%), respectively, over 200 days from the start of vaccination. Vaccination could have a substantial impact on mitigating disease burden among residents, but may not eliminate the need for other measures before population-level control of COVID-19 is achieved.

A comparison of COVID-19 epidemiological indicators in Sweden, Norway, Denmark, and Finland.

Aims: To compare the early impact of COVID-19 infections and mortality from February to July 2020 across the Nordic nations of Sweden, Norway, Denmark, and Finland through available public data sources and conduct a descriptive analysis of the potential factors that drove different epidemiological outcomes, with a focus on Sweden's response. Methods: COVID-19 cases, deaths, tests, case age distribution, and the difference between 2020 all-cause mortality and the average mortality of the previous 5 years were compared across nations. Patterns in cell phone mobility data, testing strategies, and seniors' care home deaths were also compared. Data for each nation were based on publicly available sources as of July 31, 2020. Results: Compared with its Nordic peers, Sweden had a higher incidence rate across all ages, a higher COVID-19-related death rate only partially explained by population demographics, a higher death rate in seniors' care, and higher all-cause mortality. Sweden had approximately half as much mobility change as its Nordic neighbours until April and followed similar rates as its neighbours from April to July. Denmark led its Nordic peers in testing rates, while Sweden had the highest cumulative test-positivity rate continuously from mid-March. Conclusions: COVID-19 pushed Sweden's health system to its capacity, exposed systemic weaknesses in the seniors' care system, and revealed challenges with implementing effective contact tracing and testing strategies while experiencing a high case burden. Looser government restrictions at the beginning of the outbreak are likely to have played a role in the impact of COVID-19 in Sweden. In an effort to improve epidemic control, Sweden has increased testing rates, implemented more restrictive prevention measures, and increased their intensive care unit bed capacity.

Evidence of Concomitantly Increasing Stroke and Dementia Prevalence among those 80 Years and Older in Ontario, Canada, 2003-04 to 2012-13.

Among those aged 80 years and older in Ontario, Canada, stroke and dementia incidence declined concomitantly from 2002-03 to 2013-14. This study aimed to report the concurrent temporal trends of stroke and dementia prevalence in Ontario among the same age demographic. The prevalence of both stroke and dementia increased from 2003-04 to 2012-13 in both sexes and the magnitude in which prevalence of dementia increased over time exceeded that of stroke. The substantial increase in the prevalence of dementia may be because of increased recognition and diagnoses of dementia and increased survival of stroke patients who are at higher risk of developing dementia.

Des preuves quant à une augmentation simultanée de la prévalence des AVC et de la démence. De 2002-2003 à 2013-2014, on a noté une diminution simultanée de l'incidence des AVC et de la démence parmi les individus âgés de plus de 80 ans vivant en Ontario (Canada). Ce qui nous intéresse dans cette étude, ce sont les tendances temporelles simultanées en ce qui a trait à la prévalence des AVC et de la démence au sein de la même tranche d'âge et dans la même province. On a ainsi noté que tant la prévalence des AVC que celle de la démence ont augmenté entre 2003­2004 et 2012­2013, et ce, tant chez les hommes que chez les femmes. Cela dit, l'ampleur de l'augmentation de la prévalence de la démence a fini par dépasser au fil du temps celle des AVC. Il se pourrait que l'augmentation substantielle de la prévalence des cas de démence puisse être attribuée à un dépistage accru et à l'établissement de plus nombreux diagnostics ainsi qu'à un accroissement de la survie des patients victimes d'AVC, ces derniers étant alors plus susceptibles d'être atteints de démence.

Anticoagulation Therapy for Atrial Fibrillation in Patients With Alzheimer's Disease.

