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Economic evaluation of the prophylaxis for thromboembolism in critical care trial (E-PROTECT): study… Fowler, Robert A; Mittmann, Nicole; Geerts, William H; Heels-Ansdell, Diane; Gould, Michael K; Guyatt, Gordon; Krahn, Murray; Finfer, Simon; Pinto, Ruxandra; Chan, Brian; Ormanidhi, Orges; Arabi, Yaseen; Qushmaq, Ismael; Rocha, Marcelo G; Dodek, Peter; McIntyre, Lauralyn; Hall, Richard; Ferguson, Niall D; Mehta, Sangeeta; Marshall, John C; Doig, Christopher J; Muscedere, John; Jacka, Michael J; Klinger, James R; Vlahakis, Nicholas; Orford, Neil; Seppelt, Ian; Skrobik, Yoanna K; Sud, Sachin; Cade, John F; Cooper, Jamie; Cook, Deborah Dec 20, 2014

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STUDY PROTOCOL Open AccessEconomic evaluation of the prophylaxis forthromboembolism in critical care trial (E-PROTECT):Total costs are derived from centers, proportional to the numbers of patients enrolled in each country. Direct costsTRIALSFowler et al. Trials 2014, 15:502http://www.trialsjournal.com/content/15/1/502Avenue, Room D478, Toronto, ON M4N 3M5, CanadaFull list of author information is available at the end of the articleinclude medication, physician and other personnel costs, diagnostic radiology and laboratory testing, operative andnon-operative procedures, costs associated with bleeding, transfusions and treatment-related complications. Indirectcosts include ICU and hospital ward overhead costs. Outcomes are the ratio of incremental costs per incrementaleffects of LMWH versus UFH during hospitalization; incremental cost to prevent a thrombosis at any site (primaryoutcome); incremental cost to prevent a pulmonary embolism, deep vein thrombosis, major bleeding event or episodeof heparin-induced thrombocytopenia (secondary outcomes) and incremental cost per life-year gained (tertiaryoutcome). Pre-specified subgroups and sensitivity analyses will be performed and confidence intervals for the estimatesof incremental cost-effectiveness will be obtained using bootstrapping.(Continued on next page)* Correspondence: rob.fowler@sunnybrook.ca1Sunnybrook Health Sciences Centre, University of Toronto, 2075 BayviewWe derive baseline characteristics and probabilities of instudy protocol for a randomized controlled trialRobert A Fowler1*, Nicole Mittmann2, William H Geerts3, Diane Heels-Ansdell4, Michael K Gould5, Gordon Guyatt4,Murray Krahn6, Simon Finfer7, Ruxandra Pinto1, Brian Chan8, Orges Ormanidhi9, Yaseen Arabi10, Ismael Qushmaq11,Marcelo G Rocha12, Peter Dodek13,14, Lauralyn McIntyre15, Richard Hall16, Niall D Ferguson17,18, Sangeeta Mehta19,John C Marshall20, Christopher James Doig21, John Muscedere22, Michael J Jacka23, James R Klinger24,Nicholas Vlahakis25, Neil Orford26,27, Ian Seppelt28, Yoanna K Skrobik29, Sachin Sud30, John F Cade31, Jamie Cooper32,Deborah Cook33 and On behalf of the Canadian Critical Care Trials Group and the Australia and New Zealand IntensiveCare Society Clinical Trials GroupAbstractBackground: Venous thromboembolism (VTE) is a common complication of critical illness with important clinicalconsequences. The Prophylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) is a multicenter, blinded,randomized controlled trial comparing the effectiveness of the two most common pharmocoprevention strategies,unfractionated heparin (UFH) and low molecular weight heparin (LMWH) dalteparin, in medical-surgical patients inthe intensive care unit (ICU). E-PROTECT is a prospective and concurrent economic evaluation of the PROTECT trial.Methods/Design: The primary objective of E-PROTECT is to identify and quantify the total (direct and indirect,variable and fixed) costs associated with the management of critically ill patients participating in the PROTECT trial,and, to combine costs and outcome results to determine the incremental cost-effectiveness of LMWH versus UFH,from the acute healthcare system perspective, over a data-rich time horizon of ICU admission and hospital admission.-ICU and in-hospital events from all enrolled patients.© 2014 Fowler et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.vepfuon. DemFowler et al. Trials 2014, 15:502 Page 2 of 11http://www.trialsjournal.com/content/15/1/502horizon of the ICU admission and hospital admission.Methods/DesignE-PROTECT background studies and methodologiesThe PROTECT trialThe objective of the Canadian Institutes of Health Research(CIHR)-funded PROTECT trial [7,8] was to evaluateLMWH versus UFH on the primary outcome of the inci-dence of proximal leg DVT diagnosed by compressionultrasound, with secondary outcomes of PE, venouslinkage of costs and clinical events to be measured as partof the PROTECT trial case report form. Therefore, wedesigned a more appropriate cost gathering methodologyto capture hospital-specific line-item costs according toimportant variables that we anticipated will drive costsand possible cost-effectiveness (Additional file 1).In order to determine such cost drivers, we performeda systematic review of economic analyses of thrombo-prophylaxis strategies in hospitalized patients to identifyvariables that we anticipate will drive costs and possiblecost-effectiveness in E-PROTECT, and to determine poten-(Continued from previous page)Discussion: This economic evaluation employs a prospecticontrolled blinded clinical trial, with a pre-specified analyticThis economic evaluation has received only peer-reviewedanalysis or decision to submit the manuscripts for publicatiTrial registration: Clinicaltrials.gov Identifier: NCT00182143Keywords: Economic, Cost-effectiveness, Venous, Thrombomolecular weight, Intensive, CriticalBackgroundVenous thromboembolism (VTE) is a common compli-cation of critical illness and has important clinical conse-quences, including deep vein thrombosis (DVT), pulmonaryembolism (PE), increased length of stay in the intensivecare unit (ICU) and hospital and death [1-3]. AlthoughDVT has potentially serious consequences, it is oftenunrecognized in the ICU as the clinical examination forDVT lacks sensitivity and specificity [4]. Further, routineultrasound screening for DVT is not a cost-effective diag-nostic strategy in practice [5]. Thus, thromboprophylaxisis the most appropriate mechanism to prevent VTE andits complications among critically ill patients.We have previously documented that most economicevaluations of VTE strategies are designed after the resultsof the trial are known, and are funded by the manufacturersof the agents compared [6]. This introduces the opportun-ity for biased design and interpretation of economic evalu-ations. Therefore, we designed the economic evaluation(E-PROTECT) of a multicenter randomized, blinded con-trolled trial of 3,746 patients comparing the effectivenessof unfractionated heparin (UFH) and low molecularweight heparin (LMWH) (dalteparin) [7]. The primaryobjective of