Publications by authors named "Alfonso Iorio"

188 Publications

Pharmacokinetic variability of factor VIII concentrates in Chinese pediatric patients with moderate or severe hemophilia A.

Pediatr Investig 2021 Mar 22;5(1):38-45. Epub 2021 Mar 22.

Beijing Key Laboratory of Pediatric Hematology Oncology National Key Discipline of Pediatrics Ministry of Education Hematology Oncology Center Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China.

Importance: The use of factor VIII (FVIII) concentrates under pharmacokinetic (PK) guidance has become the main approach for treatment of hemophilia. However, limited PK research has been conducted in Chinese pediatric patients.

Objective: To investigate the PK parameters of various FVIII concentrates in Chinese pediatric patients.

Methods: Seventy-nine patients were enrolled (28 treated with Kogenate FS, 23 treated with Advate , and 28 treated with GreenMono™). All enrolled patients participated in single-dose PK analysis after at least a 3-day washout period. Blood samples were collected predose, as well as at 1 h, 9 h, 24 h, and 48 h after infusion; FVIII levels were measured using a one-stage clotting assay. von Willebrand Factor Antigen (VWF:Ag) levels and blood types were also determined. PK parameters were evaluated by WAPPS-Hemo.

Results: Mean values of terminal elimination half-life time (t) for the Kogenate FS, Advate, and GreenMono™ FVIII groups were 12.24 h, 10.18 h, and 9.62 h; median clearance values were 4.16, 6.23, and 5.11 mL·kg·h; and median recovery values were 1.97, 1.55, and 1.61 IU/dL per IU/kg. Longer t, higher recovery, and lower clearance were observed in patients with higher VWF:Ag level who were treated with recombinant concentrates.

Interpretation: Chinese pediatric patients with hemophilia had FVIII PK characteristics similar to those previously observed in non-Chinese children, including large variation among individuals. VWF:Ag level and FVIII brand were associated with differences in FVIII PK. Thus, PK-guided dosing should be used to optimize individualized therapy in Chinese children.
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http://dx.doi.org/10.1002/ped4.12252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983998PMC
March 2021

Extended half-life factor VIII concentrates in adults with hemophilia A: Comparative pharmacokinetics of two products.

Res Pract Thromb Haemost 2021 Feb 23;5(2):349-355. Epub 2021 Feb 23.

Department of Health Research Methods, Evidence, and Impact McMaster University Toronto ON Canada.

Background: The use of pharmacokinetic (PK) studies to help design personalized prophylaxis regimens for factor VIII (FVIII) concentrate in individuals with hemophilia A has been recognized for many years but only became practical for routine clinical use with the availability of web-accessible population PK applications based on Bayesian analysis.

Objective: To compare PK variables using population PK studies done on 2 extended half-life recombinant FVIII concentrates in 23 individuals with hemophilia A after switching from one product to the other.

Methods: We retrospectively analyzed PK parameters derived from the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-HEMO) application on 23 individuals with severe or moderately severe hemophilia A who were required to switch from recombinant FVIII Fc (Eloctate; Biogen, Cambridge, MA, USA) to recombinant antihemophilic factor PEGylated (Adynovate; Takeda Pharmaceutical Company, Osaka, Japan) between 2016 and 2017.

Results: There were minor PK differences between Eloctate and Adynovate, but some parameters did reach statistical significance, namely in vivo recovery (mean, 2.73 IU/dL per IU/kg vs 2.41 IU/dL per IU/kg), clearance (mean, 0.163 mL/h vs 0.194 mL/h), and volume of distribution at steady state (mean, 42.5 ml/kg vs 49.8 mL/kg). Smaller nonsignificant trends toward higher values for Adynovate were seen in terminal half-life, area under the curve, and predicted times to 5% and 1% residual FVIII after infusion.

Conclusion: Population PK analysis revealed differences between the two extended half-life FVIII concentrates, reaching significance for in vivo recovery, clearance, and volume of distribution.
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http://dx.doi.org/10.1002/rth2.12476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938611PMC
February 2021

Pharmacokinetic implications of dosing emicizumab based on vial size: A simulation study.

Haemophilia 2021 Mar 2. Epub 2021 Mar 2.

School of Pharmacy, University of Waterloo, Waterloo, ON, Canada.

Introduction: Emicizumab is dosed as mg/kg and, according to the label, any unused drug left in the vial(s) must be discarded, thereby wasting expensive resources. The aim of this study was to use population pharmacokinetics to illustrate the implications of changing the dosing interval to avoid wastage.

Methods: We used a previously published emicizumab PopPK model after extending its validation to children. We simulated PK parameters for labelled dosing regimens and for regimens using full vials with infusion frequency varied to keep the steady-state drug concentration unchanged. Cost and drug savings were calculated.

Results: The model evaluation was successful. When rounding up, the average individual below 53, 47 and 39 has a time-to-trough increase of up to 5.7, 7.9 and 5.8 days for the QW, Q2 W and Q4 W regimen, respectively. This resulted in an annual cost reduction of up to $173,136, $75,747 and $61,319 USD per patient. At higher body weights, rounding down the dose to the nearest vial resulted in negligible changes in the steady state concentration and cost savings of up to $93,781, $46,891 and $23,446 USD per patient, respectively.

Conclusion: Individuals with a lower body weight may benefit from increasing dose intervals and rounding up dose up to the nearest vial, and individuals with a higher body weight from maintaining the injection frequency and rounding dose down to the nearest vial without significant change in emicizumab levels. Administering the entire vial may result in a reduction of vials used annually and potential cost savings.
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http://dx.doi.org/10.1111/hae.14292DOI Listing
March 2021

Outcomes for studies assessing the efficacy of hemostatic therapies in persons with congenital bleeding disorders.

Haemophilia 2021 Mar 6;27(2):211-220. Epub 2021 Feb 6.

Health Information Research Unit, Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, Hamilton, ON, Canada.

