Competing Risk Analysis for Evaluation of Dalteparin Versus Unfractionated Heparin for Venous Thromboembolism in Medical-Surgical Critically Ill Patients

Guowei Li, Deborah J Cook, Mitchell A H Levine, Gordon Guyatt, Mark Crowther, Diane Heels-Ansdell, Anne Holbrook, Francois Lamontagne, Stephen D Walter, Niall D Ferguson, Simon Finfer, Yaseen M Arabi, Rinaldo Bellomo, D Jamie Cooper, Lehana Thabane, PROTECT Investigators for the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Guowei Li, Deborah J Cook, Mitchell A H Levine, Gordon Guyatt, Mark Crowther, Diane Heels-Ansdell, Anne Holbrook, Francois Lamontagne, Stephen D Walter, Niall D Ferguson, Simon Finfer, Yaseen M Arabi, Rinaldo Bellomo, D Jamie Cooper, Lehana Thabane, PROTECT Investigators for the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group

Abstract

Failure to recognize the presence of competing risk or to account for it may result in misleading conclusions. We aimed to perform a competing risk analysis to assess the efficacy of the low molecular weight heparin dalteparin versus unfractionated heparin (UFH) in venous thromboembolism (VTE) in medical-surgical critically ill patients, taking death as a competing risk.This was a secondary analysis of a prospective randomized study of the Prophylaxis for Thromboembolism in Critical Care Trial (PROTECT) database. A total of 3746 medical-surgical critically ill patients from 67 intensive care units (ICUs) in 6 countries receiving either subcutaneous UFH 5000 IU twice daily (n = 1873) or dalteparin 5000 IU once daily plus once-daily placebo (n = 1873) were included for analysis.A total of 205 incident proximal leg deep vein thromboses (PLDVT) were reported during follow-up, among which 96 were in the dalteparin group and 109 were in the UFH group. No significant treatment effect of dalteparin on PLDVT compared with UFH was observed in either the competing risk analysis or standard survival analysis (also known as cause-specific analysis) using multivariable models adjusted for APACHE II score, history of VTE, need for vasopressors, and end-stage renal disease: sub-hazard ratio (SHR) = 0.92, 95% confidence interval (CI): 0.70-1.21, P-value = 0.56 for the competing risk analysis; hazard ratio (HR) = 0.92, 95% CI: 0.68-1.23, P-value = 0.57 for cause-specific analysis. Dalteparin was associated with a significant reduction in risk of pulmonary embolism (PE): SHR = 0.54, 95% CI: 0.31-0.94, P-value = 0.02 for the competing risk analysis; HR = 0.51, 95% CI: 0.30-0.88, P-value = 0.01 for the cause-specific analysis. Two additional sensitivity analyses using the treatment variable as a time-dependent covariate and using as-treated and per-protocol approaches demonstrated similar findings.This competing risk analysis yields no significant treatment effect on PLDVT but a superior effect of dalteparin on PE compared with UFH in medical-surgical critically ill patients. The findings from the competing risk method are in accordance with results from the cause-specific analysis.clinicaltrials.gov Identifier: NCT00182143.

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1
Cumulative incidence curves of PLDVT in dalteparin and UFH group. PLDVT = proximal leg deep vein thrombosis, UFH = unfractionated heparin.
FIGURE 2
FIGURE 2
Cumulative incidence curves of death in dalteparin and unfractionated heparin (UFH) group using the Kaplan–Meier method.