E-PROTECT is to identify and quantify thetotal (direct and indirect, variable and fixed) costs asso-ciated with the management of critically ill patientsparticipating in the PROTECT trial, and to combine costsand outcome results to determine the incremental cost-effectiveness of LMWH versus UFH, from the acutehealthcare system perspective, over a data-rich timethrombosis at any site, bleeding and heparin-inducedthrombocytopenia (HIT). The study design was a ran-domized, stratified, concealed double-blind multicentercosting methodology concurrent with a randomizedlan, outcome measures, subgroup and sensitivity analyses.nding and funders will not play a role in the generation,.ate of registration: 10 September 2005.bolism, PROTECT, Unfractionated, Heparin, Lowtrial with enrolment throughout Canada, Australia, theUnited States, Saudi Arabia, the United Kingdom andBrazil. The PROTECT trial enrolled 3,746 critically illpatients between May 2006 and June 2010 according topreviously published eligibility criteria [7,8]. A centralcomputerized web-based or phone-in randomization sys-tem ensured concealed randomization of patients to eitherdalteparin 5,000 international units (IU) daily or UFH5,000 IU twice daily subcutaneously for the ICU stay. Onlythe research pharmacist at each participating centre wasaware of the allocation. Bilateral proximal leg compressionultrasounds were performed within 48 hours of ICU ad-mission, twice weekly and on DVT suspicion. A prede-fined algorithm was used to diagnose PE; bleeding, HIT,other thrombosis and complications were identified usinga priori definitions and procedures. The PROTECT publi-cation itself provides complete study data [7].The E-PROTECT pilot studyTo first determine the feasibility of obtaining patient-specific line-item costing (for each aspect of care delivery),we conducted a pilot study between 2006 and 2007involving six hospitals in Canada, the United States andAustralia [9]. However, we discovered that in bothprivately funded and publically funded institutions, thevariability around patient costing was substantial andthat line-item costs were not routinely available. Manycosts were ‘rolled up’ into summary cost measures, andsubsequently, this methodology would not allow for atial ranges for willingness-to-pay to avoid DVT and PE[6]. From 5,180 potentially relevant studies, 39 met theeligibility criteria from which we extracted data on studyeconomic evaluation for publication. We developed ourthe frequency of DVT, PE, major bleeding and HIT amongFowler et al. Trials 2014, 15:502 Page 3 of 11http://www.trialsjournal.com/content/15/1/502all patients to measure the primary clinical incrementaleffect of the difference in any VTE (all limb DVT, PE andnon-limb thromboses), and secondary clinical incrementaleffects of episodes of PE, DVT, major bleeding and HIT.The PROTECT trial was designed and powered to evalu-ate differences in the rate of thrombotic events betweentwo pharmacologic thromboprophylaxis strategies, notdifferences in life expectancy; accordingly, incrementaldifferences in life years are not primary outcomes inthis economic evaluation. All measures of clinical events,medications administered, laboratory and radiology test-ing, complications, blood product transfusions, proce-dures and surgeries and duration of ventilation, ICU andanalysis according to established guidelines [10-14]. Also,we used an acute healthcare system perspective (duringthe period of hospitalization) to encompass all in-patientdirect medical and hospital costs, including physician andother personnel costs. Our preliminary analytic plan waspre-specified with public study funders (Heart and StrokeFoundation, Ontario, Canada) as part of the economicevaluation of the PROTECT trial protocol prior to com-pletion of the trial and unblinding of the economic conse-quences of clinical data.E-PROTECT patients, outcomes and effectsNo patients were lost to follow-up. Although the PROTECTtrial considered both intention-to-treat and on-treatmentanalyses, primary outcomes were based on adherence tothe intention-to-treat principle and will form the clinicalevent estimates of the economic analyses. We recordedcharacteristics, quality, costs and efficacy. In addition toidentifying variables likely to be influential in E-PROTECT,we found that LMWHs appear to be the most economicallyattractive drugs for VTE prevention in acutely ill hospital-ized patients, whereas newer agents may be more econom-ically attractive in patients receiving joint replacementsurgeries. However, the manufacturer of the new agent sup-ported approximately two-thirds of evaluations and suchdrugs were likely to be reported as economically favorable.Incremental cost-effectiveness ratios to prevent VTE eventsranged from a dominance of LMWH to under $5,000 perVTE event avoided [6].E-PROTECT methodsE-PROTECT design and economic assumptionsWe designed E-PROTECT before the results of thePROTECT trial were known. Study funding was frompeer-reviewed sources and none of the funders played arole in the generation, analysis or decision to submit thehospital stay were recorded alongside the PROTECT trialas part of the study case report form [7,8].E-PROTECT costsTotal, direct and indirect costsTotal costs for patients in the PROTECT trial comprisedirect and indirect costs [15]. To determine which costto include, we performed a systematic review of the VTEcost-effectiveness literature [6] for hospitalized patients,and reviewed evidence underlying the relative importanceamong the E-PROTECT Steering Committee, before decid-ing upon final cost variables. Direct costs are attributable tomedications, transfusions, laboratory or radiology tests orprocedures or personnel directly associated with specificcomponents of patient care. Such costs can usually bedetermined on an item-by-item, procedure-by-procedurebasis. Indirect costs are those for services or proceduresthat often benefit more than one patient at a time andtheir precise benefits to specific patients are often difficultto trace, such as maintenance of equipment and infra-structure. A large proportion of such indirect costs com-prise the ‘overhead’ in operating an ICU, laboratory orpharmacy, for example [10,15,16]. These costs can befixed (roughly the same amount on a recurring basis), orvariable (fluctuating depending upon patient circum-stances and course). E-PROTECT measured both directand estimated indirect costs at study sites.Direct costs from participating sitesDirect and indirect costs were sought from 23 of 67hospitals and five of six countries participating in thePROTECT trial (12 hospitals in Canada; five hospitalsin Australia; three hospitals in the United States; twohospitals in Saudi Arabia; one hospital in Brazil). Siteswill be invited to participate in the costing componentof the economic evaluation to reflect overall propor-tions of