Economic evaluation of the prophylaxis for thromboembolism in critical care trial (E-PROTECT): study protocol for a randomized controlled trial

Robert A Fowler, Nicole Mittmann, William H Geerts, Diane Heels-Ansdell, Michael K Gould, Gordon Guyatt, Murray Krahn, Simon Finfer, Ruxandra Pinto, Brian Chan, Orges Ormanidhi, Yaseen Arabi, Ismael Qushmaq, Marcelo G Rocha, Peter Dodek, Lauralyn McIntyre, Richard Hall, Niall D Ferguson, Sangeeta Mehta, John C Marshall, Christopher James Doig, John Muscedere, Michael J Jacka, James R Klinger, Nicholas Vlahakis, Neil Orford, Ian Seppelt, Yoanna K Skrobik, Sachin Sud, John F Cade, Jamie Cooper, Deborah Cook, Canadian Critical Care Trials Group, Australia and New Zealand Intensive Care Society Clinical Trials Group, Robert A Fowler, Nicole Mittmann, William H Geerts, Diane Heels-Ansdell, Michael K Gould, Gordon Guyatt, Murray Krahn, Simon Finfer, Ruxandra Pinto, Brian Chan, Orges Ormanidhi, Yaseen Arabi, Ismael Qushmaq, Marcelo G Rocha, Peter Dodek, Lauralyn McIntyre, Richard Hall, Niall D Ferguson, Sangeeta Mehta, John C Marshall, Christopher James Doig, John Muscedere, Michael J Jacka, James R Klinger, Nicholas Vlahakis, Neil Orford, Ian Seppelt, Yoanna K Skrobik, Sachin Sud, John F Cade, Jamie Cooper, Deborah Cook, Canadian Critical Care Trials Group, Australia and New Zealand Intensive Care Society Clinical Trials Group

Abstract

Background: Venous thromboembolism (VTE) is a common complication of critical illness with important clinical consequences. 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 in the 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. We derive baseline characteristics and probabilities of in-ICU and in-hospital events from all enrolled patients. Total costs are derived from centers, proportional to the numbers of patients enrolled in each country. Direct costs include medication, physician and other personnel costs, diagnostic radiology and laboratory testing, operative and non-operative procedures, costs associated with bleeding, transfusions and treatment-related complications. Indirect costs include ICU and hospital ward overhead costs. Outcomes are the ratio of incremental costs per incremental effects of LMWH versus UFH during hospitalization; incremental cost to prevent a thrombosis at any site (primary outcome); incremental cost to prevent a pulmonary embolism, deep vein thrombosis, major bleeding event or episode of heparin-induced thrombocytopenia (secondary outcomes) and incremental cost per life-year gained (tertiary outcome). Pre-specified subgroups and sensitivity analyses will be performed and confidence intervals for the estimates of incremental cost-effectiveness will be obtained using bootstrapping.

Discussion: This economic evaluation employs a prospective costing methodology concurrent with a randomized controlled blinded clinical trial, with a pre-specified analytic plan, outcome measures, subgroup and sensitivity analyses. This economic evaluation has received only peer-reviewed funding and funders will not play a role in the generation, analysis or decision to submit the manuscripts for publication.

Trial registration: Clinicaltrials.gov Identifier: NCT00182143 . Date of registration: 10 September 2005.

Figures

Figure 1
Figure 1
Markov model for long-term outcomes and costs of critically ill patients in E-PROTECT. See Sud et al. [5]. ICU = intensive care unit; LMWH = low molecular weight heparin; LTC = long-term care; M = Markov node; UFH = unfractionated heparin; VTE = venous thromboembolism.