Introduction: Management strategies and hemostatic treatments to achieve control of bleeding are relevant across many disease areas. Identification of primary outcomes for studies assessing hemostatic intervention was the objective of a National Heart, Lung and Blood Institute (NHLBI) sponsored multidisciplinary initiative. The aim of this report is to summarize the evidence reviewed, and the outcomes identified by the subgroup tasked to assess outcomes for inherited bleeding disorders.

Methods: The subgroup decided to focus on haemophilia, the prototypal congenital bleeding disorder and the one with the largest available body of evidence. MEDLINE, EMBASE and PsycINFO, The Cochrane Review, CINAHL, and Web of Science were searched for systematic and narrative reviews on outcomes used in haemophilia clinical trials. Three different clinical goals were identified as typical objectives of future research.

Results: Out of 1322 unique citations, 24 reviews published in the period 2002-2019 were included. We identified 113 outcome measures, categorized in 6 domains: health-related quality of life (HRQoL), comorbidities and mortality, overall physical functioning and participation, bleeding and hemostasis, joint health, and costs and resource use. Three different clinical goals were identified as typical objectives of future research: Episodic 'on demand' replacement therapy, prevention of bleeding (Prophylaxis), and long-term and overall impact of bleeding. For each of these scenarios, specific outcomes were recommended.

Conclusions: Primary outcomes for clinical trials assessing the efficacy of hemostatic treatment in achieving control, prevention and limiting long-term consequences of bleeding in inherited bleeding disorders are suggested, and their strength and limitations discussed.
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http://dx.doi.org/10.1111/hae.14247DOI Listing
March 2021

Optimizing a literature surveillance strategy to retrieve sound overall prognosis and risk assessment model papers.

J Am Med Inform Assoc 2021 Mar;28(4):766-771

Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada.

Objective: Our aim was to develop an efficient search strategy for prognostic studies and clinical prediction guides (CPGs), optimally balancing sensitivity and precision while independent of MeSH terms, as relying on them may miss the most current literature.

Materials And Methods: We combined 2 Hedges-based search strategies, modified to remove MeSH terms for overall prognostic studies and CPGs, and ran the search on 269 journals. We read abstracts from a random subset of retrieved references until ≥ 20 per journal were reviewed and classified them as positive when fulfilling standardized quality criteria, thereby assembling a standard dataset used to calibrate the search strategy. We determined performance characteristics of our new search strategy against the Hedges standard and performance characteristics of published search strategies against the standard dataset.

Results: Our search strategy retrieved 16 089 references from 269 journals during our study period. One hundred fifty-four journals yielded ≥ 20 references and ≥ 1 prognostic study or CPG. Against the Hedges standard, the new search strategy had sensitivity/specificity/precision/accuracy of 84%/80%/2%/80%, respectively. Existing published strategies tested against our standard dataset had sensitivities of 36%-94% and precision of 5%-10%.

Discussion: We developed a new search strategy to identify overall prognosis studies and CPGs independent of MeSH terms. These studies are important for medical decision-making, as they identify specific populations and individuals who may benefit from interventions.

Conclusion: Our results may benefit literature surveillance and clinical guideline efforts, as our search strategy performs as well as published search strategies while capturing literature at the time of publication.
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http://dx.doi.org/10.1093/jamia/ocaa232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973466PMC
March 2021

Core data set on safety, efficacy, and durability of hemophilia gene therapy for a global registry: Communication from the SSC of the ISTH.

J Thromb Haemost 2020 11;18(11):3074-3077

Faculty of Health Sciences and NHLS, University of the Witwatersrand, Johannesburg, South Africa.

Background: Gene therapy for people with hemophilia (PWH) will soon become available outside current clinical trials. The World Federation of Hemophilia (WFH), in collaboration with International Society of Thrombosis and Hemostasis Scientific and Standardization Committee (ISTH SSC), the European Haemophilia Consortium (EHC), the US National Hemophilia Foundation (NHF), the American Thrombosis and Hemostasis Network (ATHN), industry gene therapy development partners and Regulatory liaisons have developed the Gene Therapy Registry (GTR), designed to collect long-term data on all PWH who receive hemophilia gene therapy.

Objective: The objectives of the GTR are to record the long-term safety and efficacy data post gene therapy infusion and to assess the changes in quality of life and burden of disease post-gene-therapy infusion.

Methods: The GTR is a prospective, observational, and longitudinal registry developed under the guidance of a multi-stakeholder GTR Steering Committee (GTR SC), composed of health care professionals, patient advocates, industry representatives, and regulatory agency liaisons. All PWH who receive gene therapy by clinical trial or commercial product will be invited to enrol in the registry through their hemophilia treatment centers (HTCs). The registry aims to recruit 100% of eligible post gene therapy PWH globally. Through an iterative process, and following the guidance of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), the GTR SC has developed a core set of data to be collected on all patients post gene therapy.

Results: The core data set includes demographic information, vector infusion details, safety, efficacy, quality of life and burden of disease.

Conclusions: The GTR is a global effort to ensure that long term safety and efficacy outcomes are recorded and analysed and rare adverse events, in a small patient population, are identified. Many unknowns on the long-term safety and efficacy of gene therapy for hemophilia may also be addressed.
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http://dx.doi.org/10.1111/jth.15023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756325PMC
November 2020

Protocol for a scoping review of outcomes in clinical studies of interventions for venous thromboembolism in adults.

BMJ Open 2020 12 7;10(12):e040122. Epub 2020 Dec 7.

Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada

Introduction: Venous thromboembolism (VTE) is a common, potentially fatal yet treatable disease. Several advances in treatment of VTE have been made over the past decades, but definition and reporting of outcomes across those studies are inconsistent. Development of an international core outcome set for clinical studies of interventions for VTE addresses this lack of standardisation. The first step in the development of a core outcome set is to conduct a scoping review which aims to generate an inclusive list of unique outcomes that have been reported in previous studies.