patients enrolled in the PROTECT trial amongall participating countries. Direct costs will be dividedamong the following categories: 1) study-related drugs(unfractionated heparin, dalteparin, enoxaparin, tinza-parin, other low molecular weight heparins, protamine,Desmopressin (DDAVP), aprotinin, aminocaproic acid,danaparoid, lepirudin, argatroban, fondaparinux, activatedFactor VII, acetyl salicylic acid (ASA), clopidogrel, a repre-sentative proton-pump inhibitor (pantoprazole), vitaminK, warfarin and epinephrine for injection or infusion);2) laboratory testing (complete blood count, electrolytes,creatinine, blood urea nitrogen, arterial blood gas, partialthromboplastin and prothrombin time, anti-Xa level,enzyme-linked immunosorbent assay (ELISA) and sero-tonin release HIT assay); 3) personnel (including perdiem most responsible physician and per consultationphysician charges over the course of an ICU and hospitaladmission, nursing, pharmacist, respiratory therapist, phys-ical therapist, social work and ICU administrative and/or clerical staffing hourly wage range); 4) radiology (uni-lateral and bilateral leg compression ultrasonographycomprised components of non-physician personnel cost,eqanromcoanantove(othhwapwcadetovamFowler et al. Trials 2014, 15:502 Page 4 of 11http://www.trialsjournal.com/content/15/1/502and venography, portable chest radiograph, computerizedtomography (CT) scan of the chest with an angiogram(pulmonary embolism protocol), CT scan of the abdomen,pelvis, and head, pulmonary angiogram and ventilation-perfusion scan); 5) procedural costs (electrocardiogram,central venous catheter material costs, inferior vena cavafilter material and insertion and removal costs, naso- ororo-gastric tube, procedure costs for gastroscopy, colonos-copy, bronchoscopy, and angiography with embolizationand intermittent and continuous renal replacement ther-apy); and, 6) operative costs for laparotomy (including thesurgeon and surgical assistant, anesthesiology and nursingpersonnel costs).Operative and bedside surgical procedures were classi-fied according to procedure and body site (head and neck,cardiac, vascular, thoracic, gastrointestinal, orthopedic,genitourinary, plastic, neurosurgical or other), by twoindependent adjudicators, blinded to treatment allocation,with separate attribution as to whether the procedure wasconceivably precipitated or related to the study drug(bleeding or thromboses). Disagreements were resolved byconsensus or a third reviewer. Rates of all surgeries andstudy drug-related surgeries will be compared for eachstudy group and those we believe to be possibly related tothe study drug will be included in the cost analysis.Direct costs associated with heparin-induced thrombocytopeniaAs episodes of HIT with thrombosis (HITT) and withoutthrombosis involve complex and expensive investigationand treatment, some authors previously performed asingle-center micro-costing study in one PROTECT trialcenter. They aimed to estimate the total average attribut-able costs of an episode of HIT (and HITT includingarterial and venous thromboses), as well as associatedHIT-safe anticoagulants, associated bleeding and special-ized HIT diagnostic testing. The details of the micro-costing study are published elsewhere [17] but includeddiagnosis, investigation, treatment and administrationcosts. However, for E-PROTECT, we will capture costsand measures of resource use for complications such asbleeding, HIT and HITT as part of the PROTECT casereport and centre-specific E-PROTECT costs, and will notassign additional HIT or bleeding-specific costs in orderto avoid double counting. Bleeding and blood producttransfusion services costs (per unit of red blood cells, fro-zen plasma and thawing, cryoprecipitate, cross matchingand platelets and associated laboratory testing of bloodtype and screen) were derived from a Canadian nationaltransfusion resource, education and costing exercise [18].Prophylactic and therapeutic anticoagulation outside the ICUWard-based prophylactic and therapeutic anticoagulationwas not directly measured; therefore, we will make thefollowing assumptions:(bvauipment maintenance, some diagnostic testing and ICUd other ward overhead infrastructure costs [9]. Thislled-up indirect per day cost will be determined to esti-ate the difference between the total of individual directsts relevant for patients in the PROTECT trial (above),d the total daily costs of care that may reflect additionald indirect costs which are important in determiningtal costs, but are difficult to capture as single variables.Mean institutional costs of ICU care typically representry high costs on the first day, and substantially lowerne-quarter) costs after the second day [16], with a fur-er decrease after discharge to a ward bed. Using ourospital estimates of indirect costs in ICUs and on theard, and in accordance with prior literature, we willply a ratio of 1 (hospital ward):2.5 (ICU day two on-ards):4 (ICU day one) [16,19-21]. Most daily costs ofre in ICUs are fixed, not variable, and prior work hasmonstrated minimal direct-variable cost differences dueventilation status [16]. Because of this and because thest majority of ICU days represent days patients receivedechanical ventilation, we will apply a small incremental1. If no therapeutic anticoagulation was used in lasttwo days in ICU, we will assume UFH prophylaxiswill be used for the entire ward stay;2. If warfarin was used in last two days in ICU, we willassume that warfarin will be used for entire ward stay;3. If treatment doses of LMWH were used in last twodays in ICU, we will assume that treatment withLMWH will continue for five days on the ward,followed by warfarin for the remainder of thehospital stay;4. If treatment doses of UFH were used in last twodays in ICU, we will assume that treatment withUFH occurs for five days on the ward, followed bywarfarin for the remainder of the hospital stay;5. If treatment doses of danaparoid or other HIT-safeanticoagulants were used in last two days in ICU, wewill assume that treatment with danaparoid or otherHIT-safe anticoagulants occurs for five days on theward, followed by warfarin for the remainder of thehospital stay.Indirect costs - ICU and ward careWe will measure institution-specific estimates of indir-ect (overhead) costs per day of care in the center’shighest acuity ICU (capable of providing ventilationand hemodynamic support), and for patients receivingcare on standard medical and surgical wards. From theE-PROTECT pilot, we found that each institution deter-mined this cost per day in a unique fashion, but generallyetween 3 and 5%) daily indirect cost due to this ad-nced life support [16].Fowler et al. Trials 2014, 15:502 Page 5 of 11http://www.trialsjournal.com/content/15/1/502Direct and indirect cost data collectionWe measured all costs at each site using a costing opera-tions