Background and Purpose- Direct oral anticoagulants (DOACs) are safer, at least equally efficacious, and cost-effective compared to warfarin for stroke prevention in atrial fibrillation (AF) but they remain underused, particularly in demented patients. We estimated the cost-effectiveness of DOACs compared with warfarin in patients with AF and Alzheimer's disease (AD). Methods- We constructed a microsimulation model to estimate the lifetime costs, quality-adjusted life-years (QALYs), and cost-effectiveness of anticoagulation therapy (adjusted-dose warfarin and various DOACs) in 70-year-old patients with AF and AD from a US societal perspective. We stratified patient cohorts based on stage of AD and care setting. Model parameters were estimated from secondary sources. Health benefits were measured in the number of acute health events, life-years, and QALYs gained. We classified alternatives as cost-effective using a willingness-to-pay threshold of $100 000 per QALY gained. Results- For patients with AF and AD, compared with warfarin, DOACs increase costs but also increase QALYs by reducing the risk of stroke. For mild-AD patients living in the community, edoxaban increased lifetime costs by $6603 and increased QALYs by 0.076 compared to warfarin, yielding an incremental cost-effectiveness ratio of $86 882/QALY gained. Even though DOACs increased QALYs compared with warfarin for all patient groups (ranging from 0.019 to 0.085 additional QALYs), no DOAC treatment alternative had an incremental cost-effectiveness ratio <$150 000/QALY gained for patients with moderate to severe AD. For patients living in a long-term care facility with mild AD, the DOAC with the lowest incremental cost-effectiveness ratio (rivaroxaban) costs $150 169 per QALY gained; for patients with more severe AD, the incremental cost-effectiveness ratios were higher. Conclusions- For patients with AF and mild AD living in the community, edoxaban is cost-effective compared with warfarin. Even though patients with moderate and severe AD living in the community and patients with any stage of AD living in a long-term care setting may obtain positive clinical benefits from anticoagulation treatment, DOACs are not cost-effective compared with warfarin for these populations. Compared to aspirin, no oral anticoagulation (warfarin or any DOAC) is cost effective in patients with AF and AD.

Population-level intervention and information collection in dynamic healthcare policy.

We develop a general framework for optimal health policy design in a dynamic setting. We consider a hypothetical medical intervention for a cohort of patients where one parameter varies across cohorts with imperfectly observable linear dynamics. We seek to identify the optimal time to change the current health intervention policy and the optimal time to collect decision-relevant information. We formulate this problem as a discrete-time, infinite-horizon Markov decision process and we establish structural properties in terms of first and second-order monotonicity. We demonstrate that it is generally optimal to delay information acquisition until an effect on decisions is sufficiently likely. We apply this framework to the evaluation of hepatitis C virus (HCV) screening in the general population determining which birth cohorts to screen for HCV and when to collect information about HCV prevalence.

Concomitant vascular and neurodegenerative pathologies double the risk of dementia.

INTRODUCTION: The relative contributions of vascular and degenerative pathology to dementia are unknown. We aim to quantify the proportion of dementia explained by potentially preventable vascular lesions. METHODS: We systematically searched for population-based cohorts before February 2017 reporting clinicopathological data for individuals with and without dementia. We calculated the summary proportion and absolute risk of dementia comparing subjects with and without the pathology. RESULTS: We identified 10 studies comprising 2856 subjects. Vascular-type pathology and mixed pathology are respectively two and three times more likely in demented patients. The summary proportion of dementia is 77%-86% in subjects with mixed degenerative and vascular pathology and 45% in subjects with pure Alzheimer-type pathology. DISCUSSION: Patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer-type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component.

Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE): A Translational, Integrated, and Transdisciplinary Approach.

BACKGROUND: It has been hypothesized that ischemic stroke can cause atrial fibrillation. By elucidating the mechanisms of neurogenically mediated paroxysmal atrial fibrillation, novel therapeutic strategies could be developed to prevent atrial fibrillation occurrence and perpetuation after stroke. This could result in fewer recurrent strokes and deaths, a reduction or delay in dementia onset, and in the lessening of the functional, structural, and metabolic consequences of atrial fibrillation on the heart. METHODS: The Pathophysiology and Risk of Atrial Fibrillation Detected after Ischemic Stroke (PARADISE) study is an investigator-driven, translational, integrated, and transdisciplinary initiative. It comprises 3 complementary research streams that focus on atrial fibrillation detected after stroke: experimental, clinical, and epidemiological. The experimental stream will assess pre- and poststroke electrocardiographic, autonomic, anatomic (brain and heart pathology), and inflammatory trajectories in an animal model of selective insular cortex ischemic stroke. The clinical stream will prospectively investigate autonomic, inflammatory, and neurocognitive changes among patients diagnosed with atrial fibrillation detected after stroke by employing comprehensive and validated instruments. The epidemiological stream will focus on the demographics, clinical characteristics, and outcomes of atrial fibrillation detected after stroke at the population level by means of the Ontario Stroke Registry, a prospective clinical database that comprises over 23,000 patients with ischemic stroke. CONCLUSIONS: PARADISE is a translational research initiative comprising experimental, clinical, and epidemiological research aimed at characterizing clinical features, the pathophysiology, and outcomes of neurogenic atrial fibrillation detected after stroke.