Methods And Analysis: MEDLINE, Embase and the Cochrane Central Register of Controlled Trials will be searched with no language restriction for prospective studies reporting on interventions for treatment of VTE in patients who are adult and non-pregnant. Records will be sorted in reverse chronological order. Study screening and data extraction will be independently performed by two authors in blocks based on date of publication, starting with 2015 to 2020 and subsequent 1-year periods, until no new outcome measures are identified from the set of included studies. After homogenising spelling and combining outcomes with the same meaning, a list of unique outcomes will be determined. Those outcomes will be grouped into outcome domains. Qualitative analysis and descriptive statistics will be used to report results.

Ethics And Dissemination: Ethical approval is not required for this study. The results of this scoping review will be presented at scientific conferences, published in a peer-reviewed journal, and they will provide candidate outcome domains to be considered in subsequent steps in the development of a core outcome set for clinical studies of interventions for VTE. PROTOCOL REGISTRATION DETAILS: http://hdl.handle.net/10393/40459.
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http://dx.doi.org/10.1136/bmjopen-2020-040122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722803PMC
December 2020

GRADE Concept Paper 1: Validating the "F.A.C.E" instrument using stakeholder perceptions of feasibility, acceptability, cost, and equity in guideline implement.

J Clin Epidemiol 2021 Mar 1;131:133-140. Epub 2020 Dec 1.

Department of Family Medicine, University of Ottawa, Ottawa, Canada.

Background And Objective: To present a structured approach for assessing stakeholder perceptions and implementing the approach in guideline development.

Methods: This work was carried out by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Equity and Stakeholder Engagement Project Groups through brainstorming and iterative frameworks, stakeholder engagement, pilot testing, refinement of ideas, using input from workshops, and discussions at GRADE Working Group meetings to produce this document, which constitutes a GRADE conceptual article on implementation.

Results: We introduce the FACE implementation criteria, feasibility, acceptability, cost, and equity; priority; and "intent to implement" criterion. We outline the implementation importance of networks and approaches to patient and other stakeholder engagement. Implementation is often highly contextual and can benefit from stakeholder engagement and other assessments. Our FACE approach provides stakeholder questions and language to inform guideline implementation and tools.

Conclusion: The FACE criteria propose a series of knowledge translation questions to guide the assessment of implementation for evidence-based guidelines. It is desirable for guideline developers to use a conceptual approach, such as FACE, to tailor implementation and inform end of guideline dissemination and knowledge translation activities.
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http://dx.doi.org/10.1016/j.jclinepi.2020.11.018DOI Listing
March 2021

Interventions to Influence Opioid Prescribing Practices for Chronic Noncancer Pain: A Systematic Review and Meta-Analysis.

Am J Prev Med 2021 01 20;60(1):e15-e26. Epub 2020 Nov 20.

Department of Psychology, Memorial University of Newfoundland, St. John's, Newfoundland, Canada. Electronic address:

Context: This study is a systematic review of interventions to improve adherence to guideline recommendations for prescribing opioids for chronic noncancer pain.

Evidence Acquisition: Investigators searched CINAHL, Embase, MEDLINE, PsycINFO, the Cochrane Library, and Joanna Briggs Institute Evid Based Pract database from inception until June 3, 2019. Interventional studies to improve adherence to recommendations made by opioid guidelines for chronic noncancer pain in North America were eligible if outcomes included adherence to guideline recommendations or change in quantity of opioids prescribed. Data were extracted independently and in duplicate. Quantitative synthesis was performed using random effects meta-analysis. Confidence in evidence was determined using the Grades of Recommendation, Assessment, Development, and Evaluation.

Evidence Synthesis: A total of 20 studies (8 controlled and 12 prospective cohort) involving 1,491 providers and 72 clinics met inclusion. Interventions included education, audit and feedback, interprofessional support, shared decision making, and multifaceted strategies. Multifaceted interventions improved the use of urine drug testing (n=2, or =2.31, 95% CI=1.53, 3.49, z=3.98, p<0.01; high-certainty evidence), treatment agreements (n=2, or =1.96, 95% CI=1.47, 2.61, z=4.56, p<0.01; moderate-certainty evidence), and mental health screening (n=2, 2.57-fold, 95% CI=1.56, 4.24, z=2.32, p=0.02; low-certainty evidence) when prescribing opioids for chronic noncancer pain. Very low-certainty evidence suggests that several interventions improved the use of treatment agreements, urine drug testing, and prescription drug monitoring programs.

Conclusions: Mostly very low-certainty evidence supports a number of interventions for improving adherence to risk management strategies when prescribing opioids for chronic noncancer pain; however, the effect on patient important outcomes (e.g., overdose, addiction, death) is uncertain.
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http://dx.doi.org/10.1016/j.amepre.2020.07.012DOI Listing
January 2021

A comparison of methods for prediction of pharmacokinetics when switching to extended half-life products in hemophilia A patients.

Thromb Res 2020 12 24;196:550-558. Epub 2020 Oct 24.

School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada. Electronic address:

Introduction: Hemophilia A is a genetic bleeding disorder resulting from a lack of clotting factor VIII. Where extended half-life products are available, people with hemophilia may stop their current drug regimen and switch to a EHL product providing a more convenient dosing regimen. While most factor VIII concentrate regimens are started prophylactically based on international units per weight, this "one-size-fits-all" approach does not account for the large pharmacokinetic variability between individuals.

Aims: We explored methods to predict individual PK of an EHL product by using population pharmacokinetic models and eta-values (η), a value that quantifies how individuals deviate from a population for any PK parameter, derived from a prior product. In addition, we wanted to investigate which individuals would benefit from this method compared to using a PopPK model alone.

Methods: PK data from subjects (n = 39) who have taken both Adynovate and Eloctate was collected from clinical trial data and from the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo) database. In addition, PK data from subjects (n = 200) who switched from a standard half-life product to Eloctate was also extracted from the WAPPS-Hemo database. Two methods to estimate individual PK outcomes of the second product were compared. The PopPK method used the Eloctate PopPK model published from WAPPS-Hemo, while the η-method incorporated individually scaled η from the prior product's PopPK model. Both methods were assessed for its performance in predicting PK outcomes. Absolute percent differences were calculated between the predicted and observed PK outcomes. Infusions were parsed into subgroups based on number of samples and individual η-percentiles for analysis.