References

    1. Attia J, Ray JG, Cook DJ, Douketis J, Ginsberg JS, Geerts W. Deep vein thrombosis and its prevention in critically ill patients. Arch Intern Med. 2001;161:1268–1279. doi: 10.1001/archinte.161.10.1268.
    1. Geerts W, Selby R. Prevention of venous thromboembolism in the ICU. Chest. 2004;124:357S–363S. doi: 10.1378/chest.124.6_suppl.357S.
    1. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A Contr Trial Lancet. 1960;i:1309–1312.
    1. Crowther MA, Cook DJ, Griffith LE, Devereaux PJ, Rabbat CC, Clarke FJ, Hoad McDonald E, Meade MO, Guyatt GH, Geerts WH, Wells PS. Deep venous thrombosis: clinically silent in the intensive care unit. J Crit Care. 2005;20:334–340. doi: 10.1016/j.jcrc.2005.09.011.
    1. Sud S, Mittmann N, Cook DJ, Geerts W, Chan B, Dodek P, Gould MK, Guyatt G, Arabi Y, Fowler RA, On behalf of the E-PROTECT investigators and the Canadian critical care trials group Screening and prevention of venous thromboembolism in critically ill patients: a decision analysis and economic evaluation. Am J Respir Crit Care Med. 2011;184:1289–1298. doi: 10.1164/rccm.201106-1059OC.
    1. Thirugnanum S, Pinto R, Cook DJ, Geerts WH Fowler RA Economic analyses of venous thromboembolism prevention strategies in hospitalized patients: a systematic review. Crit Care. 2012;16(R43):1–19.
    1. 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, Rocha M, Berwanger O, Vlahakis NE, the PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011;364:1305–1314. doi: 10.1056/NEJMoa1014475.
    1. 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 Critical Care Trials Group Prophylaxis of thromboembolism in critical care (PROTECT) trial: a pilot study. J Crit Care. 2005;20:364–372. doi: 10.1016/j.jcrc.2005.09.010.
    1. 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 and countries in the prospective economic evaluation of the prophylaxis for thromboembolism in critical care trials [abstract] Crit Care Med. 2007;35:A158.
    1. American Thoracic Society (ATS) Understanding costs and cost-effectiveness in critical care. Am J Resp Crit Care Med. 2002;165:540–550. doi: 10.1164/ajrccm.165.4.16541.
    1. Canadian Agency for Drugs and Technologies in Health (CADTH) Guidelines for the economic evaluation of health technologies: Canada. 3. Ottawa: CADTH; 2006.
    1. Russell LB, Gold MR, Siegel JE, Weinstein MC. The role of cost-effectiveness analysis in health and medicine. JAMA. 1996;276:1172–1177. doi: 10.1001/jama.1996.03540140060028.
    1. Weinstein MC, Siefel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. JAMA. 1996;276:1253–1258. doi: 10.1001/jama.1996.03540150055031.
    1. Siegel JE, Weinstein MC, Russell LB, Gold MR. Recommendations for reporting cost-effectiveness analyses. JAMA. 1996;276:1339–1341. doi: 10.1001/jama.1996.03540160061034.
    1. Drummond MF, Sculpher MJ, Torrance GW. Methods for the Economic Evaluation of Health Care Programmes. Oxford: Oxford University Press; 2005. Cost Analysis; pp. 55–102.
    1. Kahn J, Rubenfeld GD, Rohrbach J, Fuchs BD. Cost savings attributable to reductions in intensive care unit length of stay for mechanically ventilated patients. Med Care. 2008;46:1226–1233. doi: 10.1097/MLR.0b013e31817d9342.
    1. Nanwa N, Mittmann N, Knowles S, Bucci C, Selby R, Shear NH, Walker SE, Geerts W. The direct medical costs associated with suspected heparin-induced thrombocytopenia. Pharmacoeconomics. 2011;29:511–520. doi: 10.2165/11584330-000000000-00000.
    1. Blood Information Resource Centre for Patients and Healthcare Professionals
    1. Rapoport J, Teres D, Lemeshow S, Avrunin JS, Haber R. Explaining variability of cost using a severity-of-illness measure for ICU patients. Med Care. 1990;28:338–348. doi: 10.1097/00005650-199004000-00005.
