Publications by authors named "Tobias Tritschler"

29 Publications

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Venous thromboembolism.

Lancet 2021 May 10. Epub 2021 May 10.

Clinical Epidemiology Program, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada; Department of Medicine, McGill University, Montreal, QC, Canada. Electronic address:

Venous thromboembolism, comprising both deep vein thrombosis and pulmonary embolism, is a chronic illness that affects nearly 10 million people every year worldwide. Strong provoking risk factors for venous thromboembolism include major surgery and active cancer, but most events are unprovoked. Diagnosis requires a sequential work-up that combines assessment of clinical pretest probability for venous thromboembolism using a clinical score (eg, Wells score), D-dimer testing, and imaging. Venous thromboembolism can be considered excluded in patients with both a non-high clinical pretest probability and normal D-dimer concentrations. When required, ultrasonography should be done for a suspected deep vein thrombosis and CT or ventilation-perfusion scintigraphy for a suspected pulmonary embolism. Direct oral anticoagulants (DOACs) are the first-line treatment for almost all patients with venous thromboembolism (including those with cancer). After completing 3-6 months of initial treatment, anticoagulation can be discontinued in patients with venous thromboembolism provoked by a major transient risk factor. Patients whose long-term risk of recurrent venous thromboembolism outweighs the long-term risk of major bleeding, such as those with active cancer or men with unprovoked venous thromboembolism, should receive indefinite anticoagulant treatment. Pharmacological venous thromboembolism prophylaxis is generally warranted in patients undergoing major orthopaedic or cancer surgery. Ongoing research is focused on improving diagnostic strategies for suspected deep vein thrombosis, comparing different DOACs, developing safer anticoagulants, and further individualising approaches for the prevention and management of venous thromboembolism.
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http://dx.doi.org/10.1016/S0140-6736(20)32658-1DOI Listing
May 2021

Development and validation of a score to assess complexity of general internal medicine patients at hospital discharge: a prospective cohort study.

BMJ Open 2021 05 6;11(5):e041205. Epub 2021 May 6.

Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Objective: We aimed to develop and validate a score to assess inpatient complexity and compare its performance with two currently used but not validated tools to estimate complexity (ie, Charlson Comorbidity Index (CCI), patient clinical complexity level (PCCL)).

Methods: Consecutive patients discharged from the department of medicine of a tertiary care hospital were prospectively included into a derivation cohort from 1 October 2016 to 16 February 2017 (n=1407), and a temporal validation cohort from 17 February 2017 to 31 March 2017 (n=482). The physician in charge assessed complexity. Potential predictors comprised 52 parameters from the electronic health record such as health factors and hospital care usage. We fit a logistic regression model with backward selection to develop a prediction model and derive a score. We assessed and compared performance of model and score in internal and external validation using measures of discrimination and calibration.

Results: Overall, 447 of 1407 patients (32%) in the derivation cohort, and 116 of 482 patients (24%) in the validation cohort were identified as complex. Eleven variables independently associated with complexity were included in the score. Using a cut-off of ≥24 score points to define high-risk patients, specificity was 81% and sensitivity 57% in the validation cohort. The score's area under the receiver operating characteristic (AUROC) curve was 0.78 in both the derivation and validation cohort. In comparison, the CCI had an AUROC between 0.58 and 0.61, and the PCCL between 0.64 and 0.69, respectively.

Conclusions: We derived and internally and externally validated a score that reflects patient complexity in the hospital setting, performed better than other tools and could help monitoring complex patients.
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http://dx.doi.org/10.1136/bmjopen-2020-041205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103941PMC
May 2021

Clinical significance of subsegmental pulmonary embolism: An ongoing controversy.

Res Pract Thromb Haemost 2021 Jan 9;5(1):14-16. Epub 2020 Dec 9.

Department of General Internal Medicine, Inselspital Bern University Hospital University of Bern Bern Switzerland.

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http://dx.doi.org/10.1002/rth2.12464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845080PMC
January 2021

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

Anticoagulant interventions in hospitalized patients with COVID-19: A scoping review of randomized controlled trials and call for international collaboration.

J Thromb Haemost 2020 11 1;18(11):2958-2967. Epub 2020 Oct 1.

Feinstein Institutes for Medical Research and The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and Department of Medicine, Anticoagulation and Clinical Thrombosis Services, Northwell Health at Lenox Hill Hospital, New York, NY, USA.

Introduction: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed.

Methods: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate.

Results: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials.

Discussion: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly.
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http://dx.doi.org/10.1111/jth.15094DOI Listing
November 2020

Applying rigorous eligibility criteria to studies evaluating prognostic utility of serum biomarkers in pulmonary embolism: A systematic review and meta-analysis.

Thromb Res 2020 11 21;195:195-208. Epub 2020 Jul 21.

Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. Electronic address:

Purpose: To evaluate the value of biomarkers to prognosticate outcomes in patients with pulmonary embolism among studies of sound methodical quality.