Results: For the three switching protocols (Adynovate to Eloctate, Eloctate to Adynovate, and SHL FVIII to Eloctate), the η-method resulted in a relative difference reduction in mean absolute percent difference of 27.8% (range 1-59%), 4.9% (range 0-129%), and 18.0% (0-79%) in half-life compared to the PopPK method respectively. With some exceptions (in particular central volume), the η-method produced relative difference reduction in mean absolute percent differences up to 33% lower compared to the PopPK method. When individuals were parsed based on their η-values (either CL or V1), the two methods differentiate up to 64% in terms of half-life and time to 0.02 IU/mL predictions for individuals with a low (0th to 20th percentile) η or η on the first product. Individuals with higher number of observations per infusion on the first product resulted in better predictions in PK parameter estimates when using the η-method.

Conclusion: The use of prior knowledge by implementing η-values into PopPK models may provide clinicians with a safer and more effective method to choose a dosing regimen for patients with hemophilia A switching from one factor concentrate to another. However, the η-method was unable to better predict an increase or decrease in half-life of a future product compared to the PopPK method, and thus supports the conclusion that most individuals would still benefit from a trial on the EHL and subsequent estimation of their individual PK profile from sparse measurements on the EHL.
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http://dx.doi.org/10.1016/j.thromres.2020.10.024DOI Listing
December 2020

Challenges and key lessons from the design and implementation of an international haemophilia registry supported by a pharmaceutical company.

Haemophilia 2020 Nov 23;26(6):966-974. Epub 2020 Oct 23.

Georgetown University Medical Center, Washington, DC, USA.

Introduction: Real-world data are lacking regarding the relationship between prospectively collected patient-reported outcomes (PROs), clinical outcomes and treatment in people with haemophilia (PWH). The Expanding Communications on Hemophilia A Outcomes (ECHO) registry was designed to address this data gap, but a range of difficulties led to early study closure.

Aim: To describe the challenges faced and lessons learned from implementing a multinational haemophilia registry.

Methods: The Expanding Communications on Hemophilia A Outcomes was planned as a five-year observational cohort study to collect data from 2000 patients in nine countries. Based on direct observations, feedback from patients enrolled in ECHO, challenges of the study design and input from study-sponsor representatives, the ECHO Steering Committee systematically identified the challenges faced and developed recommendations for overcoming or avoiding them in future studies.

Results: The study closed after two years because few countries were activated and patient recruitment was low. This was related to multiple challenges including delayed implementation, stringent pharmacovigilance requirements, objections of investigators and patients to the burden of multiple PROs, data collection issues, lack of resources at study sites, little engagement of patients and competing clinical trials, which further limited recruitment. At study closure, 269 patients had been enrolled in four of nine participating countries.

Conclusions: Researchers planning studies similar to ECHO may want to consider the barriers identified in this global registry of PWH and suggestions to mitigate these limitations, such as greater patient involvement in design and analysis, clearer assessment and understanding of local infrastructure and potential changes to the administration of the study.
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http://dx.doi.org/10.1111/hae.14144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894355PMC
November 2020

Age-sex specific pulmonary embolism-related mortality in the USA and Canada, 2000-18: an analysis of the WHO Mortality Database and of the CDC Multiple Cause of Death database.

Lancet Respir Med 2021 01 12;9(1):33-42. Epub 2020 Oct 12.

Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.

Background: Pulmonary embolism (PE)-related mortality is decreasing in Europe. However, time trends in the USA and Canada remain uncertain because the most recent analyses of PE-related mortality were published in the early 2000s.

Methods: For this retrospective epidemiological study, we accessed medically certified vital registration data from the WHO Mortality Database (USA and Canada, 2000-17) and the Multiple Cause of Death database produced by the Division of Vital Statistics of the US Centers for Disease Control and Prevention (CDC; US, 2000-18). We investigated contemporary time trends in PE-related mortality in the USA and Canada and the prevalence of conditions contributing to PE-related mortality reported on the death certificates. We also estimated PE-related mortality by age group and sex. A subgroup analysis by race was performed for the USA.

Findings: In the USA, the age-standardised annual mortality rate (PE as the underlying cause) decreased from 6·0 deaths per 100 000 population (95% CI 5·9-6·1) in 2000 to 4·4 deaths per 100 000 population (4·3-4·5) in 2006. Thereafter, it continued to decrease to 4·1 deaths per 100 000 population (4·0-4·2) in women in 2017 and plateaued at 4·5 deaths per 100 000 population (4·4-4·7) in men in 2017. Among adults aged 25-64 years, it increased after 2006. The median age at death from PE decreased from 73 years to 68 years (2000-18). The prevalence of cancer, respiratory diseases, and infections as a contributing cause of PE-related death increased in all age categories from 2000 to 2018. The annual age-standardised PE-related mortality was consistently higher by up to 50% in Black individuals than in White individuals; these rates were approximately 50% higher in White individuals than in those of other races. In Canada, the annual age-standardised mortality rate from PE as the underlying cause of death decreased from 4·7 deaths per 100 000 population (4·4-5·0) in 2000 to 2·6 deaths per 100 000 population (2·4-2·8) in 2017; this decline slowed after 2006 across age groups and sexes.

Interpretation: After 2006, the initially decreasing PE-related mortality rates in North America progressively reached a plateau in Canada, while a rebound increase was observed among young and middle-aged adults in the USA. These findings parallel recent upward trends in mortality from other cardiovascular diseases and might reflect increasing inequalities in the exposure to risk factors and access to health care.

Funding: None.
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http://dx.doi.org/10.1016/S2213-2600(20)30417-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550106PMC
January 2021

Risk-assessment models for VTE and bleeding in hospitalized medical patients: an overview of systematic reviews.

Blood Adv 2020 10;4(19):4929-4944

Department of Health Research Methods, Evidence, and Impact, Michael G. DeGroote Cochrane Canada, McMaster GRADE Centres, McMaster University, Hamilton, ON, Canada.

