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Published in: Systematic Reviews 1/2018

Open Access 01-12-2018 | Protocol

Prothrombin complex concentrate versus placebo, no intervention, or other interventions in critically bleeding patients associated with oral anticoagulant administration: a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis

Authors: Christian Ovesen, Jan Purrucker, Christian Gluud, Janus Christian Jakobsen, Hanne Christensen, Thorsten Steiner

Published in: Systematic Reviews | Issue 1/2018

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Abstract

Background

Acute critical bleeding is one of the most feared complications during treatment with oral anticoagulating agents. As more patients undergo treatment with anticoagulating agents, critically bleeding episodes in patients with vitamin K antagonists, thrombin inhibitor, or factor Xa inhibitor-inducted coagulopathy will be encountered frequently by physicians. Hence, an effective treatment capable of reversing the iatrogenic coagulopathy in the acute setting is needed. In randomised clinical trials and observational studies, prothrombin complex concentrate has been reported to be superior to other acute interventions, and many guidelines recommend prothrombin complex concentrate in treatment of critically bleeding patients. The aim of this systematic review is to synthesise the evidence of the effects of prothrombin complex concentrate compared with placebo, no intervention, or other treatment options in critically bleeding patients treated with oral anticoagulants.

Methods/design

A comprehensive search for relevant published literature will be undertaken in Cochrane Central Register of Controlled Trials, MEDLINE, Embase, WHO International Clinical Trials Registry Platform, Science Citation Index, regulatory databases, and trial registers. We will include randomised clinical trials comparing prothrombin complex concentrate versus placebo, no intervention, or other interventions in critically bleeding patients with oral anticoagulant-induced coagulopathy. Data extraction and risk of bias assessment will be handled by two independent review authors. Meta-analysis will be performed as recommended by Cochrane Handbook for Systematic Reviews of Interventions, bias will be assessed with domains, and trial sequential analysis will be conducted to control random errors. Certainty will be assessed by GRADE.

Discussion

As critical bleeding in patients treated with oral anticoagulants is an increasing problem, an up-to-date systematic review evaluating the benefits and harms of prothrombin complex concentrate is urgently needed. It is the hope that this review will be able to guide best practice in treatment and clinical research of these critically bleeding patients.