Methods: Ovid MEDLINE, Embase, CENTRAL, and non-indexed citations were searched from inception to March 2019. Biomarkers of interest included troponin I (TnI), troponin T (TnT), high-sensitive TnT (HS-TnT), brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), heart fatty acid binding protein (H-FABP), and D-dimer (DD). Included studies utilized key features of the Reporting Recommendations for Tumour Marker Prognostic Studies (REMARK) checklist and satisfied requirements of the Quality in Prognosis Studies (QUIPS) tool. The primary outcome was 30-day all-cause mortality (ACM). Secondary outcomes included PE-related mortality, or complicated clinical course (CCC). Pooled relative risk ratios (RR) were calculated using inverse-variance-weighted random-effects method.

Results: Seventeen studies were analyzed. TnT ≥ 0.1 ng/mL and HS-TnT ≥ 14 pg/mL were associated with an increased 30-day ACM with RRs of 6.24 (95% CI, 1.86-20.96, I = 35%) and 6.81 (95% CI, 2.46-18.88, I = 0%), respectively. In the short-term (≤30 days): (1) TnI can prognosticate PE-related mortality; (2) both TnT and HS-TnT can prognosticate a CCC; (3) H-FABP can prognosticate a CCC; and (4) NT-proBNP can prognosticate a CCC. In the long-term (>30 days): (1) HS-TnT can prognosticate ACM; and (2) NT-proBNP can prognosticate ACM and PE-related mortality.

Conclusions: Several methodically sound studies allow for data pooling, and suggest that TnT, HS-TnT, TnI, NT-proBNP and H-FABP have prognostic value in patients with PE but confidence intervals are wide and relatively few patients constitute the analyses. The value of such markers on influencing clinical management remains to be determined.

Systematic Review Registration: PROSPERO CRD42019129889.
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http://dx.doi.org/10.1016/j.thromres.2020.07.037DOI Listing
November 2020

Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease 2019: CHEST Guideline and Expert Panel Report.

Chest 2020 09 2;158(3):1143-1163. Epub 2020 Jun 2.

Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.

Background: Emerging evidence shows that severe coronavirus disease 2019 (COVID-19) can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and VTE. This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE.

Methods: A group of approved panelists developed key clinical questions by using the PICO (Population, Intervention, Comparator, Outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis, and treatment of VTE in patients with COVID-19. MEDLINE (via PubMed or Ovid), Embase, and Cochrane Controlled Register of Trials were systematically searched for relevant literature, and references were screened for inclusion. Validated evaluation tools were used to grade the level of evidence to support each recommendation. When evidence did not exist, guidance was developed based on consensus using the modified Delphi process.

Results: The systematic review and critical analysis of the literature based on 13 Population, Intervention, Comparator, Outcome questions resulted in 22 statements. Very little evidence exists in the COVID-19 population. The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements.

Conclusions: The evidence on the optimal strategies to prevent, diagnose, and treat VTE in patients with COVID-19 is sparse but rapidly evolving.
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http://dx.doi.org/10.1016/j.chest.2020.05.559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265858PMC
September 2020

Definition of pulmonary embolism-related death and classification of the cause of death in venous thromboembolism studies: Communication from the SSC of the ISTH.

J Thromb Haemost 2020 06;18(6):1495-1500

Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.

Pulmonary embolism (PE)-related death is often a component of the primary outcome in venous thromboembolism (VTE) clinical studies. Definitions for PE-related death vary widely, which may lead to biased risk estimates of clinical outcomes, thereby affecting both internal and external validity of study results. We here provide a standardized definition of PE-related death and propose guidance for classification and reporting of the cause of death for clinical studies in VTE. The proposal was developed in a four-step process, including a systematic review of definitions used for PE-related death in previous studies, two subsequent surveys with VTE experts, and meetings held within the Scientific and Standardization Committee (SSC) working group until consensus on the proposal was reached. The proposed classification comprises three categories: Category A: PE-related death, category B: undetermined cause of death, and category C: cause of death other than PE. Category A includes A1: autopsy-confirmed PE in the absence of another more likely cause of death; A2: objectively confirmed PE before death in the absence of another more likely cause of death; and A3: PE is not objectively confirmed, but is most likely the main cause of death. Category B includes B1: cause of death is undetermined, despite available information; and B2: insufficient clinical information available to determine the cause of death. The use of the proposed definition will hopefully improve the accuracy of study outcomes, between-study comparisons, meta-analyses, and validity of future clinical VTE studies.
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http://dx.doi.org/10.1111/jth.14769DOI Listing
June 2020

Validation of risk assessment models predicting venous thromboembolism in acutely ill medical inpatients: A cohort study.

J Thromb Haemost 2020 06 16;18(6):1398-1407. Epub 2020 Apr 16.

Département de Médecine d'Urgence, CHU d'Angers, Institut MITOVASC, UMR CNRS 6015, UMR INSERM 1083, InnoVTE F-CRIN, Université d'Angers, Angers, France.

Background: Because hospital-acquired venous thromboembolism (VTE) represents a frequent cause of preventable deaths in medical inpatients, identifying at-risk patients requiring thromboprophylaxis is critical. We aimed to externally assess the Caprini, IMPROVE, and Padua VTE risk scores and to compare their performance to advanced age as a stand-alone predictor.