Multiple risk-assessment models (RAMs) for venous thromboembolism (VTE) in hospitalized medical patients have been developed. To inform the 2018 American Society of Hematology (ASH) guidelines on VTE, we conducted an overview of systematic reviews to identify and summarize evidence related to RAMs for VTE and bleeding in medical inpatients. We searched Epistemonikos, the Cochrane Database, Medline, and Embase from 2005 through June 2017 and then updated the search in January 2020 to identify systematic reviews that included RAMs for VTE and bleeding in medical inpatients. We conducted study selection, data abstraction and quality assessment (using the Risk of Bias in Systematic Reviews [ROBIS] tool) independently and in duplicate. We described the characteristics of the reviews and their included studies, and compared the identified RAMs using narrative synthesis. Of 15 348 citations, we included 2 systematic reviews, of which 1 had low risk of bias. The reviews included 19 unique studies reporting on 15 RAMs. Seven of the RAMs were derived using individual patient data in which risk factors were included based on their predictive ability in a regression analysis. The other 8 RAMs were empirically developed using consensus approaches, risk factors identified from a literature review, and clinical expertise. The RAMs that have been externally validated include the Caprini, Geneva, IMPROVE, Kucher, and Padua RAMs. The Padua, Geneva, and Kucher RAMs have been evaluated in impact studies that reported an increase in appropriate VTE prophylaxis rates. Our findings informed the ASH guidelines. They also aim to guide health care practitioners in their decision-making processes regarding appropriate individual prophylactic management.
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http://dx.doi.org/10.1182/bloodadvances.2020002482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556144PMC
October 2020

Evaluating prophylactic heparin in ambulatory patients with solid tumours: a systematic review and individual participant data meta-analysis.

Lancet Haematol 2020 Oct;7(10):e746-e755

Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.

Background: Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type.

Methods: In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526.

Findings: We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta-analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93-1·06) and a hazard ratio of 1·01 (95% CI 0·96-1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low-molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47-0·71) for venous thromboembolism, 1·27 (0·92-1·74) for major bleeding, and 1·34 (1·19-1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42-0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high.

Interpretation: Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival.

Funding: Canadian Institutes of Health Research.
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http://dx.doi.org/10.1016/S2352-3026(20)30293-3DOI Listing
October 2020

Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A.

Ann Hematol 2020 Nov 24;99(11):2689-2698. Epub 2020 Sep 24.

Specialized Hospital for Active Treatment, Sofia, Bulgaria.

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC, primary parameter), dose-normalized AUC (AUC), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUC was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 ( ClinicalTrials.gov identifier). Date of registration: July 9, 2019.
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http://dx.doi.org/10.1007/s00277-020-04280-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536163PMC
November 2020

ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura.

J Thromb Haemost 2020 10 11;18(10):2486-2495. Epub 2020 Sep 11.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Milan, Italy.

Background: Despite an increase in our understandings of pathogenesis of thrombotic thrombocytopenic purpura (TTP), the approaches for initial diagnosis and management of TTP vary significantly.

Objective: The evidence-based guidelines of the International Society on Thrombosis and Haemostasis (ISTH) are intended to support patients, clinicians, and other health care professionals in their decisions about the initial diagnosis and management of acute TTP.

Methods: In June 2018, ISTH formed a multidisciplinary panel that included hematologists, an intensive care physician, nephrologist, clinical pathologist, biostatistician, and patient representatives, as well as a methodology team from McMaster University. The panel composition was designed to minimize the potential conflicts of interests. The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach and the Population, Intervention, Comparison, Outcome framework to develop and grade their recommendations. Public comments were sought and incorporated in the final document.

Results: The panel agreed on three recommendations covering the initial diagnosis with emphasis on the importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or inhibitor) and assessment of the pretest probability of TTP by clinical assessment and/or the risk assessment models like the PLASMIC or French score. The panel noted how availability and turnaround time of ADAMTS13 test results might affect early diagnosis and management, in particular the use of caplacizumab.

Conclusions: There is a lack of high-quality evidence to support strong recommendations for the initial diagnosis and management of a suspected TTP. The panel emphasized the importance of obtaining ADAMTS13 testing in a proper clinical context. Future research should focus on how to monitor and act on ADAMTS13 levels during remission.
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http://dx.doi.org/10.1111/jth.15006DOI Listing
October 2020

Good practice statements (GPS) for the clinical care of patients with thrombotic thrombocytopenic purpura.

J Thromb Haemost 2020 10 11;18(10):2503-2512. Epub 2020 Sep 11.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its management.

Methods: In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to both immune-mediated TTP (iTTP) and hereditary/congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations.

Results: The panel agreed on eleven recommendations based on evidence ranging from very low to moderate certainty. For first episode and relapses of acute iTTP, the panel made a strong recommendation for the addition of corticosteroids to therapeutic plasma exchange (TPE), and a conditional recommendation for addition of rituximab and caplacizumab. For asymptomatic iTTP with low ADAMTS13, the panel made a conditional recommendation for rituximab outside of pregnancy, and for prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, but a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy.

Conclusions: The panel's recommendations are based on all the available evidence for the treatment effects of various approaches including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing ADAMTS13 antibody production. There was insufficient evidence for further comparison of different treatment approaches, for which future high-quality studies in iTTP (e.g., rituximab, corticosteroids, recombinant ADAMTS13, and caplacizumab) and in cTTP (eg, recombinant ADAMTS13) are needed.
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http://dx.doi.org/10.1111/jth.15009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880820PMC
October 2020

ISTH guidelines for treatment of thrombotic thrombocytopenic purpura.

J Thromb Haemost 2020 10 11;18(10):2496-2502. Epub 2020 Sep 11.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and Fondazione Luigi Villa, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its appropriate treatment.

Methods: In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to immune-mediated TTP (iTTP) and hereditary or congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations.

Results: The panel agreed on 11 recommendations based on evidence ranging from very low to moderate certainty. For first acute episode and relapses of iTTP, the panel made a strong recommendation for adding corticosteroids to therapeutic plasma exchange (TPE) and a conditional recommendation for adding rituximab and caplacizumab. For asymptomatic iTTP with low plasma ADAMTS13 activity, the panel made a conditional recommendation for the use of rituximab outside of pregnancy, but prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, and a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy.