Systematic review registration

Appendix
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Literature
1.
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133:160S–98S.CrossRef
2.
Bjorck F, Renlund H, Lip GY, Wester P, Svensson PJ, Sjalander A. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiol. 2016;1:172–80.CrossRef
3.
Oake N, Fergusson DA, Forster AJ, van Walraven C. Frequency of adverse events in patients with poor anticoagulation: a meta-analysis. CMAJ. 2007;176:1589–94.CrossRef
4.
Oake N, Jennings A, Forster AJ, Fergusson D, Doucette S, van Walraven C. Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis. CMAJ. 2008;179:235–44.CrossRef
5.
Adelborg K, Grove EL, Sundboll J, Laursen M, Schmidt M. Sixteen-year nationwide trends in antithrombotic drug use in Denmark and its correlation with landmark studies. Heart. 2016;102:1883–9.CrossRef
6.
Lopez-Lopez JA, Sterne JAC, Thom HHZ, Higgins JPT, Hingorani AD, Okoli GN, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017;359:j5058.CrossRef
7.
Oktay K. Will NOACs become the new standard of care in anticoagulation therapy? Int J Cardiovasc Acad. 2015;1:1–4.CrossRef
8.
9.
10.
11.
Al-Horani RA, Desai UR. Factor XIa inhibitors: a review of the patent literature. Expert Opin Ther Pat. 2016;26:323–45.CrossRef
12.
Buller HR, Bethune C, Bhanot S, Gailani D, Monia BP, Raskob GE, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372:232–40.CrossRef
13.
Jackson LR 2nd, Becker RC. Novel oral anticoagulants: pharmacology, coagulation measures, and considerations for reversal. J Thromb Thrombolysis. 2014;37:380–91.CrossRef
14.
Brouwers HB, Chang Y, Falcone GJ, Cai X, Ayres AM, Battey TW, et al. Predicting hematoma expansion after primary intracerebral hemorrhage. JAMA Neurol. 2014;71:158–64.CrossRef
15.
Cucchiara B, Messe S, Sansing L, Kasner S, Lyden P, Investigators C. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke. 2008;39:2993–6.CrossRef
16.
Rosand J, Eckman MH, Knudsen KA, Singer DE, Greenberg SM. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004;164:880–4.CrossRef
17.
Dowlatshahi D, Butcher KS, Asdaghi N, Nahirniak S, Bernbaum ML, Giulivi A, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke. 2012;43:1812–7.CrossRef
18.
Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology. 2006;66:1175–81.CrossRef
19.
Delcourt C, Huang Y, Arima H, Chalmers J, Davis SM, Heeley EL, et al. Hematoma growth and outcomes in intracerebral hemorrhage: the INTERACT1 study. Neurology. 2012;79:314–9.CrossRef
20.
Dowlatshahi D, Demchuk AM, Flaherty ML, Ali M, Lyden PL, Smith EE, et al. Defining hematoma expansion in intracerebral hemorrhage: relationship with patient outcomes. Neurology. 2011;76:1238–44.CrossRef
21.
Leira R, Davalos A, Silva Y, Gil-Peralta A, Tejada J, Garcia M, et al. Early neurologic deterioration in intracerebral hemorrhage: predictors and associated factors. Neurology. 2004;63:461–7.CrossRef
22.
Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA. 2015;313:824–36.CrossRef
23.
Caldeira D, Rodrigues FB, Barra M, Santos AT, de Abreu D, Goncalves N, et al. Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis. Heart. 2015;101:1204–11.CrossRef
24.
Marques-Matos C, Alves JN, Marto JP, Ribeiro JA, Monteiro A, Araujo J, et al. POST-NOAC: Portuguese observational study of intracranial hemorrhage on non-vitamin K antagonist oral anticoagulants. Int J Stroke. 2017;12:623–7.CrossRef
25.
Takahashi H, Jimbo Y, Takano H, Abe H, Sato M, Fujii Y, et al. Intracerebral hematoma occurring during warfarin versus non-vitamin K antagonist oral anticoagulant therapy. Am J Cardiol. 2016;118:222–5.CrossRef
26.
von der Brelie C, Doukas A, Naumann R, Dempfle A, Larsen N, Synowitz M, et al. Clinical and radiological course of intracerebral haemorrhage associated with the new non-vitamin K anticoagulants. Acta Neurochir. 2017;159:101–9.CrossRef
27.
Wilson D, Charidimou A, Shakeshaft C, Ambler G, White M, Cohen H, et al. Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type. Neurology. 2016;86:360–6.CrossRef
28.
Purrucker JC, Haas K, Rizos T, Khan S, Wolf M, Hennerici MG, et al. Early clinical and radiological course, management, and outcome of intracerebral hemorrhage related to new oral anticoagulants. JAMA Neurol. 2016;73:169–77.CrossRef
29.
Wilson D, Seiffge DJ, Traenka C, Basir G, Purrucker JC, Rizos T, et al. Outcome of intracerebral hemorrhage associated with different oral anticoagulants. Neurology. 2017;88:1693–700.CrossRef
30.
Skaistis J, Tagami T. Risk of fatal bleeding in episodes of major bleeding with new oral anticoagulants and vitamin K antagonists: a systematic review and meta-analysis. PLoS One. 2015;10:e0137444.CrossRef
31.
32.
Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol. 2011;154:311–24.CrossRef
33.
Hylek EM, Regan S, Go AS, Hughes RA, Singer DE, Skates SJ. Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin. Ann Intern Med. 2001;135:393–400.CrossRef
34.
Schulman S, Elbazi R, Zondag M, O'Donnell M. Clinical factors influencing normalization of prothrombin time after stopping warfarin: a retrospective cohort study. Thromb J. 2008;6:15.CrossRef
35.
Lubetsky A, Yonath H, Olchovsky D, Loebstein R, Halkin H, Ezra D. Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study. Arch Intern Med. 2003;163:2469–73.CrossRef
36.
Patel RJ, Witt DM, Saseen JJ, Tillman DJ, Wilkinson DS. Randomized, placebo-controlled trial of oral phytonadione for excessive anticoagulation. Pharmacotherapy. 2000;20:1159–66.CrossRef
37.
Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE. A comparison of the efficacy and rate of response to oral and intravenous vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol. 2001;115:145–9.CrossRef
38.
Practice Guidelines for blood component therapy. A report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology. 1996;84:732–47.CrossRef
39.