The complexity of atrial fibrillation newly diagnosed after ischemic stroke and transient ischemic attack: advances and uncertainties.

PURPOSE OF REVIEW: Atrial fibrillation is being increasingly diagnosed after ischemic stroke and transient ischemic attack (TIA). Patient characteristics, frequency and duration of paroxysms, and the risk of recurrent ischemic stroke associated with atrial fibrillation detected after stroke and TIA (AFDAS) may differ from atrial fibrillation already known before stroke occurrence. We aim to summarize major recent advances in the field, in the context of prior evidence, and to identify areas of uncertainty to be addressed in future research. RECENT FINDINGS: Half of all atrial fibrillations in ischemic stroke and TIA patients are AFDAS, and most of them are asymptomatic. Over 50% of AFDAS paroxysms last less than 30 s. The rapid initiation of cardiac monitoring and its duration are crucial for its timely and effective detection. AFDAS comprises a heterogeneous mix of atrial fibrillation, possibly including cardiogenic and neurogenic types, and a mix of both. Over 25 single markers and at least 10 scores have been proposed as predictors of AFDAS. However, there are considerable inconsistencies across studies. The role of AFDAS burden and its associated risk of stroke recurrence have not yet been investigated. SUMMARY: AFDAS may differ from atrial fibrillation known before stroke in several clinical dimensions, which are important for optimal patient care strategies. Many questions remain unanswered. Neurogenic and cardiogenic AFDAS need to be characterized, as it may be possible to avoid some neurogenic cases by initiating timely preventive treatments. AFDAS burden may differ in ischemic stroke and TIA patients, with distinctive diagnostic and treatment implications. The prognosis of AFDAS and its risk of recurrent stroke are still unknown; therefore, it is uncertain whether AFDAS patients should be treated with oral anticoagulants.

Milder Alzheimer's disease pathology in heart failure and atrial fibrillation.

INTRODUCTION: Heart failure (HF) and atrial fibrillation (AF) have been associated with a higher risk of Alzheimer's disease (AD). Whether HF and AF are related to AD by enhancing AD neuropathological changes is unknown. METHODS: We applied network analyses and multiple logistic regression models to assess the association between HF and AF with severity of AD neuropathology in patients from the National Alzheimer's Coordinating Center database with primary neuropathological diagnosis of AD. RESULTS: We included 1593 patients, of whom 129 had HF and 250 had AF. HF and AF patients were older and had milder AD pathology. In the network analyses, HF and AF were associated with milder AD neuropathology. In the regression analyses, age (odds ratio [OR] 0.94, 95% confidence interval [CI] 0.93-0.95 per 1-year increase in age, P < .001) and the interaction term HF × AF (OR 0.61, 95% CI 0.40-0.91, P = .014) were inversely related to severe AD pathology, whereas APOE ε4 genotype showed a direct association (OR 1.68, 95% CI 1.31-2.16). Vascular neuropathology was more frequent in patient with HF and AF patients than in those without. DISCUSSION: HF and AF had milder AD neuropathology. Patients with milder AD lived longer and had more exposure to vascular risk factors. HF and AF patients showed a higher frequency of vascular neuropathology, which could have contributed to lower the threshold for clinically evident dementia.

Population-based stroke and dementia incidence trends: Age and sex variations.