Conclusions: The panel's recommendations are based on all the available evidence for the effects of an individual component of various treatment approaches, including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing the formation of ADAMTS13 autoantibody. There was insufficient evidence for further comparing different treatment approaches (eg, TPE, corticosteroids, rituximab, and caplacizumab, etc.), for which high quality studies are needed.
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http://dx.doi.org/10.1111/jth.15010DOI Listing
October 2020

Non-severe haemophilia: Is it benign? - Insights from the PROBE study.

Haemophilia 2021 Jan 1;27 Suppl 1:17-24. Epub 2020 Sep 1.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

Introduction: There are limited data on the impact of haemophilia on health status and health-related quality of life (HRQL) in people with non-severe (mild and moderate) haemophilia.

Aim: To evaluate the health status of people living with mild or moderate haemophilia.

Methods: Data on respondents with no bleeding disorder (NoBD), mild and moderate haemophilia patients were drawn from the PROBE study. Respondents were enrolled using network patient organizations. This analysis was performed as a cross-sectional study. Primary outcomes were reported bleeding, acute and chronic pain, activities of daily living and HRQL.

Results: A total of 862 respondents with NoBD (n = 173), mild (n = 102) and moderate (n = 134) haemophilia were eligible, with a median age of 33, 42 and 43, respectively. In relation to haemophilia-related sequalae, 53% of male and 29% of female patients with mild and 83% of males with moderate haemophilia had more than 2-3 bleeds in the last 12 months. Reporting of acute and chronic pain is less in those with NoBD compared to the mild and moderate cohorts for both genders. Multivariate analysis demonstrates significant reductions in quality of life using VAS, EQ-5D-5L and PROBE for males with mild and moderate haemophilia (P ≤ .001) with only PROBE indicating a significant reduction for females with mild (P = .002).

Conclusion: People affected by mild or moderate haemophilia report a significant HRQL impact due to haemophilia-related bleeding. Future research is needed to identify the optimal care management of patients with mild and moderate haemophilia.
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http://dx.doi.org/10.1111/hae.14105DOI Listing
January 2021

Risk models for VTE and bleeding in medical inpatients: systematic identification and expert assessment.

Blood Adv 2020 06;4(12):2557-2566

Michael G. DeGroote Cochrane Canada Centre.

Risk assessment models (RAMs) for venous thromboembolism (VTE) and bleeding in hospitalized medical patients inform appropriate use of thromboprophylaxis. Our aim was to use a novel approach for selecting risk factors for VTE and bleeding to be included in RAMs. First, we used the results of a systematic review of all candidate factors. Second, we used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence for the identified factors. Third, we using a structured approach to select factors to develop the RAMs, by building on clinical and methodological expertise. The expert panel made judgments on whether to include, potentially include, or exclude risk factors, according to domains of the GRADE approach and the Delphi method. The VTE RAM included age >60 years, previous VTE, acute infections, immobility, acute paresis, active malignancy, critical illness, and known thrombophilia. The bleeding RAM included age ≥65 years, renal failure, thrombocytopenia, active gastroduodenal ulcers, hepatic disease, recent bleeding, and critical illness. We identified acute infection as a factor that was not considered in widely used RAMs. Also, we identified factors that require further research to confirm or refute their importance in a VTE RAM (eg, D-dimer). We excluded autoimmune disease which is included in the IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) bleeding RAM. Our results also suggest that sex, malignancy, and use of central venous catheters (factors in the IMPROVE bleeding RAM) require further research. In conclusion, our study presents a novel approach to systematically identifying and assessing risk factors to be included or further explored during RAM development.
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http://dx.doi.org/10.1182/bloodadvances.2020001937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322970PMC
June 2020

The World Federation of Hemophilia Annual Global Survey 1999-2018.

Haemophilia 2020 Jul 4;26(4):591-600. Epub 2020 Jun 4.

World Federation of Hemophilia, Montréal, QC, Canada.

Introduction: The World Federation of Hemophilia (WFH) strives to achieve care for all patients with inherited bleeding disorders through research, advocacy, capacity building and education. The WFH developed and implemented the Annual Global Survey (AGS), through which comprehensive demographic and treatment data on bleeding disorders are collected each year from its constituent non-governmental national organizations.

Aim: To describe the development, methodology and achievements of the WFH AGS over the past 20 years.

Methods: The AGS is a yearly cross-sectional survey. Data are collected using a standardized form (available online and on paper), quality checked and reviewed, and published in English, French and Spanish. Over time, the AGS has been modified in response to changes in treatment landscape or emerging new issues.

Results: Over the past 20 years, the AGS has reported an increase in the number of countries participating in the survey, a tripling in the number of people identified with rare bleeding disorders and an increase in the amount of factor used to treat people with haemophilia. Yet, a large treatment inequity gap still exists across the globe. In response to this gap, the WFH has analysed the AGS reports which has stimulated further development in quality of care indicators, estimates of the global prevalence of haemophilia, patient-level data collection efforts like the World Bleeding Disorders Registry and the Gene Therapy Registry.

Conclusion: The AGS has provided evidence to support research, programme planning and development activities of the WFH.
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http://dx.doi.org/10.1111/hae.14012DOI Listing
July 2020

Context and Approach in Reporting Evaluations of Electronic Health Record-Based Implementation Projects.

Ann Intern Med 2020 06;172(11 Suppl):S73-S78

McMaster University, Hamilton, Ontario, Canada (R.B.H., A.I.).