References

    1. Gooley TA, Leisenring W, Crowley J, et al. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18:695–706.
    1. Putter H, Fiocco M, Geskus R. Tutorial in biostatistics: competing risks and multi-state models. Stat Med 2007; 26:2389–2430.
    1. Pintilie M. An introduction to competing risks analysis. Revista Española de Cardiología (English Edition) 2011; 64:599–605.
    1. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:381S–453S.
    1. Cook D, Crowther M, Meade M, et al. Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 2005; 33:1565–1571.
    1. Geerts W, Selby R. Prevention of venous thromboembolism in the ICU. Chest J 2003; 124:357S–363S.
    1. Alhazzani W, Lim W, Jaeschke RZ, et al. Heparin thromboprophylaxis in medical-surgical critically ill patients: A Systematic Review and Meta-Analysis of Randomized Trials∗. Crit Care Med 2013; 41:2088–2098.
    1. Cook D, Meade M, Guyatt G, et al. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 2011; 364:1305–1314.
    1. Forsblom C, Harjutsalo V, Thorn LM, et al. Competing-risk analysis of ESRD and death among patients with type 1 diabetes and macroalbuminuria. J Am Soc Nephrol 2011; 22:537–544.
    1. Berry SD, Ngo L, Samelson EJ, et al. Competing risk of death: an important consideration in studies of older adults. J Am Geriatr Soc 2010; 58:783–787.
    1. Resche-Rigon M, Azoulay E, Chevret S. Evaluating mortality in intensive care units: contribution of competing risks analyses. Crit Care 2005; 10:R5.
    1. Cook D, Meade M, Guyatt G, et al. PROphylaxis for ThromboEmbolism in Critical Care Trial protocol and analysis plan. J Crit Care 2011; 26:223.e221-223.e229.
    1. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94:496–509.
    1. Bakoyannis G, Touloumi G. Practical methods for competing risks data: a review. Stat Methods Med Res 2012; 21:257–272.
    1. Thabane L, Mbuagbaw L, Zhang S, et al. A tutorial on sensitivity analyses in clinical trials: the what, why, when and how. BMC Med Res Methodol 2013; 13:92.
    1. Kleinbaum DG, Klein M. Survival Analysis – A Self-Learing Text. 3rd ed. Springer Science and Business Media, LLC, New York, NY, USA: Springer; 2012.
    1. Pepe MS, Mori M. Kaplan–Meier, marginal or conditional probability curves in summarizing competing risks failure time data? Stat Med 1993; 12:737–751.
    1. Cook D, Crowther M, Meade M, et al. Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 2005; 33:1565–1571.
    1. Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994; 81:515–526.
    1. Fisher LD, Lin DY. Time-dependent covariates in the Cox proportional-hazards regression model. Ann Rev Public Health 1999; 20:145–157.
    1. Lamontagne F, McIntyre L, Dodek P, et al. Nonleg venous thrombosis in critically ill adults: a nested prospective cohort study. JAMA Inter Med 2014; 174:689–696.
    1. Satagopan J, Ben-Porat L, Berwick M, et al. A note on competing risks in survival data analysis. Br J Cancer 2004; 91:1229–1235.
    1. Ay C, Posch F, Kaider A, et al. Estimating risk of venous thromboembolism in patients with cancer in the presence of competing mortality. J Thromb Haemost 2015; 13:390–397.
    1. Melberg T, Nygård OK, Kuiper KK-J, et al. Competing risk analysis of events 10 years after revascularization. Scand Cardiovasc J 2010; 44:279–288.
    1. Hsieh KP, Chen LC, Cheung KL, et al. A competing risk analysis of hormone therapy interruption in Asian women with breast cancer. Pharmacoepidemiol Drug Saf 2015; 24:301–309.
    1. Koller MT, Raatz H, Steyerberg EW, et al. Competing risks and the clinical community: irrelevance or ignorance? Stat Med 2012; 31:1089–1097.
    1. Andersen PK, Geskus RB, de Witte T, et al. Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol 2012; 41:861–870.
    1. Berry SD, Ngo L, Samelson EJ, et al. Competing risk of death: an important consideration in studies of older adults. J Am Geriatr Soc 2010; 58:783–787.
    1. Shorr AF, Williams MD. Venous thromboembolism in critically ill patients. Observations from a randomized trial in sepsis. Thromb haemost 2009; 101:139–144.
    1. De A, Roy P, Garg VK, et al. Low-molecular-weight heparin and unfractionated heparin in prophylaxis against deep vein thrombosis in critically ill patients undergoing major surgery. Blood Coagul Fibrinolysis 2010; 21:57–61.
    1. Goldhaber SZ, Kett DH, Cusumano CJ CAK. Low molecular weight heparin versus minidose unfractionated heparin for prophylaxis against venous thromboembolism in medical intensive care unit patients: a randomized controlled trial (Abstract). J Am Coll Cardiol 2000; 35 Suppl:325A.
    1. Parpia S, Julian J, Thabane L, et al. Competing events in patients with malignant disease who are at risk for recurrent venous thromboembolism. Contemp Clin Trials 2011; 32:829–833.

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