manual outlining a standardized multistep process(Additional file 1). Between 2007 and 2011, the principalinvestigator and a research assistant contacted the siteprincipal investigator and research coordinator at eachparticipating center with the list of variable costs required,who then subsequently contacted the most appropriateindividual in each hospital’s accounting, human resources,pharmacy, radiology and laboratory services and bloodbank. Standard definitions (per unit of measurement ortime, and so on) were created and explained and hospital-specific costs requested for each variable. Where costswere influenced by extra-hospital jurisdictions (such asjurisdictional payer physician costs, unionized employeesand reference laboratory costs), these were recorded. In allcases, costs were requested but if only charges wereknown, then we converted to costs by the institution’scost-to-charge estimate for that item. Both professional(performance and/or interpretation) and technical costswere recorded for procedures when applicable. We under-took an iterative series of communications until no furtherdata could be gleaned. All data are without patient identi-fiers and are be maintained in password-protected andencrypted laptop or desktop, in locked offices.Exploring cost variability among sitesTo explore variability among centers and countries, costdata will be summarized by means (and standard devia-tions) and medians (and interquartile ranges) among allsites, and by country for all variables, as per our pilotcosting study [9]. Visible outliers will be reconfirmedwith individual hospital contacts before determiningmedian costs among all centers for each variable in thedataset to be used for all primary and secondary ana-lyses. Data from sites that have cost accounting method-ologies precluding the inclusion of certain data will benoted, but multi-country median costs will be used toimprove the generalizability of our estimates and to miti-gate the influence of high and low cost outliers. Prior tofinal analyses being undertaken, participating sites will bere-queried to determine if particular costs have changedsubstantially (for example, by more than 25%), beyondinflationary or deflationary changes, over the course of thestudy and if so, the most current costs will be used. Coun-try and year-specific costs will be converted to US dollars,first accounting for annual inflation [22-25]. We planon using international currency conversion, instead ofpurchase power parity (PPP)-based conversions, becausehealth-specific PPPs are not available for all participatingcountries, and non-health PPP conversion rates varysubstantially over the period of the analysis [23]. Country-specific costs will be considered only in sensitivity ana-lyses. As of 1 June 2013, 1 United States dollar was worthapproximately 1.03 Canadian dollars, 1.04 Australian dol-lars, 2.12 Brazilian Real, and 3.75 Saudi Arabian Riyal [23].E-PROTECT analytic planThe base case cost-efficacy ratio is the ratio of incrementalcosts per incremental effects of LMWH versus unfrac-tionated heparin during the period of hospitalization.Incremental costs will be derived for all patients by firstcalculating total costs for all patients in each arm of thePROTECT trial. Item costs will be multiplied by thefrequency or event rates for medications administered,laboratory and radiological tests incurred, other diagnosticor therapeutic procedures performed, transfusions received,per day personnel and ICU or ward costs, depending uponnumber of events and length of stay in the ICU and hos-pital. Total, then median and mean per patient costs foreach of the LMWH and unfractionated heparin groups willbe calculated. Incremental costs will be taken as the differ-ence in median per patient costs between groups; however,mean costs will also be provided in order to generate totalcosts. Effects for the base case analysis will be calculatedseparately for each primary (all thromboses), secondary(PE, DVT, major bleeding and HIT) and tertiary (survival)endpoints. Incremental effects will be taken as the differ-ence in per patient event rates between groups. Thereforecost-effectiveness ratios will be displayed in terms of incre-mental costs divided by incremental effects, specifically, thecost to prevent a thrombosis at any site, the cost to preventa PE, DVT, major bleeding event and episode of HIT, andlife-year gained as is commonly used in cost-effectivenessanalysis for VTE prevention strategies (Box 2) [6]. If costsare less in the LMWH group, a cost-minimization analysiswill be reported, highlighting the difference in costs (with95% confidence intervals) between groups.Evaluation Framework Overview1. Question: Is the use of LMWH as compared toUFH cost-effective for the prevention of VTE incritically ill medical-surgical patients?2. Perspective: Our primary perspective is the acutehealthcare system perspective. We will performsensitivity analyses from various geographic regionsparticipating in the PROTECT trial.3. Clinical outcomes: Rates of all thromboses, DVT, PEand complications (for example, bleeding and HIT),length of stay and mortality (ICU and hospital).4. Costs: All direct and indirect medical costsassociated with treatment and complications (suchas ICU and non-ICU hospitalization, personnel,medications, diagnostic testing and procedures)will be identified and evaluated. Costs will beconverted to Canadian and United States(2013 dollar rates) costs.Fowler et al. Trials 2014, 15:502 Page 6 of 11http://www.trialsjournal.com/content/15/1/502Outcomes Overview1. Primary outcome:Incremental cost per thromboses (any site) avoided2. Secondary outcomes:(i.) Incremental cost per PE avoided(ii.) Incremental cost per DVT avoided(iii.) Incremental cost per major bleeding event avoided(iv.) Incremental cost per episode of HIT avoided3. Tertiary outcomes:4. Incremental cost per life year and quality-adjustedlife year gained (lifetime horizon)E-PROTECT subgroupsAs subgroup analyses, we will investigate specific patientsin the PROTECT trial who may have differential effectsand costs as compared to the entire population, includ-ing patients with higher and lower severity of illness(APACHE1 II score ≥25 versus <25), patients with abody mass index of ≥40 kg/m2 versus <40 kg/m2, patientsrequiring inotropes or vasopressors at enrollment versusthose who do not and medical versus surgical patients.Although ventilation status was initially planned as a sub-group, approximately 90% of patients were mechanicallyventilated at enrollment [7] and thus analysis in this sub-group will not be informative. We will directly calculatethe incremental cost difference and generate 95% confi-5. Evaluation: Our primary outcome is the incrementalcost per in-hospital thrombotic event avoided.Long-term results will be presented in terms of costsper life year and quality-adjusted