Methods: We performed a retrospective analysis of patients prospectively enrolled in the PREVENU trial. Patients aged 40 years and older, hospitalized for at least 2 days on a medical ward were consecutively enrolled and followed for 3 months. Critical ill patients were not recruited. Patients diagnosed with VTE within 48 hours from admission, or receiving full dose anticoagulant treatment or who underwent surgery were excluded. All suspected VTE and deaths occurring during the 3-month follow-up were adjudicated by an independent committee. The three scores were retrospectively assessed. Body mass index, needed for the Padua and Caprini scores, was missing in 44% of patients.

Results: Among 14 910 eligible patients, 14 660 were evaluable, of which 1.8% experienced symptomatic VTE or sudden unexplained death during the 3-month follow-up. The area under the receiver operating characteristic curves (AUC) were 0.60 (95% confidence interval [CI] 0.57-0.63), 0.63 (95% CI 0.60-0.66) and 0.64 (95% CI 0.61-0.67) for Caprini, IMPROVE, and Padua scores, respectively. None of these scores performed significantly better than advanced age as a single predictor (AUC 0.61, 95% CI 0.58-0.64).

Conclusion: In our study, Caprini, IMPROVE, and Padua VTE risk scores have poor discriminative ability to identify not critically ill medical inpatients at risk of VTE, and do not perform better than a risk evaluation based on patient's age alone.
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http://dx.doi.org/10.1111/jth.14796DOI Listing
June 2020

Treatment of venous thromboembolism in elderly patients in the era of direct oral anticoagulants.

Pol Arch Intern Med 2020 06 3;130(6):529-538. Epub 2020 Mar 3.

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

The incidence of venous thromboembolism (VTE) and VTE‑related morbidity and mortality increase with advancing age. Over the past decade, substantial advances in the treatment of VTE have been achieved. Most notably, direct oral anticoagulants (DOACs) were introduced, which offer simple treatment regimens across a broad spectrum of patients with VTE and have become the first‑choice anticoagulants in many individuals in this population. Even though elderly patients are underrepresented in clinical trials, the extrapolation of overall study results to the elderly subpopulation can be considered justified regarding acute VTE treatment and the choice of anticoagulant agent. In the elderly, DOACs are not only associated with a lower bleeding risk but they also appear to be even more efficacious than vitamin K antagonists in preventing recurrent VTE during the acute treatment period. Determining the optimal treatment duration is the most challenging aspect of VTE management in elderly patients. The risk of bleeding increases with advancing age, and several risk factors for recurrent VTE after stopping anticoagulation are also more frequent in the elderly. Clinical decision rules estimating the risk of recurrent VTE and bleeding have limited utility in elderly patients. Shared decision making considering patients' preferences and values is therefore crucial to help determine individual treatment duration in these patients.
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http://dx.doi.org/10.20452/pamw.15225DOI Listing
June 2020

Development of a standardized definition of pulmonary embolism-related death: A cross-sectional survey of international thrombosis experts.

J Thromb Haemost 2020 06 30;18(6):1415-1420. Epub 2020 Mar 30.

Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.

Introduction: Pulmonary embolism (PE)-related death is often part of the primary outcome in venous thromboembolism (VTE) studies. The Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis developed a definition for PE-related death and classification of the cause of death. The present survey evaluated a preliminary version of this definition and classification.

Methods: Sixty-nine VTE experts from nine countries were invited for a cross-sectional online survey on January 15, 2019, including multiple-choice and open-ended questions on a seven-subcategory classification of the cause of death. Descriptive statistics were used to describe the results; qualitative comments were summarized.

Results: Forty of 69 (58%) invitees completed the survey. All respondents agreed that guidance on classification of the cause of death in VTE studies is required. There was high agreement on the proposal (median overall score, 6; interquartile range, 6-7; scale from 1 [poor] to 7 [excellent]). All respondents approved the wording and content of the seven subcategories, except for one disagreeing vote for two subcategories (A3: "PE is not objectively confirmed, but is most likely the main cause of death" and C1: "Another cause of death is more likely than PE but has not been objectively confirmed"). Suggestions for improvement mainly concerned the extensiveness of the criteria and clinical situations described to define the cause of death.

Conclusion: Acceptance of the proposal was excellent. Suggestions for improvement were incorporated in the SSC communication on the definition of PE-related death and classification of the cause of death in VTE studies.
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http://dx.doi.org/10.1111/jth.14775DOI Listing
June 2020

Persisting autoimmune heparin-induced thrombocytopenia after elective abdominal aortic aneurysm repair: a case report.

J Thromb Thrombolysis 2020 Oct;50(3):674-677

Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.

Persisting heparin-induced thrombocytopenia (HIT) is characterized by ongoing thrombocytopenia more than 7 days after stopping heparin. It is part of cases referred to as autoimmune HIT (aHIT). In contrast to typical HIT cases, aHIT involves heparin-independent platelet activation mechanism highlighted by a strongly positive functional assay done without heparin. We report the first case of persisting HIT after an elective abdominal aortic aneurysm repair presenting with arterial and venous thrombosis, and describe the potential role of intravenous immunoglobulin in such patients.
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http://dx.doi.org/10.1007/s11239-020-02062-2DOI Listing
October 2020

Clinical presentation and outcomes in elderly patients with symptomatic isolated subsegmental pulmonary embolism.

Thromb Res 2019 Dec 22;184:24-30. Epub 2019 Oct 22.

Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Objectives: Data are limited on clinical presentation and outcomes in elderly patients with acute symptomatic isolated subsegmental pulmonary embolism (SSPE). We compared clinical presentation, risk factors, processes of care, and outcomes between elderly patients with SSPE and patients with more proximal pulmonary embolism (PE).

Methods: We prospectively followed 578 patients aged ≥65 years with acute symptomatic isolated SSPE or proximal PE in a multicentre Swiss cohort study. We compared quality of life at three months using the PEmb-QoL, and examined the independent association between localization of PE and clinical outcomes (recurrent venous thromboembolism [VTE], overall mortality) using regression models with adjustment for potential confounders.

Results: Overall, 11% of patients had isolated SSPE. Patients with SSPE were less likely to have a pulse ≥110/min (3% vs. 13%), but more likely to have active cancer (28% vs. 15%) and to receive outpatient care (11% vs. 4%) than patients with proximal PE. Virtually all patients (98%) with SSPE received anticoagulants. Quality of life did not differ between the groups at 3 months. No patient with SSPE vs. seven patients with proximal PE died from the index PE event. No significant difference was observed for the 3-year cumulative incidence of recurrent VTE (7% vs. 12%) and death (29% vs. 20%). After adjustment, SSPE was not associated with a lower risk of clinical outcomes than proximal PE.

Conclusions: Clinical presentation and incidences of adverse outcomes did not differ significantly between elderly patients with SSPE or proximal PE, although the power to detect differences might have been limited given the small number of events. Thus, our study does not provide evidence that unselected, elderly patients with SSPE have a more benign clinical course.
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http://dx.doi.org/10.1016/j.thromres.2019.10.008DOI Listing
December 2019

Risk of major bleeding during extended oral anticoagulation in patients with first unprovoked venous thromboembolism: a systematic review and meta-analysis protocol.

Syst Rev 2019 10 28;8(1):245. Epub 2019 Oct 28.

School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada.

Background: The optimal duration of anticoagulation after a first unprovoked venous thromboembolism (VTE) remains controversial. Deciding to stop or continue anticoagulant therapy indefinitely after completing 3 to 6 months of initial treatment requires balancing the long-term risk of recurrent VTE if anticoagulation is stopped against the long-term risk of major bleeding if anticoagulation is continued. However, knowledge of the long-term risk for major bleeding events during extended anticoagulation in this patient population is limited. We plan to conduct a systematic review and meta-analysis to quantify the risk for major bleeding events during extended oral anticoagulation in patients with first unprovoked VTE.

Methods: Electronic databases including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials will be systematically searched with the assistance of an information specialist (from inception to March 1, 2019) to identify randomized controlled trials and prospective cohort studies reporting major bleeding during extended oral anticoagulation in patients with first unprovoked VTE, who have completed at least 3 months of initial anticoagulant therapy. Study selection, risk of bias assessment, and data extraction will be performed independently by at least two investigators. The number of major bleeding events and person-years of follow-up will be used to calculate the rate (events per 100 person-years) with its 95% confidence interval for each study cohort, during clinically relevant time periods of extended anticoagulant therapy. Results will be pooled using random effect meta-analysis.

Discussion: The planned systematic review and meta-analysis will provide reliable estimates of the risk for major bleeding events during extended anticoagulation. This information will help inform patient prognosis and assist clinicians with balancing the risks and benefits of treatment to guide management of unprovoked VTE.

Systematic Review Registration: PROSPERO CRD42019128597 .
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http://dx.doi.org/10.1186/s13643-019-1175-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819358PMC
October 2019

Definitions, adjudication, and reporting of pulmonary embolism-related death in clinical studies: A systematic review.

J Thromb Haemost 2019 10 31;17(10):1590-1607. Epub 2019 Jul 31.

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

Background: Pulmonary embolism (PE)-related death is a component of the primary outcome in many venous thromboembolism (VTE) studies. The absence of a standardized definition for PE-related death hampers study outcome evaluation and between-study comparisons.

Objectives: To summarize definitions for PE-related death used in recent VTE studies and to assess the PE-related death rate.

Patients/methods: A systematic literature search was conducted on 26 April 2018 from 1 January 2014 up to the search date in MEDLINE, Embase, and CENTRAL. Cohort studies and randomized trials in which PE-related death was included in the primary outcome were eligible. Screening of titles, abstracts, and full-text articles, and data extraction were independently performed in duplicate by two authors. Study outcomes included the definition for PE-related death, VTE case-fatality rate, and death due to PE rate. Descriptive statistics were used to analyze the data.

Results: Of the 6807 identified citations, 83 studies were included of which 27% were randomized trials, 31% were prospective, and 42% retrospective cohort studies. Thirty-five studies (42%) had a central adjudication committee. Thirty-eight (46%) reported a definition for PE-related death of which the most frequently used components were "autopsy-confirmed PE" (50%), "objectively confirmed PE before death" (55%), and "unexplained death" (58%). Median VTE case-fatality rate was 1.8% (interquartile range, 0.0-13).

Conclusions: Only half of the included studies reported definitions for PE-related death, which were very heterogeneous. Case-fatality rate of VTE events varied widely across studies. Standardization of the definition and guidance on adjudication and reporting of PE-related death is needed.
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http://dx.doi.org/10.1111/jth.14570DOI Listing
October 2019

Prognostic Value of Electrocardiography in Elderly Patients with Acute Pulmonary Embolism.