Electronic health records (EHRs) are ubiquitous yet still evolving, resulting in a moving target for determining the effects of context (features of the work environment, such as organization, payment systems, user training, and roles) on EHR implementation projects. Electronic health records have become instrumental in effecting quality improvement innovations and providing data to evaluate them. However, reports of studies typically fail to provide adequate descriptions of contextual details to permit readers to apply the findings. As for any evaluation, the quality of reporting is essential to learning from, and disseminating, the results. Extensive guidelines exist for reporting of virtually all types of applied health research, but they are not tailored to capture some contextual factors that may affect the outcomes of EHR implementations, such as attitudes toward implementation, format and amount of training, post go-live support, amount of local customization, and time diverted from direct interaction with patients to computers. Nevertheless, evaluators of EHR-based innovations can choose reporting guidelines that match the general purpose of their evaluation and the stage of their investigation (planning, protocol, execution, and analysis) and should report relevant contextual details (including, if pertinent, any pressures to help justify the huge investments and many years required for some implementations). Reporting guidelines are based on the scientific principles and practices that underlie sound research and should be consulted from the earliest stages of planning evaluations and onward, serving as guides for how evaluations should be conducted as well as reported.
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http://dx.doi.org/10.7326/M19-0874DOI Listing
June 2020

Methodology for the American Society of Hematology VTE guidelines: current best practice, innovations, and experiences.

Blood Adv 2020 05;4(10):2351-2365

Michael G. DeGroote Cochrane Canada Centre.

Background: Methods for the development of clinical guidelines have advanced dramatically over the past 2 decades to strive for trustworthiness, transparency, user-friendliness, and rigor. The American Society of Hematology (ASH) guidelines on venous thromboembolism (VTE) have followed these advances, together with application of methodological innovations.

Objective: In this article, we describe methods and methodological innovations as a model to inform future guideline enterprises by ASH and others to achieve guideline standards. Methodological innovations introduced in the development of the guidelines aim to address current challenges in guideline development.

Methods: We followed ASH policy for guideline development, which is based on the Guideline International Network (GIN)-McMaster Guideline Development Checklist and current best practices. Central coordination, specialist working groups, and expert panels were established for the development of 10 VTE guidelines. Methodological guidance resources were developed to guide the process across guidelines panels. A methods advisory group guided the development and implementation of methodological innovations to address emerging challenges and needs.

Results: The complete set of VTE guidelines will include >250 recommendations. Methodological innovations include the use of health-outcome descriptors, online voting with guideline development software, modeling of pathways for diagnostic questions, application of expert evidence, and a template manuscript for publication of ASH guidelines. These methods advance guideline development standards and have already informed other ASH guideline projects.

Conclusions: The development of the ASH VTE guidelines followed rigorous methods and introduced methodological innovations during guideline development, striving for the highest possible level of trustworthiness, transparency, user-friendliness, and rigor.
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http://dx.doi.org/10.1182/bloodadvances.2020001768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252554PMC
May 2020

Methodological Considerations for Investigating Oral Anticoagulation Persistence in Atrial Fibrillation.

Eur Heart J Cardiovasc Pharmacother 2020 May 19. Epub 2020 May 19.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.

Aims: Reports of long-term oral anticoagulant (OAC) therapy for atrial fibrillation (AF) reveal highly variable, and generally suboptimal estimates of medication persistence. The objective of this review is to summarize current literature and highlight important methodological considerations for interpreting persistence research and designing studies of persistence on OAC treatment.

Methods And Results: We summarize differences in study methodology, setting, timing, treatment and other factors associated with reports of better or worse persistence. For example, prospective compared to retrospective study designs are associated with higher reported persistence. Similarly, patient factors such as permanent AF or high stroke risk, and treatment with non-vitamin K oral antagonists relative to vitamin K antagonists are associated with higher persistence. Persistence has also been reported to be higher in Europe compared to North America and higher when the treating physician is a general practitioner compared to a specialist.We propose a framework for assessing and designing persistence studies. This framework includes aspects of patient selection, reliability and validity of measures, persistence definitions, clinical utility of measurements, follow-up periods and analytic approaches.

Conclusions: Differences in study design, patient selection, treatments and factors such as the countries/regions where studies are conducted or the type of treating physician may help explain the variability in OAC persistence estimates. A framework is proposed to assess persistence studies. This may have utility to compare and interpret published studies as well as for planning of future studies.
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http://dx.doi.org/10.1093/ehjcvp/pvaa052DOI Listing
May 2020

Obtaining and managing data sets for individual participant data meta-analysis: scoping review and practical guide.

BMC Med Res Methodol 2020 05 12;20(1):113. Epub 2020 May 12.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.

Background: Shifts in data sharing policy have increased researchers' access to individual participant data (IPD) from clinical studies. Simultaneously the number of IPD meta-analyses (IPDMAs) is increasing. However, rates of data retrieval have not improved. Our goal was to describe the challenges of retrieving IPD for an IPDMA and provide practical guidance on obtaining and managing datasets based on a review of the literature and practical examples and observations.

Methods: We systematically searched MEDLINE, Embase, and the Cochrane Library, until January 2019, to identify publications focused on strategies to obtain IPD. In addition, we searched pharmaceutical websites and contacted industry organizations for supplemental information pertaining to recent advances in industry policy and practice. Finally, we documented setbacks and solutions encountered while completing a comprehensive IPDMA and drew on previous experiences related to seeking and using IPD.

Results: Our scoping review identified 16 articles directly relevant for the conduct of IPDMAs. We present short descriptions of these articles alongside overviews of IPD sharing policies and procedures of pharmaceutical companies which display certification of Principles for Responsible Clinical Trial Data Sharing via Pharmaceutical Research and Manufacturers of America or European Federation of Pharmaceutical Industries and Associations websites. Advances in data sharing policy and practice affected the way in which data is requested, obtained, stored and analyzed. For our IPDMA it took 6.5 years to collect and analyze relevant IPD and navigate additional administrative barriers. Delays in obtaining data were largely due to challenges in communication with study sponsors, frequent changes in data sharing policies of study sponsors, and the requirement for a diverse skillset related to research, administrative, statistical and legal issues.

