Abstract
Purpose
To compare benefits and harms of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) as thromboprophylaxis in intensive care unit (ICU) patients.
Methods
We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomised controlled trials (RCTs) comparing LMWH with UFH as thromboprophylaxis in adult ICU patients. We searched Ovid Medline, PubMed, Embase, Cochrane Library, UpToDate, Guidelines International Network, PROSPERO and the metaRegister of Controlled Trials through 3 December 2014. Random effects risk ratios (RR) and 95 % confidence intervals (CI) were derived for the endpoints deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, mortality and net clinical benefit (any DVT, any PE, major bleeding and/or mortality).
Results
Eight RCTs (5567 patients) were included, whereof two were considered to have overall low risk of bias. Pooled analyses showed that LMWH compared with UFH reduced the risk of any DVT (RR 0.84, 95 % CI 0.71–0.98, p = 0.03) and resulted in a net clinical benefit (RR 0.90, 95 % CI 0.83–0.97, p = 0.01). There was no statistically significant difference in the risk of any PE (RR 0.65, 95 % CI 0.41–1.03, p = 0.06), major bleeding (RR 0.99, 95 % CI 0.77–1.28, p = 0.96) or mortality (RR 0.93, 95 % CI 0.78–1.12, p = 0.43). TSA supported the results of the conventional analysis on the outcome net clinical benefit but not on risk of any DVT.
Conclusions
Evidence from this systematic review revealed a beneficial effect of LMWH compared with UFH when used as thromboprophylaxis in ICU patients.
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References
Cook D, Crowther M, Meade M et al (2005) Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 33:1565–1571
Geerts WH, Pineo GF, Heit JA et al (2004) Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:338S–400S
Ribic C, Lim W, Cook D et al (2009) Low-molecular-weight heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review. J Crit Care 24:197–205
Geerts WH, Bergqvist D, Pineo GF et al (2008) Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 133:381S–453S
Guyatt GH, Akl EA, Crowther M et al (2012) Executive summary: antithrombotic therapy and prevention of thrombosis, American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(2 Suppl):7S–47S
Alhazzani W, Lim W, Jaeschke RZ et al (2013) Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis of randomized trials. Crit Care Med 41:2088–2098
Dentali F, Douketis JD, Gianni M et al (2007) Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 146:278–288
Mismetti P, Laporte S, Darmon JY et al (2001) Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br J Surg 88:913–930
Barrera LM, Perel P, Ker K et al (2013) Thromboprophylaxis for trauma patients. Cochrane Database Syst Rev 3:1–79
Kakkos SK, Caprini JA, Geroulakos G et al (2008) Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism in high-risk patients. Cochrane Database Syst Rev 4:1–37
Arnold DM, Donahoe L, Clarke FJ et al (2007) Bleeding during critical illness: a prospective cohort study using a new measurement tool. Clin Invest Med 30:E93–102
Briegel J, Mohnle P (2013) International guidelines of the Surviving Sepsis Campaign: update 2012. Anaesthesist 62:304–309
Higgins JP, Altman DG, Gotzsche PC et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188
Cohran WG (1954) The combination of estimates from different experiments. Biometrics 10:101–129
Higgins JP, Thompson SG, Deeks JJ et al (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560
Peduzzi P, Concato J, Kemper E et al (1996) A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 49:1373–1379
Egger M, Davey SG, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Sterne JA, Sutton AJ, Ioannidis JP et al (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343:d4002
Pogue JM, Yusuf S (1997) Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis. Control Clin Trials 18:580–593
Pogue J, Yusuf S (1998) Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet 351:47–52
Wetterslev J, Thorlund K, Brok J et al (2008) Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 61:64–75
Greenland S, Robins JM (1985) Estimation of a common effect parameter from sparse follow-up data. Biometrics 41:55–68
Copenhagen Trial Unit (2015) Trial sequential analysis. http://www.ctu.dk/tsa/. Accessed 24 Feb 2015
Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012
Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–34
Cohn SA, Moller BA, Feinstein AJ et al (1999) Prospective trial of low-molecular-weight heparin versus unfractionated heparin in moderately injured patients. Vasc Surg 33:219–223
Cook D, Meade M, Guyatt G et al (2011) Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 364:1305–1314
De A, Roy P, Garg VK et al (2010) Low-molecular-weight heparin and unfractionated heparin in prophylaxis against deep vein thrombosis in critically ill patients undergoing major surgery. Blood Coagul Fibrinolysis 21:57–61
Geerts WH, Jay RM, Code KI et al (1996) A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 335:701–707
Goldhaber S, Kett D, Cusumano CJ et al (2000) Low molecular weight heparin versus minidose unfractionated heparin for prophylaxis against venous thromboembolism in medical intensive care unit patients: a randomized controlled trial. J Am Coll Cardiol 35(Suppl):A325
Greenfield LJ, Proctor MC, Rodriguez JL et al (1997) Posttrauma thromboembolism prophylaxis. J Trauma 42:100–103
Roque T, Thompson J, Kuru T (2005) A clinical trial to compare thromboprophylaxis options in the medical ICU: challanges to treatment (conference abstract). Chest 128:296
Shorr AF, Williams MD (2009) Venous thromboembolism in critically ill patients. Observations from a randomized trial in sepsis. Thromb Haemost 101:139–144
Baker SP, O’Neill B, Haddon W Jr et al (1974) The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma 14:187–196