Am J Med 2019 12 24;132(12):e835-e843. Epub 2019 Jun 24.

Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.

Background: Electrocardiographic (ECG) signs of right ventricular strain could be used as a simple tool to risk-stratify patients with acute pulmonary embolism.

Methods: We studied consecutive patients aged ≥65 years with acute pulmonary embolism in a prospective multicenter cohort study. Two readers independently analyzed 12 predefined ECG signs of right ventricular strain in all patients. The outcome was the occurrence of an adverse clinical event, defined as death from any cause within 90 days or a complicated in-hospital course. We determined the interrater reliability for each ECG sign and examined the association between right ventricular strain signs and adverse events using logistic regression, adjusting for the Pulmonary Embolism Severity Index and cardiac troponin.

Results: Overall, 320/390 patients (82%) showed at least one ECG sign of right ventricular strain. The interrater reliability for individual ECG signs was highly variable (ᴋ 0.40-0.95). Patients with ≥1 of the 3 classic signs of right ventricular strain (S1Q3T3, right bundle branch block, or T wave inversions in V1-V4) had a higher incidence of adverse events than those without (13% vs 6%; P = .026). After adjustment, the presence of ≥1 of the 3 classic signs of right ventricular strain (odds ratio 2.11; 95% confidence interval, 1.00-4.46) and the number of right ventricular strain signs present were significantly associated with adverse events (odds ratio 1.35 per sign; 95% confidence interval, 1.08-1.69).

Conclusions: ECG signs of right ventricular strain are common in elderly patients with acute pulmonary embolism. Although such signs may have prognostic value, their variable reliability and the rather modest prognostic effect size may limit their usefulness in the risk stratification of pulmonary embolism.
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http://dx.doi.org/10.1016/j.amjmed.2019.05.041DOI Listing
December 2019

It's time for head-to-head trials with direct oral anticoagulants.

Thromb Res 2019 Aug 31;180:64-69. Epub 2019 May 31.

Division of Hematology, Department of Medicine, University of Ottawa, ON, Canada; School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. Electronic address:

Direct oral anticoagulants (DOACs) have become the recommended first choice anticoagulant agent for treatment of acute venous thromboembolism (VTE) in non-cancer patients and are increasingly prescribed worldwide. They have not only intrinsic advantages, such as rapid onset of action and wide therapeutic windows, but also a lower risk of major, intracranial and fatal bleeding in VTE patients compared to vitamin K antagonists. Even though DOACs are often referred to as uniform drug class, there is growing evidence that each DOAC has a specific risk profile. Indirect comparisons and retrospective cohort studies suggest that apixaban may be associated with a lower risk of major bleeding than other DOACs, but there are no head-to-head trials with DOACs. Therefore, current guidelines do not recommend one DOAC over another and the choice of a specific DOAC is mainly based on physician and patient preferences, reimbursement and availability. Retrospective cohort studies and VTE registries are important to identify potential differences in efficacy and safety between DOACs; but they are methodologically too limited to inform the optimal choice of oral anticoagulant agent. Randomized controlled trials are crucial to inform sound treatment recommendations, because proper randomization is the key to unprejudiced treatment allocation and minimization of unmeasured and unknown confounding. Given increasing evidence of differences in safety profiles of DOACs from indirect comparisons and observational studies, it's time for head-to-head trials with DOACs.
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http://dx.doi.org/10.1016/j.thromres.2019.05.019DOI Listing
August 2019

Inferior Vena Cava Filters in the Management of Venous Thromboembolism-Reply.

JAMA 2019 03;321(10):1007

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

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http://dx.doi.org/10.1001/jama.2018.21127DOI Listing
March 2019

Anticoagulation quality and clinical outcomes in multimorbid elderly patients with acute venous thromboembolism.

Thromb Res 2019 May 15;177:10-16. Epub 2019 Feb 15.

Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: Multimorbid patients with acute venous thromboembolism (VTE) are often excluded from clinical trials and little is known about their prognosis.

Objectives: To examine whether multimorbidity is associated with adverse clinical outcomes and lower anticoagulation quality in older patients with VTE.

Patients/methods: We studied 991 patients aged ≥65 years with acute VTE in a Swiss prospective multicenter cohort study. A modified Charlson Comorbidity Index was used to measure multimorbidity, which was defined as the presence ≥2 of 17 predefined comorbid conditions. We examined the association between multimorbidity and recurrent VTE and major bleeding, adjusting for confounders and periods of anticoagulation. We assessed whether the percentage of time spent in the therapeutic international normalized ratio (INR) range varied by the number of comorbidities present.

Results: Overall, 708 (71%) patients were multimorbid. Multimorbid patients had a higher 3-year cumulative incidence of recurrent VTE (16.8 vs. 10.8%; P = 0.056) and major bleeding (18.7 vs. 9.0%; P = 0.001) than non-multimorbid patients. After adjustment, multimorbid patients had a significantly higher risk of recurrent VTE (sub-hazard ratio [SHR] 1.66, 95% confidence interval [CI] 1.08-2.57) and a higher risk of major bleeding (SHR 1.55, 95% CI 0.96-2.50), although the latter failed to achieve statistical significance. With increasing numbers of comorbid conditions, patients spent less time in and more time above and below the therapeutic INR range.