    1. Rapoport J, Teres D, Zhao Y, Lemeshow S. Length of stay data as a guide to hospital economic performance for ICU patients. Med Care. 2003;41:386–397.
    1. Dasta JF, McLaughlin TP, Mody SH, Piech CT. Daily cost of an intensive care unit day: the contribution of mechanical ventilation. Crit Care Med. 2005;33:1266–1271. doi: 10.1097/01.CCM.0000164543.14619.00.
    1. Bank of Canada. 10-year currency converter
    1. The World Bank Official Exchange Rate
    1. RatesFx
    1. Ng R, Hasan B, Mittmann N, Florescu M, Shepherd FA, Ding K, Butts CA, Cormier Y, Darling G, Goss GD, Inculet R, Seymour L, Winton TL, Evans WK, Leighl NB, Working Group on Economic Analysis; Lung Disease Site Group; National Cancer Institute of Canada Clinical Trials Group An economic analysis of National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) JBR.10, a randomized trial of adjuvant vinorelbine plus cisplatin versus observation in early stage non-small cell lung cancer (NSCLC) J Clin Oncol. 2007;25:2256–2261. doi: 10.1200/JCO.2006.09.4342.
    1. Fieller C. Some problems in interval estimation. J R Stat Soc Series B (Methodological) 1954;16:175–183.
    1. Doubilet P, Begg CB, Weinstein MC, Braun P, McNeil BJ. Probabilistic sensitivity analysis using Monte Carlo simulation. Med Decis Making. 1985;5:157–177. doi: 10.1177/0272989X8500500205.
    1. Cuthbertson BH, Roughton S, Jenkinson D, Maclennan G, Vale L. Quality of life in the five years after intensive care: a cohort study. Crit Care. 2010;14:R6. doi: 10.1186/cc8848.
    1. Williams TA, Dobb GJ, Finn JC, Knuiman MW, Geelhoed E, Lee KY, Webb SA. Determinants of long-term survival after intensive care. Crit Care Med. 2008;36:1523–1530. doi: 10.1097/CCM.0b013e318170a405.
    1. Angus DC, Musthafa AA, Clermont G, Griffin MF, Linde-Zwirble WT, Dremsizov TT, Pinsky MR. Quality-adjusted survival in the first year after the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;163:1389–1394. doi: 10.1164/ajrccm.163.6.2005123.
    1. Hung MC, Yan YH, Fan PS, Lin MS, Chen CR, Kuo LC, Yu CJ, Yao G, Hsieh CL, Wang JD. Measurement of quality of life using EQ-5D in patients on prolonged mechanical ventilation: comparison of patients, family caregivers, and nurses. Qual Life Res. 2010;19:721–727. doi: 10.1007/s11136-010-9629-1.
    1. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304:1787–1794. doi: 10.1001/jama.2010.1553.
    1. Quartin AA, Schein RM, Kett DH, Peduzzi PN. Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. JAMA. 1997;277:1058–1063. doi: 10.1001/jama.1997.03540370048035.
    1. Torrance G. Measurement of health state utilities for economic appraisal: a review. J Health Econ. 1986;5:1–30. doi: 10.1016/0167-6296(86)90020-2.
    1. Fryback DG, Dasbach EJ, Klein R, Klein BEK, Dorn N, Peterson K, Martin PA. The beaver dam health outcomes study: initial catalog of health-state quality factors. Med Decis Making. 1993;13:89–102. doi: 10.1177/0272989X9301300202.
    1. Tengs TO, Wallace A. One thousand health-related quality-of-life estimates. Med Care. 2000;38:583–637. doi: 10.1097/00005650-200006000-00004.
    1. Rubin DB. Multiple Imputation for Nonresponse Surveys. New York: John Wiley & Sons; 1987.
    1. Rubin DB, Schenker N. Multiple imputation in health-care databases: an overview and some applications. Stat Med. 1991;10:585–598. doi: 10.1002/sim.4780100410.
    1. Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann J-F, for the LIFENOX Investigators Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011;365:2463–2472. doi: 10.1056/NEJMoa1111288.
    1. Thomson-Reuters . Red Book: Pharmacy’s Fundamental Reference. Montvale: Thomson Medical Economics; 2013.

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