Kvåle R (2013) Årsrapport for 2012. Norsk intensivregister (NIR) http://www.intensivregister.no/LinkClick.aspx?fileticket=C6y7hQoWLK0%3d&tabid=55&mid=377. Accessed 21 Nov 2014
Marik PE, Andrews L, Maini B (1997) The incidence of deep venous thrombosis in ICU patients. Chest 111:661–664
Hirsch DR, Ingenito EP, Goldhaber SZ (1995) Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA 274:335–337
Harris LM, Curl GR, Booth FV et al (1997) Screening for asymptomatic deep vein thrombosis in surgical intensive care patients. J Vasc Surg 26:764–769
Twigg SJ, McCrirrick A, Sanderson PM (2001) A comparison of post mortem findings with post hoc estimated clinical diagnoses of patients who die in a United Kingdom intensive care unit. Intensive Care Med 27:706–710
Wahl WL, Ahrns KS, Zajkowski PJ et al (2003) Normal d-dimer levels do not exclude thrombotic complications in trauma patients. Surgery 134:529–532
Cook DJ, Donadini MP (2010) Pulmonary embolism in medical-surgical critically ill patients. Hematol Oncol Clin North Am 24:677–688
Cook D, Meade M, Guyatt G et al (2004) Clinically important deep vein thrombosis in the intensive care unit: a survey of intensivists. Crit Care 8:R145–R152
Hinz P, Lubenow N, Wessel A et al (2009) Thrombosis prophylaxis in trauma surgery units in Germany: a survey. Unfallchirurg 112:1029–1033
Junqueira DR, Perini E, Penholati RR et al (2012) Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev 9:1–35
Fareed J, Jeske W, Fareed D et al (2008) Are all low molecular weight heparins equivalent in the management of venous thromboembolism? Clin Appl Thromb Hemost 14:385–392
Nenci GG (2003) Low molecular weight heparins: are they interchangeable? No. J Thromb Haemost 1:12–13
Prandoni P (2003) Low molecular weight heparins: are they interchangeable? Yes. J Thromb Haemost 1:10–11
van der Heijden JF, Prins MH, Buller HR (2000) Low-molecular-weight heparins: are they interchangeable? Haemostasis 30(Suppl 2):148–157
Limpus A, Chaboyer W, McDonald E et al (2006) Mechanical thromboprophylaxis in critically ill patients: a systematic review and meta-analysis. Am J Crit Care 15:402–410
Huo MH, Muntz J (2009) Extended thromboprophylaxis with low-molecular-weight heparins after hospital discharge in high-risk surgical and medical patients: a review. Clin Ther 31:1129–1141
Garcia-Olivares P, Guerrero JE, Galdos P et al (2014) PROF-ETEV study: prophylaxis of venous thromboembolic disease in critical care units in Spain. Intensive Care Med 40:1698–1708
Schaden E, Metnitz PG, Pfanner G et al (2012) Coagulation day 2010: an Austrian survey on the routine of thromboprophylaxis in intensive care. Intensive Care Med 38:984–990
Wilbur K, Lynd LD, Sadatsafavi M (2011) Low-molecular-weight heparin versus unfractionated heparin for prophylaxis of venous thromboembolism in medicine patients—a pharmacoeconomic analysis. Clin Appl Thromb Hemost 17:454–465
Fowler RA, Mittmann N, Geerts W et al (2014) Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients. JAMA 312:2135–2145
Thorlund K, Imberger G, Walsh M et al (2011) The number of patients and events required to limit the risk of overestimation of intervention effects in meta-analysis—a simulation study. PLoS One 6:e25491
Guyatt GH, Oxman AD, Kunz R et al (2011) GRADE guidelines 6. Rating the quality of evidence—imprecision. J Clin Epidemiol 64:1283–1293
Schulz KF, Chalmers I, Hayes RJ et al (1995) Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1(273):408–412
Oxman AD, Guyatt GH (1992) A consumer’s guide to subgroup analyses. Ann Intern Med 16:78–84
Sun X, Briel M, Walter SD et al (2010) Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ 30(340):c11
Egger M, Juni P, Bartlett C et al (2003) How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study. Health Technol Assess 7:1–76
Egger M, Smith GD, Altman DG (1995) Systematic reviews in health care: meta-analysis in context, 2nd edn. BMJ, London
Raskob GE, Hirsh J (2003) Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest 124(Suppl 6):379S–385S
Tribout B, Colin-Mercier F (2007) New versus established drugs in venous thromboprophylaxis: efficacy and safety considerations related to timing of administration. Am J Cardiovasc Drugs 7:1–15
Bottaro FJ, Elizondo MC, Doti C et al (2008) Efficacy of extended thrombo-prophylaxis in major abdominal surgery: what does the evidence show? A meta-analysis. Thromb Haemost 99:1104–1111
Skeik N, Rumery KK, Rodriguez GT (2014) The new era of anticoagulation. Ann Vasc Surg 28:503–514
Cheng SS, Nordenholz K, Matero D et al (2012) Standard subcutaneous dosing of unfractionated heparin for venous thromboembolism prophylaxis in surgical ICU patients leads to subtherapeutic factor Xa inhibition. Intensive Care Med 38:642–648
Malinoski D, Jafari F, Ewing T et al (2010) Standard prophylactic enoxaparin dosing leads to inadequate anti-Xa levels and increased deep venous thrombosis rates in critically ill trauma and surgical patients. J Trauma 68:874–880
Robinson S, Zincuk A, Strom T et al (2010) Enoxaparin, effective dosage for intensive care patients: double-blinded, randomised clinical trial. Crit Care 14:R41
Acknowledgments
The authors are grateful to Marie Isachsen for performing the literature search and documenting the search strategy, and to Kjetil Gundro Brurberg for helpful input on the result presentation.
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The authors declare that they have no competing interests.
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Beitland, S., Sandven, I., Kjærvik, LK. et al. Thromboprophylaxis with low molecular weight heparin versus unfractionated heparin in intensive care patients: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 41, 1209–1219 (2015). https://doi.org/10.1007/s00134-015-3840-z
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DOI: https://doi.org/10.1007/s00134-015-3840-z