life years gained,using utilities from studies of appropriate duration,to allow for broad comparison of cost-efficacy withother medical interventions.6. Comparators: We will compare LMWH with UFHfor outcomes and associated costs.7. Time horizon: We will focus on near-term horizons;costs and incremental cost effectiveness ratiooutcomes at ICU and hospital discharge. We willmodel long-term outcomes over a lifetime horizon.8. Discounting: We will discount cost and utilities at3% for any longer-term (over one year) analyses.9. Uncertainty: We will use sensitivity analyses andbootstrapping to produce confidence intervals.DVT = deep vein thrombosis; HIT = heparin inducedthrombocytopenia; ICER = incremental cost-effectivenessratio; ICU = intensive care unit; LMWH= low molecularweight heparin; PE = pulmonary embolism; UFH = unfrac-tionated heparin; VTE = venous thromboembolism.dence intervals using the bias corrected and accelerated(BCa) method in R, among 1,000 bootstrap samples. Wewill examine the relative influence of all individual costsusing a Tornado diagram.E-PROTECT sensitivity analysesAs patient characteristics, effects and costs may differoutside of tightly controlled clinical trials and in variousjurisdictions, we plan a number of sensitivity analyses toexplore how incremental cost-effectiveness ratios maychange with plausible differences in values, includingcosts of LMWH and UFH, and per day cost of care inICU and hospital wards. We will also perform sensitivityanalyses using the efficacy analysis of the PROTECTtrial that considered only patients who received thestudy drug for two days or more and had two or more legcompression ultrasounds, and by considering only symp-tomatic thromboses. Multi-way sensitivity analyses will beperformed by varying the estimates of pairs of potentiallyinfluential variables. We will perform a probabilistic sensi-tivity analysis of pairs of known costs and effects from thePROTECT trial, using bootstrapping techniques, among1,000 samples, with replacement, in order to generate anincremental cost-effectiveness plot [26,27].Secondary analysesE-PROTECT post-hospital discharge modelingSome clinical events may occur after ICU and hospitaldischarge and these events may utilize resources (suchas re-admission to the ICU, rehabilitation and physicianvisits). Because we cannot follow all patients in the PRO-TECT trial over their actual life expectancy, we may usedischarge vital statistics and known post-critical illnessfollow-up literature to model the lifetime effects andcost-efficacy ratios of prevention strategies for all patientsin the PROTECT trial, depending upon the results for thein-hospital time horizon. We will know clinical events andoutcomes until death or discharge from hospital. However,if the primary analysis implies that long-term effects andcosts are important to explore (particularly if the primaryanalysis demonstrates one strategy is more costly but withgreater effects), post-discharge, a Markov-based process(Figure 1) will be used to model longer-term events andwill allow patients to transition between states of health orillness until all patients in the model have died [5].Both background mortality and increased mortality dueto the initial illness, thrombosis event or complication willbe considered. The cycle length will be one month. Tran-sition probabilities will be taken from the E-PROTECTfollow-up cohort and literature of post-ICU survival. TheE-PROTECT long-term model is informed by the struc-tures of published models for prophylaxis with LMWH inother populations [5] and the actual course of the patientsin the PROTECT trial. We will combine these data, andknown utilities of post-ICU discharge states, with out-comes and life years determined by the PROTECT trially inoFowler et al. Trials 2014, 15:502 Page 7 of 11http://www.trialsjournal.com/content/15/1/502and the long-term model in order to derive a measure ofquality-adjusted life years and associated incrementalFigure 1 Markov model for long-term outcomes and costs of criticalLMWH= low molecular weight heparin; LTC = long-term care; M =Markovcost-efficacy ratios. Given our in-hospital primary timehorizon and focus on thrombotic events in the PROTECTtrial, we intentionally will not directly measure short-termhealth-related quality of life measurements for our primarytime horizon, but will apply measures of health-relatedquality of life for modeled post-hospital survival using datafrom longitudinal studies of critically ill patients over an ap-propriate time horizon [28-36]. We will apply 3% discount-ing for all effects and costs for any lifetime modeled events.Statistical analysesAll primary analyses will be based on the intention-to-treat principle, as per the primary analyses for the PRO-TECT trial. We use descriptive analyses to describe thebaseline characteristics. Means (and standard deviations)or medians (and interquartile ranges) will be used to de-scribe average effect and cost estimates, and Chi-squaretests and two-sample t-test comparisons will be used asappropriate. We will test for differences in costs usingstandard non-parametric tests, and use nonparametricanalysis of variance techniques to test for interactionswith the heparin strategies. For missing or unavailabledata, we will use imputation of the median value fromthe appropriate subgroups in E-PROTECT and compareresults obtained with and without imputation to ensurelarge variations do not exist [37,38]. Statistical signifi-cance for differences among a priori comparisons will beset at a P value of 0.05. Primary analysis will be undertakenusing Excel (Microsoft Corp, Redmond Washington,ll patients in E-PROTECT. See Sud et al. [5]. ICU = intensive care unit;de; UFH = unfractionated heparin; VTE = venous thromboembolism.United States), R (Free Software Foundation) and SAS(Cary, North Carolina, United States). Post-hospital dis-charge models will be constructed using Excel and TreeAgesoftware (TreeAge Software Inc., Williamstown,Massachusetts, United States).EthicsResearch ethics approval for E-PROTECT was granted bySunnybrook Health Sciences Centre (project identifier:115-2007). All other sites participating in the economicevaluation of the PROTECT trial have obtained researchethics approval for involvement in the PROTECT trial,or appropriate approval to include non-specific patient-based costing data (Canada: Queen Elizabeth II Hospital(Halifax); Hôpital Maisonneuve-Rosemont (Montréal);Ottawa Hospital (Ottawa); Kingston General Hospital(Kingston); Mount Sinai Hospital, University HealthNetwork, St Michael’s Hospital, Sunnybrook Health Sci-ences Centre (Toronto); St Joseph’s Hospital (Hamilton);Foothills Hospital (Calgary); University of Alberta Hospital(Edmonton); St Paul’s Hospital (Vancouver). Australia: RoyalNorth Shore Hospital (Sydney); Barwon Health (Geelong);Nepean Hospital (Penrith); Royal