Conclusions: Knowledge of current data sharing practices and platforms as well as anticipation of necessary tasks and potential obstacles may reduce time and resources required for obtaining and managing data for an IPDMA. Sufficient project funding and timeline flexibility are pre-requisites for successful collection and analysis of IPD. IPDMA researchers must acknowledge the additional and unexpected responsibility they are placing on corresponding study authors or data sharing administrators and should offer assistance in readying data for sharing.
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http://dx.doi.org/10.1186/s12874-020-00964-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218569PMC
May 2020

Tolerance to FVIII: Role of the Immune Metabolic Enzymes Indoleamine 2,3 Dyoxigenase-1 and Heme Oxygenase-1.

Front Immunol 2020 15;11:620. Epub 2020 Apr 15.

Department of Health Research Methods, Evidence, and Impact, Hamilton, ON, Canada.

The occurrence of neutralizing anti-FVIII antibodies is a major complication in the treatment of patients affected by hemophilia A. The immune response to FVIII is a complex, multi-factorial process that has been extensively studied for the past two decades. The reasons why only a proportion of hemophilic patients treated with FVIII concentrates develop a clinically significant immune response is incompletely understood. The "danger theory" has been proposed as a possible explanation to interpret the findings of some observational clinical studies highlighting the possible detrimental impact of inflammatory stimuli at the time of replacement therapy on inhibitor development. The host immune system is often challenged to react to FVIII under steady state or inflammatory conditions (e.g., bleeding, infections) although fine tuning of mechanisms of immune tolerance can control this reactivity and promote long-term unresponsiveness to the therapeutically administered factor. Recent studies have provided evidence that multiple interactions involving central and peripheral mechanisms of tolerance are integrated by the host immune system with the environmental conditions at the time of FVIII exposure and influence the balance between immunity and tolerance to FVIII. Here we review evidences showing the involvement of two key immunoregulatory oxygenase enzymes (IDO1, HO-1) that have been studied in hemophilia patients and pre-clinical models, showing that the ability of the host immune system to induce such regulatory proteins under inflammatory conditions can play important roles in the balance between immunity and tolerance to exogenous FVIII.
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http://dx.doi.org/10.3389/fimmu.2020.00620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174632PMC
March 2021

The Khorana score for prediction of venous thromboembolism in cancer patients: An individual patient data meta-analysis.

J Thromb Haemost 2020 08 8;18(8):1940-1951. Epub 2020 Jul 8.

Michael G. DeGroote Cochrane Canada and McGRADE Centres, Department of Health Research Methods, Evidence and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Canada.

Background: Oncology guidelines suggest using the Khorana score to select ambulatory cancer patients receiving chemotherapy for primary venous thromboembolism (VTE) prevention, but its performance in different cancers remains uncertain.

Objective: To examine the performance of the Khorana score in assessing 6-month VTE risk, and the efficacy and safety of low-molecular-weight heparin (LMWH) among high-risk Khorana score patients.

Methods: This individual patient data meta-analysis evaluated (ultra)-LMWH in patients with solid cancer using data from seven randomized controlled trials.

Results: A total of 3293 patients from the control groups with an available Khorana score had lung (n = 1913; 58%), colorectal (n = 452; 14%), pancreatic (n = 264; 8%), gastric (n = 201; 6%), ovarian (n = 184; 56%), breast (n = 164; 5%), brain (n = 84; 3%), or bladder cancer (n = 31; 1%). The 6-month VTE incidence was 9.8% among high-risk Khorana score patients and 6.4% among low-to-intermediate-risk patients (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.2). The dichotomous Khorana score performed differently in lung cancer patients (OR 1.1; 95% CI, 0.72-1.7) than in the group with other cancer types (OR 3.2; 95% CI, 1.8-5.6; P  = .002). Among high-risk patients, LMWH decreased the risk of VTE by 64% compared with controls (OR 0.36; 95% CI, 0.22-0.58), without increasing the risk of major bleeding (OR 1.1; 95% CI, 0.59-2.1).

Conclusion: The Khorana score was unable to stratify patients with lung cancer based on their VTE risk. Among those with other cancer types, a high-risk score was associated with a three-fold increased risk of VTE compared with a low-to-intermediate risk score. Thromboprophylaxis was effective and safe in patients with a high-risk Khorana score.
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http://dx.doi.org/10.1111/jth.14824DOI Listing
August 2020

COVID-19 coronavirus research has overall low methodological quality thus far: case in point for chloroquine/hydroxychloroquine.

J Clin Epidemiol 2020 07 21;123:120-126. Epub 2020 Apr 21.

Health Research Methods, Evidence and Impact (HEI), Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada; GUIDE Research Methods Group, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada.

Objectives/background And Objectives: Prior epidemics of high-mortality human coronaviruses, such as the acute respiratory syndrome coronavirus (SARS-CoV or SARS-1) in 2003, have driven the characterization of compounds that could be possibly active against the currently emerging novel coronavirus SARS-CoV-2 (COVID-19). Presently, no approved treatment or prophylaxis is available for COVID-19. We comment on the existing COVID-19 research methodologies in general and the published reporting. Given the media attention and claims of effectiveness, we chose chloroquine and hydroxychloroquine, in combination with azithromycin, as an area of COVID-19 research to examine.

Methods/study Design And Setting: MEDLINE and EMBASE electronic databases were searched from 2019 to present (April 3rd, 2020) using a mix of keywords such as COVID-19 and chloroquine and hydroxychloroquine. We also searched the largest clinical medicine preprint repository, medRxiv.org.

Results: We found 6 studies, 3 randomized control trials and 3 observational studies, focusing on chloroquine and hydroxychloroquine (with azithromycin). We critically appraised the evidence.

Conclusion: We found that the COVID-19 research methodology is very poor in the area of chloroquine/hydroxychloroquine research. In screening the literature, we observed the same across COVID-19 research in relation to potential treatments. The reporting is very poor and sparse, and patient-important outcomes needed to discern decision-making priorities are not reported. We do understand the barriers to perform rigorous research in health care settings overwhelmed by a novel deadly disease. However, this emergency pandemic situation does not transform flawed methods and data into credible results. The adequately powered, comparative, and robust clinical research that is needed for optimal evidence-informed decision-making remains absent in COVID-19.
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http://dx.doi.org/10.1016/j.jclinepi.2020.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194626PMC
July 2020