INTRODUCTION: We discovered a concomitant decline in stroke and dementia incidence rates at a whole population level in Ontario, Canada. This study explores these trends within demographic subgroups. METHODS: We analyzed administrative data sources using validated algorithms to calculate stroke and dementia incidence rates from 2002 to 2013. RESULTS: For more than 12 years, stroke incidence remained unchanged among those aged 20 to 49 years and decreased for those aged 50 to 64, 65 to 79, and 80+ years by 22.7%, 36.9%, and 37.9%, respectively. Dementia incidence increased by 17.3% and 23.5% in those aged 20 to 49 and 50 to 64 years, respectively, remained unchanged in those aged 65 to 79 years, and decreased by 15.4% in those aged 80+ years. DISCUSSION: The concomitant decline in stroke and dementia incidence rates may depict how successful stroke prevention has targeted shared risk factors of both conditions, especially at advanced ages where such risk factors are highly prevalent. We lend support for the development of an integrated system of stroke and dementia prevention.

Ischemic Stroke Risk in Patients With Atrial Fibrillation and CHA2DS2-VASc Score of 1: Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: The CHA2DS2-VASc score aims to improve risk stratification of ischemic stroke among patients with atrial fibrillation to identify those who can safely forego oral anticoagulation. Oral anticoagulation treatment guidelines remain uncertain for CHA2DS2-VASc score of 1. We conducted a systematic review and meta-analysis of the risk of ischemic stroke for patients with atrial fibrillation and CHA2DS2-VASc score of 0, 1, or 2 not treated with oral anticoagulation. METHODS: We searched MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science from the start of the database up until April 15, 2015. We included studies that stratified the risk of ischemic stroke by CHA2DS2-VASc score for patients with nonvalvular atrial fibrillation. We estimated the summary annual rate of ischemic stroke using random effects meta-analyses and compared the estimated stroke rates with published net-benefit thresholds for initiating anticoagulants. RESULTS: 1162 abstracts were retrieved, of which 10 met all inclusion criteria for the study. There was substantial heterogeneity among studies. The summary estimate for the annual risk of ischemic stroke was 1.61% (95% confidence interval 0%-3.23%) for CHA2DS2-VASc score of 1, meeting the theoretical threshold for using novel oral anticoagulants (0.9%), but below the threshold for warfarin (1.7%). The summary incident risk of ischemic stroke was 0.68% (95% confidence interval 0.12%-1.23%) for CHA2DS2-VASc score of 0 and 2.49% (95% confidence interval 1.16%-3.83%) for CHA2DS2-VASc score of 2. CONCLUSIONS: Our meta-analysis of ischemic stroke risk in atrial fibrillation patients suggests that those with CHA2DS2-VASc score of 1 may be considered for a novel oral anticoagulant, but because of high heterogeneity, the decision should be based on individual patient characteristics.

First-Ever Stroke and Transient Ischemic Attack Incidence and 30-Day Case-Fatality Rates in a Population-Based Study in Argentina.

BACKGROUND AND PURPOSE: Epidemiological data about stroke are scarce in low- and middle-income Latin-American countries. We investigated annual incidence of first-ever stroke and transient ischemic attack (TIA) and 30-day case-fatality rates in a population-based setting in Tandil, Argentina. METHODS: We prospectively identified all first-ever stroke and TIA cases from overlapping sources between January 5, 2013, and April 30, 2015, in Tandil, Argentina. We calculated crude and standardized incidence rates. We estimated 30-day case-fatality rates. RESULTS: We identified 334 first-ever strokes and 108 TIAs. Age-standardized incidence rate per 100 000 for Segi's World population was 76.5 (95% confidence interval [CI], 67.8-85.9) for first-ever stroke and 25.1 (95% CI, 20.2-30.7) for first-ever TIA, 56.1 (95% CI, 48.8-64.2) for ischemic stroke, 13.5 (95% CI, 9.9-17.9) for intracerebral hemorrhage, and 4.9 (95% CI, 2.7-8.1) for subarachnoid hemorrhage. Stroke incidence was slightly higher for men (87.8; 95% CI, 74.6-102.6) than for women (73.2; 95% CI, 61.7-86.1) when standardized for the Argentinean population. Thirty-day case-fatality rate was 14.7% (95% CI, 10.8-19.5) for ischemic stroke, 24.1% (95% CI, 14.2-36.6) for intracerebral hemorrhage, and 1.9% (95% CI, 0.4-5.8) for TIA. CONCLUSIONS: This study provides the first prospective population-based stroke and TIA incidence and case-fatality estimate in Argentina. First-ever stroke incidence was lower than that reported in previous Latin-American studies, but first-ever TIA incidence was higher. Thirty-day case-fatality rates were similar to those of other population-based Latin-American studies.