Melbourne Hospital,The Alfred Centre (Melbourne). United States: RhodeIsland Hospital (Providence); Mayo Clinic (Rochester).Saudi Arabia: King Saud Bin Abdulaziz University forHealth Sciences (Riyadh); King Faisal Specialist Hospital &Fowler et al. Trials 2014, 15:502 Page 8 of 11http://www.trialsjournal.com/content/15/1/502Research Centre (Jeddah). Brazil: Hospitalar Santa Casa(Porto Alegre).Informed consent was obtained from each participant inthe PROTECT trial, or their substitute decision-maker, inaccordance with local research ethics approvals.Study oversightStudy operations, methods, submission for funding andmanuscript generation are under the oversight of theE-PROTECT steering committee (RF, NM, DC, WG,MG, GG and MK) on behalf of the Canadian CriticalCare Trials Group.DiscussionThe PROTECT trial is the largest trial undertaken ofVTE prophylaxis for critically ill patients. AlthoughLMWH has been shown to be an effective means ofVTE prophylaxis for many patient populations, it hashistorically been associated with a higher drug acquisi-tion cost than UFH, and the relative effects, side-effectsand broader costs of VTE prophylaxis are unknown. Aprospective economic evaluation is critical to the inter-pretation of the results of the PROTECT trial. The PRO-TECT trial results suggest that LMWH may reduce thefrequency of pulmonary embolus and heparin-inducedthrombocytopenia. Thus, physicians, pharmacists and pol-icy makers will need to know whether the cost providesgood value for the healthcare dollar. An economic evalu-ation is still critical for alternative clinical outcomes,particularly for differences in the adverse event profilebetween treatments that may lead to additional resourceconsumption. E-PROTECT provides an opportunity toanswer these questions and address the cost-efficacy ofVTE prevention using results with minimal risk of bias.In preparation for E-PROTECT, we have performed anumber of preliminary and sub-studies, including a sys-tematic review of the VTE economic evaluation literatureto inform cost-drivers, the E-PROTECT pilot study inthree countries to determine feasible and valid cost datacollection, and we have developed a decision-analyticmodel to explore both the importance of protocoledscreening versus clinical case finding for VTE, and evalu-ate the long-term outcomes of various detection and treat-ment strategies [5,6,9].Prospective measurement of economic and health out-come data alongside randomized controlled trials, althoughpreviously rare, has become increasingly common. Thereare several advantages [10]. Firstly, the costs of collectingclinical, economic and long-term follow-up data can bereduced if they are collected simultaneously. Secondly,certain data, such as information resource use, are imprac-tical or impossible to gather retrospectively. Thirdly, theanalysis can take full advantage of randomization to collectdata unlikely to be confounded by differences in baselinecharacteristics between treatment arms. Fourthly, all ele-ments of the analysis, including decisions regarding model-ing assumptions and sensitivity analysis parameters andranges, can be specified before investigators see unblindeddata, reducing the risk of investigator bias. Finally, theeconomic analysis results can be generated at, or onlyslightly after, the time that clinical results are available.Such timely economic data can be particularly useful tothose making budgetary and healthcare resource alloca-tion decisions, especially if the intervention that is beingevaluated is already in current practice. By conducting oureconomic analysis concurrent with the PROTECT trial,we take advantage of each of these strengths.The major disadvantage of conducting an economicanalysis concurrently with a randomized clinical trial isthat a randomized clinical trial may not represent thesame effects and costs as routine clinical practice. How-ever, both the PROTECT and E-PROTECT trials addressthis limitation in that we will expose estimates generatedfrom the PROTECT trial to adjustments in medical andsurgical case-mix and severity of illness, intention-to-treatand on-treatment estimates, among others. Another po-tential disadvantage is that the primary outcome of thePROTECT trial was proximal leg DVT during ICU admis-sion, confirmed by ultrasound, but which in critically illpatients is usually asymptomatic. However, the other ven-ous thrombosis outcomes of the DVT and PE arm werelargely clinically suspected and also objectively confirmed.There are other aspects of the E-PROTECT trial meth-odology that deserve consideration. Firstly, our primaryperspective is from the acute healthcare system (notsocietal) and our primary time horizon is in-hospital, notlifetime. This is because patients in the ICU receivingthromboprophylaxis do not receive it beyond their hos-pital stay; the intervention is focused on the reduction ofin-hospital VTE events and thus the E-PROTECT trial isfocused upon in-hospital costs. However, we will estimatepost-discharge events and costs using our previously de-veloped models, should the primary analyses indicate thisto be informative [5].Secondly, the primary outcome of E-PROTECT is theincremental cost to avoid a VTE event, not the incrementalcost per life-year gained. This is because the PROTECTtrial is not designed to estimate differences in survival, norpowered to detect differences in life expectancy; thus, itwould be inappropriate to make this a primary outcomefor E-PROTECT. However, if there were differences in lifeexpectancy during the PROTECT trial we would addressthis as a tertiary outcome. Whereas there are broadly dis-cussed thresholds of willingness-to-pay for a year ofquality-adjusted life, there are no clear cost thresholdsfor VTE event avoidance. To address this, in our system-atic review of economic evaluations in the VTE litera-ture, we have summarized the ranges of incrementalFowler et al. Trials 2014, 15:502 Page 9 of 11http://www.trialsjournal.com/content/15/1/502costs associated with various pharmacoprevention strat-egies. However, if E-PROTECT determines an incrementalcost of LMWH over UFH, we will perform a specificfollow-up study for E-PROTECT that will seek to establishsuch a threshold among patients, physicians, pharmacistsand policy makers.Thirdly, we capture both direct and indirect costs inE-PROTECT by seeking acute healthcare system line-item costs as opposed to line-item costs of each patientenrolled in the PROTECT trial. This stems from our pilotstudy demonstrating widely variable institution practicesin reporting patient-specific cost accounting. We willderive valid direct and indirect costs of care, and avoiddouble counting among individual resources used andinstitution specific rolled-up patient and overhead costs.Fourthly, we have chosen to gather costs from acutehealthcare systems in many countries participating inthe