Conclusions: Multimorbid patients with acute VTE have not only a lower anticoagulation quality but also more complications. Clinical trials should explicitly enroll multimorbid patients to determine the optimal anticoagulation strategy in such patients.
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http://dx.doi.org/10.1016/j.thromres.2019.02.017DOI Listing
May 2019

Extended therapy for unprovoked venous thromboembolism: when is it indicated?

Blood Adv 2019 02;3(3):499

Department of Medicine, University of Ottawa, Ottawa, ON, Canada; and.

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http://dx.doi.org/10.1182/bloodadvances.2018026518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373737PMC
February 2019

Association between insurance status, anticoagulation quality, and clinical outcomes in patients with acute venous thromboembolism.

Thromb Res 2019 01 12;173:124-130. Epub 2018 Nov 12.

Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Introduction: A higher level of health insurance coverage may be related to better quality of care and outcomes. Whether insurance status is associated with anticoagulation quality and clinical outcomes in patients with venous thromboembolism (VTE) is unknown.

Methods: We studied 819 elderly patients treated with vitamin K antagonists for VTE in a Swiss prospective multicenter cohort (09/2009-12/2013). The study outcomes were the anticoagulation quality, defined as the time spent in the therapeutic INR range, and clinical events, i.e. the time to a first VTE recurrence, major bleeding, and mortality. We assessed the association between insurance status (private vs. general), anticoagulation quality, and clinical outcomes using regression models, adjusting for potential confounders.

Results: Although the unadjusted mean percentage of time spent in the therapeutic INR range (2.0-3.0) was slightly higher in patients with private vs. general insurance (65% vs. 61%; p = 0.030), the adjusted difference was not statistically significant (1.53%, 95% CI -1.97 to 5.04). Patients with private insurance had a lower 36-month cumulative incidence of major bleeding (9.7% vs. 15.7%; p = 0.018). After adjustment, privately insured patients had a lower risk of major bleeding compared to patients with general insurance (sub-hazard ratio 0.57, 95% CI 0.32 to 0.98). Insurance status was not associated with recurrent VTE or mortality.

Conclusion: Privately insured patients spent somewhat more time in therapeutic INR range and had a lower rate of major bleeding than generally insured patients. Basic (general) health insurance may be a marker of lower anticoagulation quality and higher risk of major bleeding.
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http://dx.doi.org/10.1016/j.thromres.2018.11.011DOI Listing
January 2019

Venous Thromboembolism: Advances in Diagnosis and Treatment.

JAMA 2018 Oct;320(15):1583-1594

Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Ontario, Canada.

Importance: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common and potentially fatal disease.

Objective: To summarize the advances in diagnosis and treatment of VTE of the past 5 years.

Evidence Review: A systematic search was conducted in EMBASE Classic, EMBASE, Ovid MEDLINE, and other nonindexed citations using broad terms for diagnosis and treatment of VTE to find systematic reviews and meta-analyses, randomized trials, and prospective cohort studies published between January 1, 2013, and July 31, 2018. The 10th edition of the American College of Chest Physicians Antithrombotic Therapy Guidelines was screened to identify additional studies. Screening of titles, abstracts, and, subsequently, full-text articles was performed in duplicate, as well as data extraction and risk-of-bias assessment of the included articles.

Findings: Thirty-two articles were included in this review. The application of an age-adjusted D-dimer threshold in patients with suspected PE has increased the number of patients in whom imaging can be withheld. The Pulmonary Embolism Rule-Out Criteria safely exclude PE when the pretest probability is low. The introduction of direct oral anticoagulants has allowed for a simplified treatment of VTE with a lower risk of bleeding regardless of etiology or extent of the VTE (except for massive PE) and has made extended secondary prevention more acceptable. Thrombolysis is best reserved for patients with massive PE or those with DVT and threatened limb loss. Insertion of inferior vena cava filters should be avoided unless anticoagulation is absolutely contraindicated in patients with recent acute VTE. Graduated compression stockings are no longer recommended to treat DVT but may be used when acute or chronic symptoms are present. Anticoagulation may no longer be indicated for patients with isolated distal DVT at low risk of recurrence.

Conclusions And Relevance: Over the past 5 years, substantial progress has been made in VTE management, allowing for diagnostic and therapeutic strategies tailored to individual patient characteristics, preferences, and values.
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http://dx.doi.org/10.1001/jama.2018.14346DOI Listing
October 2018

Predictors and Outcomes of Recurrent Venous Thromboembolism in Elderly Patients.

Am J Med 2018 06 4;131(6):703.e7-703.e16. Epub 2018 Jan 4.

Department of General internal Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.

Background: Little is known about predictors and outcomes of recurrent venous thromboembolism in elderly patients.

Methods: We prospectively followed up 991 patients aged ≥65 years with acute venous thromboembolism in a multicenter Swiss cohort study. The primary outcome was symptomatic recurrent venous thromboembolism. We explored the association between baseline characteristics and treatments and recurrent venous thromboembolism using competing risk regression, adjusting for periods of anticoagulation as a time-varying covariate. We also assessed the clinical consequences (case-fatality, localization) of recurrent venous thromboembolism.