Cost-Effectiveness Analysis of Pharmacogenomics (PGx)-Based Warfarin, Apixaban, and Rivaroxaban Versus Standard Warfarin for the Management of Atrial Fibrillation in Ontario, Canada.

OBJECTIVE: To assess the cost-effectiveness of pharmacogenomics (PGx)-based warfarin (i.e., warfarin dosing following genetic testing), apixaban, and rivaroxaban oral anticoagulation versus standard warfarin for the treatment of newly diagnosed patients with nonvalvular atrial fibrillation (AF) aged ≥ 65 years. METHODS: We developed a Markov decision-analytic model to compare costs [2017 Canadian dollars (C$)] and quality-adjusted life years (QALYs) from the Ontario health care payer perspective over a life-time horizon. The parameters used in the model were derived from the published literature, the Ontario health care administrative database, and expert opinion. To account for the uncertainty of model parameters, we conducted extensive deterministic and probabilistic sensitivity analyses. The results were summarized using incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves. RESULTS: We found that PGx-based warfarin had an ICER of C$17,584/QALY compared with standard warfarin, and apixaban had an ICER of C$64,590/QALY compared with PGx-based warfarin in our base-case analysis. Rivaroxaban was extendedly dominated by PGx-based warfarin and apixaban. The probabilistic sensitivity analysis showed that apixaban, rivaroxaban, PGx-based warfarin, and standard warfarin were cost-effective at some willingness-to-pay (WTP) thresholds. PGx-based warfarin had a higher probability of being cost-effective than apixaban (51.3% versus 14.3%) at a WTP threshold of C$50,000/QALY. At a WTP threshold of C$100,000/QALY, apixaban had a higher probability of being cost-effective than PGx-based warfarin (54.6% versus 22.6%). CONCLUSION: We found that PGx-based warfarin for patients with AF is cost-effective at a WTP threshold of C$50,000/QALY. Apixaban had a higher probability of being cost-effective (> 50%) at a WTP threshold of C$93,000/QALY.

Propofol sedation does not improve measures of colonoscopy quality but increase cost - findings from a large population-based cohort study.

Background: Propofol is often used for sedation during colonoscopy. We assessed the impact of propofol sedation on colonoscopy related quality metrics and cost in a population-based cohort study. Methods: All colonoscopies performed at 21 hospitals in the province of Ontario, Canada, during an 18-month period, from April 1, 2017 to October 31, 2018, using either propofol or conscious sedation were evaluated. The primary outcome was adenoma detection rate (ADR) and secondary outcomes were sessile serrated polyp detection rate (ssPDR), polyp detection rate (PDR), cecal intubation rate (CIR), and perforation rate. Binary outcomes were assessed using a modified Poisson regression model adjusted for clustering and potential confounders based on patient, procedure, and physician characteristics. Findings: A total of 46,634 colonoscopies were performed, of which 16,408 (35.2%) received propofol and 30,226 (64.8%) received conscious sedation. Compared to conscious sedation, the use of propofol was associated with a lower ADR (24.6% vs. 27.0%, p < 0.0001) but not ssPDR (5.0% vs. 4.7%, p = 0.26), PDR (40.5% vs 40.4%, p = 0.79), CIR (97.1% vs. 96.8%, p = 0.15) or perforation rate (0.04% vs. 0.06%, p = 0.45). On multi-variable analysis, propofol sedation was not associated with any differences in ADR (RR = 0.90, 95% CI 0.74-1.10, p = 0.30), ssPDR (RR = 1.20, 95% CI 0.90-1.60, p = 0.22), PDR (RR = 1.00, 95% CI 0.90-1.11, p = 0.99), or CIR (RR = 1.00, 95% CI 0.80-1.26, p = 0.99). The additional cost associated with propofol sedation was $12,730,496 for every 100,000 cases. Interpretation: The use of propofol sedation was not associated with improved colonoscopy related quality metrics but increased costs. The routine use of propofol for colonoscopy should be reevaluated. Funding: None.