PROTECT trial. Although this has the potential tointroduce variability in cost estimates, we believe thiswill help our findings be generalizable to more than onesystem. We will use international currency conversioninstead of PPP conversions, because health-specific PPPsare not available for Saudi Arabia, and non-health PPPconversion rates vary substantially over the period of theanalysis [23]. We will report our findings in a commoncurrency, using appropriate currency conversion tech-niques, and adjusted for country specific inflation anddeflation from the date of data acquisition to finalreporting.Finally, over the course of a five-year clinical trial it ispossible that new data will have emerged to make theprimary trial question less relevant, or that costs for keyvariables will have changed. In one recent study, 8,307patients were randomly assigned to receive enoxaparinplus elastic stockings with graduated compression, orplacebo plus elastic stockings with graduated compres-sion [39]. Among all patients, there were similar 30-daymortality and major bleeding rates. Although important,there was no ability in the trial to detect actual VTE,which itself can have important clinical and economicimpact aside from death. Also, although LMWH has his-torically had a higher drug acquisition cost than UFH,since the initiation of the PROTECT trial, the drugacquisition cost for LMWHs has diminished and UFHhas increased [40]. This will be an important consider-ation for E-PROTECT in order to make the resultscontemporary and relevant.In summary, administration of heparins is a commonlyused strategy for VTE prevention. The PROTECT trialis important in determining the balance of effects, sideeffects and complications associated with LMWH andUFH thromboprophylaxis in medical-surgical ICU patients.The PROTECT trial leaves unanswered what consequenceLWMH or UFH use has on the costs of care of patientswith critical illness. E-PROTECT will complement thePROTECT trial with a pre-specified prospective compre-hensive economic evaluation. Components of this studyplan could be considered for other economic evaluations incritical care.Trial statusThe PROTECT trial ClinicalTrials.gov number is NCT00182143. At the time of submission, the costing deter-mination of E-PROTECT has not yet been completedand subsequent costs and analyses other than thosereported here may be considered and reported, withjustification.Additional fileAdditional file 1: E-PROTECT: The economic evaluation of thePROTECT (Prophylaxis for ThromboEmbolism in Critical Care Trial)Study.AbbreviationsASA: Acetyl salicylic acid; CT: Computerized tomography; DVT: Deep veinthrombosis; ELISA: Enzyme-linked immunosorbent assay; HIT: Heparin-inducedthrombocytopenia; HITT: Heparin induced thrombocytopenia with thrombosis;ICU: Intensive care unit; IU: International units; LWMH: Low molecular weightheparin; PE: Pulmonary embolism; PROTECT: Prophylaxis for ThromboEmbolism inCritical Care Trial; UFH: Unfractionated heparin; VTE: Venous thromboembolism.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsConception and design: RF, NM, DC, WHG, MG, GG, MK. Data collection: RF, NM,DC, MG, SF, BC, OO, YA, IQ, MR, PD, LLM, RH, NF, SM, JCM, CD, JM, MJ, JK, NV,NO, IS, YS, JFC, JC. Analysis and interpretation: RF, NM, DHA, DC, RP, WG, MG,GG, MK. Manuscript writing: RF, NM, DHA, DC, RP, WHG, MG, GG, MK. Criticalrevision and final approval of the manuscript: RF, NM, DHA, DC, RP, WHG, MG,GG, MK, SF, BC, OO, YA, IQ, MR, PD, LLM, RH, NF, SM, JCM, CD, JM, MJ, JK, NV,NO, IS, YS, SS, JFC, JC. Obtained funding: RF, DC. Administrative, technical ormaterial support: RF, DC. Study supervision: RF, NM, DC, WG, MG, GG, MK. Allauthors read and approved the final manuscript.AcknowledgementsThis economic evaluation is funded by the Heart and Stroke Foundation(Ontario), the University of Toronto and the Canadian Intensive CareFoundation. RF received support from the Ontario Ministry of Health andLong-term Care and is a Clinician Scientist of the Heart and Stroke Foundation(Ontario, Canada). DC is a Canada Research Chair of the Canadian Institutes ofHealth Research. The funding agencies had no role in the design and conductof the study, the collection, analysis and interpretation of the data, or in thepreparation, review or approval of the manuscript.No funding for the economic evaluation was received from the manufacturersof any agent involved in VTE prevention or treatment and none of the fundersplay a role in the generation, analysis or decision to submit the manuscripts forpublication. The PROTECT trial was funded by the Canadian Institutes for HealthResearch and the Australian and New Zealand College of Anesthetists ResearchFoundation and the Heart and Stroke Foundation of Canada.(Individuals)Canada: Nicole Marinoff, John Iazzetta, Brian Chan, Bill Bartle, Dawn Dawkins,Jeannie Callum, Meredith Malloy, Margaret Herridge, Cathy Tansey, AngelaCheung, Lori Anne Rayburn, Cheryl Ethier, John Granton, Orla Smith, JanFriedrich, Diane Heels-Ansdell, Nicole Zytaruk, Ellen McDonald, MarkCrowther, Roy Ilan, Colleen Knapp, Mae Squires, Lisa Julien, Caroline Roy,Irene Watpool, Claude Gaudert, Johanne Harvey, Martine LeBlanc, Nicole5. Sud S, Mittmann N, Cook DJ, Geerts W, Chan B, Dodek P, Gould MK, Guyatt G,Fowler et al. Trials 2014, 15:502 Page 10 of 11http://www.trialsjournal.com/content/15/1/502Godfrey, Aslam Anis, Denise Foster, Betty-Jean Ashley, Sheilagh Mans, LindaKnox, Deidre Hennessey, Stafford Dean, Andrea Matte, Leeca Sonnema,Elizabeth Seib, Mary Lou McKenzie, Sharlene Hammond, Elizabeth Mann.Australia Julie Potter, Lynette Murray, Deborah Barge, Patzy Low, LeoneWeisbrodt, Chris Wright, Tania Elderkin, Anne Kinmonth, Melissa Fraser.United States: Todd Wagner, Laurie Meade, Barbara Smithson, Laura Roberts.Saudi Arabia: Jean Brennick, Mohammad Alsultan. Brazil: Aline Ghiot.(Participating Centres)Canada: Queen Elizabeth II Hospital (Halifax); Hôpital Maisonneuve-Rosemont(Montréal); Ottawa Hospital (Ottawa); Kingston General Hospital (Kingston);Mount Sinai Hospital, University Health Network, St Michael’s Hospital,Sunnybrook Health Sciences Centre (Toronto); St Joseph’s Hospital(Hamilton); Foothills Hospital (Calgary); University of Alberta Hospital(Edmonton); St Paul’s Hospital (Vancouver). Australia: Royal North ShoreHospital (Sydney); Barwon Health (Geelong); Nepean Hospital (Penrith); RoyalMelbourne Hospital, The Alfred Centre (Melbourne). United States: StanfordUniversity (Palo Alto); Rhode Island Hospital (Providence); Mayo Clinic(Rochester). Saudi Arabia: King Saud Bin Abdulaziz University for HealthSciences (Riyadh); King Faisal Specialist Hospital & Research Centre (Jeddah).Brazil: Hospitalar Santa Casa (Porto Alegre).Author details1Sunnybrook Health Sciences Centre, University of Toronto, 2075 BayviewAvenue, Room D478, Toronto, ON M4N 3M5, Canada. 