Results: During a median follow-up period of 30 months, 122 patients developed recurrent venous thromboembolism, corresponding to a 3-year cumulative incidence of 14.8%. The case-fatality of recurrence was high (20.5%), particularly in patients with unprovoked (23%) and cancer-related venous thromboembolism (29%). After adjustment, only unprovoked venous thromboembolism (sub-hazard ratio, 1.67 compared with provoked venous thromboembolism; 95% confidence interval, 1.00-2.77) and proximal deep vein thrombosis (sub-hazard ratio, 2.41 compared with isolated distal deep vein thrombosis; 95% confidence interval, 1.07-5.38) were significantly associated with recurrence. Patients with initial pulmonary embolism were more likely to have another pulmonary embolism as a recurrent event than patients with deep vein thrombosis.

Conclusions: Elderly patients with acute venous thromboembolism have a substantial long-term risk of recurrent venous thromboembolism, and recurrence carries a high case-fatality rate. Only 2 factors, unprovoked venous thromboembolism and proximal deep vein thrombosis, were independently associated with recurrent venous thromboembolism, indicating that traditional risk factors for venous thromboembolism recurrence (eg, cancer) may be less relevant in the elderly.
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http://dx.doi.org/10.1016/j.amjmed.2017.12.015DOI Listing
June 2018

Association between computed tomography obstruction index and mortality in elderly patients with acute pulmonary embolism: A prospective validation study.

PLoS One 2017 8;12(6):e0179224. Epub 2017 Jun 8.

Department of Radiology, Lausanne University Hospital, Lausanne, Switzerland.

Introduction: Computed tomography pulmonary angiography (CTPA) has not only become the method of choice for diagnosing acute pulmonary embolism (PE), it also allows for risk stratification of patients with PE. To date, no study has specifically examined the predictive value of CTPA findings to assess short-term prognosis in elderly patients with acute PE who are particularly vulnerable to adverse outcomes.

Methods: We studied 291 patients aged ≥65 years with acute symptomatic PE in a prospective multicenter cohort. Outcomes were 90-day overall and PE-related mortality, recurrent venous thromboembolism (VTE), and length of hospital stay (LOS). We examined associations of the computed tomography obstruction index (CTOI) and the right ventricular (RV) to left ventricular (LV) diameter ratio with mortality and VTE recurrence using survival analysis, adjusting for provoked VTE, Pulmonary Embolism Severity Index (PESI), and anticoagulation as a time-varying covariate.

Results: Overall, 15 patients died within 90 days. There was no association between the CTOI and 90-day overall mortality (adjusted hazard ratio per 10% CTOI increase 0.92; 95% confidence interval [CI] 0.70-1.21; P = 0.54), but between the CTOI and PE-related 90-day mortality (adjusted sub-hazard ratio per 10% CTOI increase 1.36; 95% CI 1.03-1.81; P = 0.03). The RV/LV diameter ratio was neither associated with overall nor PE-related 90-day mortality. The CTOI and the RV/LV diameter ratio were significantly associated with VTE recurrence and LOS.

Conclusions: In elderly patients with acute PE, the CTOI was associated with PE-related 90-day mortality but not with overall 90-day mortality. The RV/LV diameter ratio did not predict mortality. Both measures predicted VTE recurrence and LOS. The evaluated CTPA findings do not appear to offer any advantage over the PESI in terms of mortality prediction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179224PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464630PMC
September 2017

Usefulness of D-Dimer Testing in Predicting Recurrence in Elderly Patients with Unprovoked Venous Thromboembolism.

Am J Med 2017 10 15;130(10):1221-1224. Epub 2017 May 15.

Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.

Background: Whether post-anticoagulation D-dimer levels are useful in predicting recurrence in elderly patients with unprovoked venous thromboembolism is unknown.

Methods: We followed up 157 patients aged ≥65 years with acute symptomatic, unprovoked venous thromboembolism in a prospective, multicenter cohort study. All patients completed 3-12 months of anticoagulation and then underwent quantitative D-dimer testing (enzyme-linked immunosorbent assay) 12 months after the index venous thromboembolism. The outcome was recurrent symptomatic venous thromboembolism after D-dimer measurement. We examined associations between log-transformed and dichotomized D-dimer values and the time to venous thromboembolism recurrence using competing risk regression, adjusting for age, sex, and overt pulmonary embolism.

Results: There was no statistically significant association between quantitative or dichotomized D-dimer levels and venous thromboembolism recurrence. The area under the receiver operating characteristic curve for predicting recurrent venous thromboembolism was moderate (0.66; 95% confidence interval [CI], 0.51-0.82). The negative likelihood ratios were 0.34 (95% CI, 0.05-2.38) at the usual and 0.34 (95% CI, 0.09-1.29) at the age-adjusted cutoff values. Among patients with normal D-dimer results, venous thromboembolism recurrence rates were 6.8 (95% CI, 2.2-21.2) per 100 patient-years using the usual and 7.1 (95% CI, 3.2-15.8) per 100 patient-years using the age-adjusted cutoff values.