Microsimulation model predicts survival benefit of radiofrequency ablation and stereotactic body radiotherapy versus radiotherapy for treating inoperable stage I non-small cell lung cancer.

OBJECTIVE: A subset of patients with stage IA and IB non-small cell lung cancer (NSCLC) is ineligible for surgical resection and undergoes radiation therapy. Radiofrequency ablation (RFA) and stereotactic body radiotherapy are newer potentially attractive alternative therapies. MATERIALS AND METHODS: We added RFA and stereotactic body radiotherapy treatment modules to a microsimulation model that simulates lung cancer's natural history, detection, and treatment. Natural history parameters were previously estimated via calibration against tumor registry data and cohort studies; the model was validated with screening study and cohort data. RFA model parameters were calibrated against 2-year survival from the Radiofrequency Ablation of Pulmonary Tumor Response Evaluation (RAPTURE) study, and stereotactic body radiotherapy model parameters were calibrated against 3-year survival from a phase 2 prospective trial. We simulated lifetime histories of identical patients with early-stage NSCLC who were ineligible for resection, who were treated with radiation therapy, RFA, or stereotactic body radiotherapy under a range of scenarios. From 5,000,000 simulated individuals, we selected a cohort of patients with stage I medically inoperable cancer for analysis (n = 2056 per treatment scenario). Main outcomes were life expectancy gains. RESULTS: RFA or stereotactic body radiotherapy treatment in patients with peripheral stage IA or IB NSCLC who were nonoperative candidates resulted in life expectancy gains of 1.71 and 1.46 life-years, respectively, compared with universal radiation therapy. A strategy where patients with central tumors underwent stereotactic body radiotherapy and those with peripheral tumors underwent RFA resulted in a gain of 2.02 life-years compared with universal radiation therapy. Findings were robust with respect to changes in model parameters. CONCLUSION: Microsimulation modeling results suggest that RFA and stereotactic body radiotherapy could provide life expectancy gains to patients with stage IA or IB NSCLC who are ineligible for resection.

New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis.

BACKGROUND: Chronic hepatitis C virus is difficult to treat and affects approximately 3 million Americans. Protease inhibitors increase the effectiveness of standard therapy, but they are costly. A genetic assay may identify patients most likely to benefit from this treatment advance. OBJECTIVE: To assess the cost-effectiveness of new protease inhibitors and an interleukin (IL)-28B genotyping assay for treating chronic hepatitis C virus. DESIGN: Decision-analytic Markov model. DATA SOURCES: Published literature and expert opinion. TARGET POPULATION: Treatment-naive patients with chronic, genotype 1 hepatitis C virus monoinfection. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Strategies are defined by the use of IL-28B genotyping and type of treatment (standard therapy [pegylated interferon with ribavirin]; triple therapy [standard therapy and a protease inhibitor]). Interleukin-28B-guided triple therapy stratifies patients with CC genotypes to standard therapy and those with non-CC types to triple therapy. OUTCOME MEASURES: Discounted costs (in 2010 U.S. dollars) and quality-adjusted life-years (QALYs); incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: For patients with mild and advanced fibrosis, universal triple therapy reduced the lifetime risk for hepatocellular carcinoma by 38% and 28%, respectively, and increased quality-adjusted life expectancy by 3% and 8%, respectively, compared with standard therapy. Gains from IL-28B-guided triple therapy were smaller. If the protease inhibitor costs $1100 per week, universal triple therapy costs $102,600 per QALY (mild fibrosis) or $51,500 per QALY (advanced fibrosis) compared with IL-28B-guided triple therapy and $70,100 per QALY (mild fibrosis) and $36,300 per QALY (advanced fibrosis) compared with standard therapy. RESULTS OF SENSITIVITY ANALYSIS: Results were sensitive to the cost of protease inhibitors and treatment adherence rates. LIMITATION: Data on the long-term comparative effectiveness of the new protease inhibitors are lacking. CONCLUSION: Both universal triple therapy and IL-28B-guided triple therapy are cost-effective when the least-expensive protease inhibitor are used for patients with advanced fibrosis. PRIMARY FUNDING SOURCE: Stanford University.