2Health Outcomes andPharmacoEconomic (HOPE) Research Centre, Sunnybrook Health SciencesCentre, Department of Pharmacology, University of Toronto, 2075 BayviewAvenue, E240, Toronto, ON M4N 3M5, Canada. 3Department of Medicine,Room D674, Sunnybrook Health Sciences Centre, Room D674, 2075 BayviewAvenue, Toronto, ON M4N 3M5, Canada. 4Department of ClinicalEpidemiology & Biostatistics, McMaster University, Faculty of Health Sciences,1280 Main Street West, HSC-2C12, Hamilton, ON L8S 4K1, Canada.5Department of Research and Evaluation, Kaiser Permanente SouthernCalifornia, 100 S Los Robles, Pasadena, CA 91101, USA. 6Department ofMedicine, 144 College Street, Room 600, Toronto, ON M5S 3M2, Canada.7The George Institute for Global Health, Royal North Shore Hospital,University of Sydney, Pacific Highway, St Leonards, NSW 2065, Australia.8Institute of Health Policy, Management and Evaluation University of TorontoHealth Sciences Building, 155 College Street, Suite 425, Toronto, ON M5T3M6, Canada. 9Toronto Health Economics and Technology Assessment(THETA) Collaborative, Leslie Dan Pharmacy Building, University of Toronto,144 College Street, 6th Floor, Toronto, ON M5S 3M2, Canada. 10IntensiveCare Department, Medical Director, Respiratory Services, King Saud BinAbdulaziz University for Health Sciences, King Abdulaziz Medical City, ICU1425 PO Box 22490, Riyadh 11426, Kingdom of Saudi Arabia. 11Departmentof Medicine, King Faisal Specialist Hospital & Research Centre-Gen. Org, POBox 40047, Jeddah 21499 MBC# J-46, Saudi Arabia. 12Department of IntensiveCare, Hospitalar Santa Casa, Rua Professor Annes Dias, 295 - Centro Histórico,Porto Alegre, RS 90020-200, Brazil. 13Division of Critical Care Medicine, Centerfor Health Evaluation and Outcome Sciences, St Paul’s Hospital andUniversity of British Columbia, 1081 Burrard St, Vancouver, BC V6Z 1Y6,Canada. 14Center for Health Evaluation and Outcome Sciences, 1081 BurrardStreet, Vancouver, BC V6Z 1Y6, Canada. 15Department of Medicine (CriticalCare), Ottawa Hospital, Ottawa Hospital Research Institute, Centre forTransfusion and Critical Care Research, 725 Parkdale Ave, Ottawa, ON K1Y4E9, Canada. 16Departments of Anesthesiology, Medicine, Pharmacology andSurgery, Dalhousie University and the Capital District Health Authority, HalifaxNS, Room 5452-Halifax Infirmary, 1796 Summer St, Halifax NSB3H 3A7,Canada. 17Interdepartmental Division of Critical Care Medicine andDepartments of Medicine & Physiology, University of Toronto, 600 UniversityAvenue, Toronto, ON M5G 1X5, Canada. 18Department of Medicine, Divisionof Respirology, University Health Network and Mount Sinai Hospital, 600University Avenue, Toronto, ON M5G 1X5, Canada. 19Department of Medicineand Interdepartmental Division of Critical Care, Mount Sinai Hospital andUniversity of Toronto, 600 University Avenue, Toronto, ON M5G 1X5, Canada.20Department of Surgery, University of Toronto, Keenan Research Centre, LiKa Shing Knowledge Institute, St Michael’s Hospital, 4-007 Bond Wing, StMichael’s Hospital, 30 Bond Street, Toronto M5B 1W8, Canada. 21Departmentof Community Health Sciences, Departments of Critical Care Medicine,University of Calgary, Attending Physician, Foothills Medical CentreMultisystem Intensive Care Unit, Alberta Health Services, Room 3D39,Arabi Y, Fowler RA, On behalf of the E-PROTECT investigators and the Canadiancritical care trials group: Screening and prevention of venousthromboembolism in critically ill patients: a decision analysis andeconomic evaluation. Am J Respir Crit Care Med 2011, 184:1289–1298.6. Thirugnanum S, Pinto R, Cook DJ, Geerts WH Fowler RA: Economicanalyses of venous thromboembolism prevention strategies inhospitalized patients: a systematic review. Crit Care 2012, 16(R43):1–19.7. Cook D, Meade M, Guyatt G, Walter S, Heels-Ansdell D, Warkentin TE,Zytaruk N, Crowther M, Geerts W, Cooper DJ, Vallance S, Qushmaq I, RochaM, Berwanger O, Vlahakis NE, the PROTECT Investigators for the CanadianCritical Care Trials Group and the Australian and New Zealand IntensiveCare Society Clinical Trials Group: Dalteparin versus unfractionated heparinin critically ill patients. N Engl J Med 2011, 364:1305–1314.8. Cook DJ, Rocker G, Meade M, Guyatt G, Geerts W, Anderson D, Skrobik Y,Hebert P, Albert M, Cooper J, Bates S, Caco C, Finfer S, Fowler R, Freitag A,Granton J, Jones G, Langevin S, Mehta S, Pagliarello G, Poirier G, Rabbat C,Schiff D, Griffith L, Crowther M, PROTECT Investigators; Canadian CriticalCare Trials Group: Prophylaxis of thromboembolism in critical care(PROTECT) trial: a pilot study. J Crit Care 2005, 20:364–372.9. Fowler R, Pinto R, Sud R, Chan B, Mittmann N, Geerts W, Murray L, Cooper J,Wagner T, Gould M, Hennessy D, Dean S, Doig C, Anis A, Dodek P, Guyatt G,Zytaruk N, Cook D: Variability of direct medical costs among centres andcountries in the prospective economic evaluation of the prophylaxis forthromboembolism in critical care trials [abstract]. Crit Care Med 2007,35:A158.10. American Thoracic Society (ATS): Understanding costs and cost-effectivenessin critical care. Am J Resp Crit Care Med 2002, 165:540–550.Teaching Research and Wellness Building, 3280 Hospital Dr NW, Calgary, ABT2N 4Z6, Canada. 22Department of Medicine, Angada 4 Kingston GeneralHospital, 76 Stuart Street, Kingston, ON K7L 2V7, Canada. 23Department ofAnesthesiology and Critical Care, University of Alberta Hospital, 8440-112 St,Edmonton, AB T6G 2B7, Canada. 24Division of Pulmonary, Sleep and CriticalCare Medicine, Rhode Island Hospital, Professor of Medicine, Alpert MedicalSchool of Brown University, 222 Richmond Street, Providence, RI 02903, USA.25Department of Pulmonary & Critical Care Medicine, Mayo Clinic, 200 FirstStreet, SW, Rochester, MN 55905, USA. 26Intensive Care Barwon Health,Australian and New Zealand Intensive Care Research Centre, MonashUniversity School of Medicine, 99 Commercial Road, Geelong, VIC 3004,Australia. 27Intensive Care Barwon Health, Australian and New ZealandIntensive Care Research Centre, Deakin University, 1 Gheringhap Street,Geelong, VIC 3220, Australia. 28Critical Care Medicine, Nepean Hospital, DerbyStreet, Penrith, NSW 2747, Australia. 29Critical Care Medicine, HôpitalMaisonneuve-Rosemont, 5415 Blvd. De l’Assomption, Montreal, QC H1T 2M4,Canada. 30Department of Medicine, University Trillium Hospital, 100Queensway West, Toronto, ON L5B 1B8, Canada. 31Intensive Care Unit, RoyalMelbourne Hospital, Grattan Street, Parkville, VIC 3050, Australia. 32ANZIC-RCDepartment of Epidemiology and Preventive Medicine Monash University,The Alfred Centre Level 6, 99 Commercial Road, Melbourne, VIC 3004,Australia. 33Departments of Medicine, Clinical Epidemiology & Biostatistics,McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada.Received: 14 January 2014 Accepted: 25 November 2014Published: 20 December 2014References1. 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