Conclusion: D-dimer testing alone may not be useful in identifying elderly patients with unprovoked venous thromboembolism who are at low risk of recurrent venous thromboembolism and in whom anticoagulants may be safely stopped.
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http://dx.doi.org/10.1016/j.amjmed.2017.04.018DOI Listing
October 2017

Educational Level, Anticoagulation Quality, and Clinical Outcomes in Elderly Patients with Acute Venous Thromboembolism: A Prospective Cohort Study.

PLoS One 2016 8;11(9):e0162108. Epub 2016 Sep 8.

Department of General Internal Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.

Whether the level of education is associated with anticoagulation quality and clinical outcomes in patients with acute venous thromboembolism (VTE) is uncertain. We thus aimed to investigate the association between educational level and anticoagulation quality and clinical outcomes in elderly patients with acute VTE. We studied 817 patients aged ≥65 years with acute VTE from a Swiss prospective multicenter cohort study (09/2009-12/2013). We defined three educational levels: 1) less than high school, 2) high school, and 3) post-secondary degree. The primary outcome was the anticoagulation quality, expressed as the percentage of time spent in the therapeutic INR range (TTR). Secondary outcomes were the time to a first recurrent VTE and major bleeding. We adjusted for potential confounders and periods of anticoagulation. Overall, 56% of patients had less than high school, 25% a high school degree, and 18% a post-secondary degree. The mean percentage of TTR was similar across educational levels (less than high school, 61%; high school, 64%; and post-secondary, 63%; P = 0.36). Within three years of follow-up, patients with less than high school, high school, and a post-secondary degree had a cumulative incidence of recurrent VTE of 14.2%, 12.9%, and 16.4%, and a cumulative incidence of major bleeding of 13.3%, 15.1%, and 15.4%, respectively. After adjustment, educational level was neither associated with anticoagulation quality nor with recurrent VTE or major bleeding. In elderly patients with VTE, we did not find an association between educational level and anticoagulation quality or clinical outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162108PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015908PMC
August 2017

Predicting recurrence after unprovoked venous thromboembolism: prospective validation of the updated Vienna Prediction Model.

Blood 2015 Oct 4;126(16):1949-51. Epub 2015 Sep 4.

Department of General Internal Medicine, Bern University Hospital, Bern, Switzerland;

The updated Vienna Prediction Model for estimating recurrence risk after an unprovoked venous thromboembolism (VTE) has been developed to identify individuals at low risk for VTE recurrence in whom anticoagulation (AC) therapy may be stopped after 3 months. We externally validated the accuracy of the model to predict recurrent VTE in a prospective multicenter cohort of 156 patients aged ≥65 years with acute symptomatic unprovoked VTE who had received 3 to 12 months of AC. Patients with a predicted 12-month risk within the lowest quartile based on the updated Vienna Prediction Model were classified as low risk. The risk of recurrent VTE did not differ between low- vs higher-risk patients at 12 months (13% vs 10%; P = .77) and 24 months (15% vs 17%; P = 1.0). The area under the receiver operating characteristic curve for predicting VTE recurrence was 0.39 (95% confidence interval [CI], 0.25-0.52) at 12 months and 0.43 (95% CI, 0.31-0.54) at 24 months. In conclusion, in elderly patients with unprovoked VTE who have stopped AC, the updated Vienna Prediction Model does not discriminate between patients who develop recurrent VTE and those who do not. This study was registered at www.clinicaltrials.gov as #NCT00973596.
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http://dx.doi.org/10.1182/blood-2015-04-641225DOI Listing
October 2015

Is the number of drugs independently associated with mortality?

Intensive Care Med 2013 Nov 31;39(11):2060-2. Epub 2013 Aug 31.

Department of Intensive Care and Neonatology, University Children's Hospital, 8032, Zurich, Switzerland,

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http://dx.doi.org/10.1007/s00134-013-3065-yDOI Listing
November 2013

Are immigrant children admitted to intensive care at increased risk?

Swiss Med Wkly 2011 29;141:w13190. Epub 2011 Apr 29.

Department of Intensive Care and Neonatology, University Children's Hospital, 8032 Zürich, Switzerland.

Background: Racial and ethnic disparities in health care are significant predictors of the quality of health care received. Studies documenting these disparities are largely based on an adult chronic care model. There are only few reports in paediatric populations. Our objective was to evaluate the severity of illness of immigrants at admission to PICU, the proportion of immigrants in PICU compared to the general population and the quality of care they receive, in order to examine whether there are disparities in health care.

Methods: Prospectively collected data of 1009 sequential first admissions in 2007 to a multidisciplinary, 19-bed, PICU of a university children's hospital in Switzerland. The main outcome measures were expected mortality, standardised mortality ratio, proportion of immigrants in general population and in PICU.

Results: Children with an immigrant background are overrepresented in PICU compared with their proportion in the general population. Parents of these children are more likely to be in the lowest strata of socio-professional status than parents of Swiss children hospitalised in PICU (relative risk 9.82, 95% CI 5.16 to 18.7). However, the distribution of immigrant children and Swiss children along the strata of illness severity is equal and there is no difference in standardised mortality ratio between these two groups.

Conclusions: These findings indicate that disparities may exist at a lower level of illness severity, due to many possible reasons (for example shortcomings in primary health care). However, once a child enters tertiary health care, nationality and socio-economic factors no longer influence quality of health care delivery.
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http://dx.doi.org/10.4414/smw.2011.13190DOI Listing
July 2011