Ahmed N, Steiner T, Caso V, Wahlgren N. Recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 13–15 November 2016. European Stroke J. 2017;2:95–102.CrossRef
40.
Yasaka M, Sakata T, Minematsu K, Naritomi H. Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Thromb Res. 2002;108:25–30.CrossRef
41.
Marshall AL, Levine M, Howell ML, Chang Y, Riklin E, Parry BA, et al. Dose-associated pulmonary complication rates after fresh frozen plasma administration for warfarin reversal. J Thromb Haemost. 2016;14:324–30.CrossRef
42.
Milling TJ Jr, Refaai MA, Sarode R, Lewis B, Mangione A, Durn BL, et al. Safety of a four-factor prothrombin complex concentrate versus plasma for vitamin K antagonist reversal: an integrated analysis of two phase IIIb clinical trials. Acad Emerg Med. 2016;23:466–75.CrossRef
43.
Frontera JA, Gordon E, Zach V, Jovine M, Uchino K, Hussain MS, et al. Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage. Neurocrit Care. 2014;21:397–406.CrossRef
44.
Hanger HC, Geddes JA, Wilkinson TJ, Lee M, Baker AE. Warfarin-related intracerebral haemorrhage: better outcomes when reversal includes prothrombin complex concentrates. Intern Med J. 2013;43:308–16.CrossRef
45.
Hickey M, Gatien M, Taljaard M, Aujnarain A, Giulivi A, Perry JJ. Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation. 2013;128:360–4.CrossRef
46.
Huttner HB, Schellinger PD, Hartmann M, Kohrmann M, Juettler E, Wikner J, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke. 2006;37:1465–70.CrossRef
47.
Woo CH, Patel N, Conell C, Rao VA, Faigeles BS, Patel MC, et al. Rapid warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate. World Neurosurg. 2014;81:110–5.CrossRef
48.
Kushimoto S, Fukuoka T, Kimura A, Toyoda K, Brainsky A, Harman A, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate for rapid vitamin K antagonist reversal in Japanese patients presenting with major bleeding or requiring urgent surgical or invasive procedures: a prospective, open-label, single-arm phase 3b study. Int J Hematol. 2017;106:777–86.CrossRef
49.
Goldstein JN, Refaai MA, Milling TJ Jr, Lewis B, Goldberg-Alberts R, Hug BA, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385:2077–87.CrossRef
50.
Sarode R, Milling TJ Jr, Refaai MA, Mangione A, Schneider A, Durn BL, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128:1234–43.CrossRef
51.
Steiner T, Poli S, Griebe M, Husing J, Hajda J, Freiberger A, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15:566–73.CrossRef
52.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–9.CrossRef
53.
Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015;373:511–20.CrossRef
54.
Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med. 2017;377:431–41.CrossRef
55.
Hu TY, Vaidya VR, Asirvatham SJ. Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab. Vasc Health Risk Manag. 2016;12:35–44.PubMedPubMedCentral
56.
Connolly SJ, Milling TJ Jr, Eikelboom JW, Gibson CM, Curnutte JT, Gold A, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375:1131–41.CrossRef
57.
Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413–24.CrossRef
58.
Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371:2141–2.CrossRef
59.
Milling TJ Jr, Refaai MA, Goldstein JN, Schneider A, Omert L, Harman A, et al. Thromboembolic events after vitamin K antagonist reversal with 4-factor prothrombin complex concentrate: exploratory analyses of two randomized, plasma-controlled studies. Ann Emerg Med. 2016;67:96–105 e105.CrossRef
60.
Laible M, Jenetzky E, Beynon C, Muller OJ, Sander P, Schuler S, et al. Adverse events following international normalized ratio reversal in intracerebral hemorrhage. Cerebrovasc Dis. 2016;42:446–54.CrossRef
61.
62.
Brekelmans MPA, Ginkel KV, Daams JG, Hutten BA, Middeldorp S, Coppens M. Benefits and harms of 4-factor prothrombin complex concentrate for reversal of vitamin K antagonist associated bleeding: a systematic review and meta-analysis. J Thromb Thrombolysis. 2017;44:118–29.CrossRef
63.
64.
65.
66.
Lundh A, Lexchin J, Mintzes B, Schroll JB, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2017;2:MR000033.
67.
Gluud LL. Bias in clinical intervention research. Am J Epidemiol. 2006;163:493–501.CrossRef
68.
Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001;135:982–9.CrossRef
69.
Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet. 1998;352:609–13.CrossRef
70.
Savovic J, Jones H, Altman D, Harris R, Juni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies. Health Technol Assess. 2012;16:1–82.CrossRef
71.
Schulz KF, Chalmers I, Grimes DA, Altman DG. Assessing the quality of randomization from reports of controlled trials published in obstetrics and gynecology journals. JAMA. 1994;272:125–8.CrossRef
72.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.CrossRef
73.
Lau J, Ioannidis JP, Terrin N, Schmid CH, Olkin I. The case of the misleading funnel plot. BMJ. 2006;333:597–600.CrossRef
74.
Tang JL, Liu JL. Misleading funnel plot for detection of bias in meta-analysis. J Clin Epidemiol. 2000;53:477–84.CrossRef
75.
Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol. 2014;14:120.CrossRef
76.
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23:1351–75.CrossRef
77.
Cheng J, Pullenayegum E, Marshall JK, Iorio A, Thabane L. Impact of including or excluding both-armed zero-event studies on using standard meta-analysis methods for rare event outcome: a simulation study. BMJ Open. 2016;6.CrossRef
78.
Kuss O. Statistical methods for meta-analyses including information from studies without any events-add nothing to nothing and succeed nevertheless. Stat Med. 2015;34:1097–116.CrossRef
79.
Sharma T, Gotzsche PC, Kuss O. The Yusuf-Peto method was not a robust method for meta-analyses of rare events data from antidepressant trials. J Clin Epidemiol. 2017;91:129–36.CrossRef
80.
Castellini G, Nielsen EE, Gluud C. Comment on: “Cell therapy for heart disease: Trial sequential analyses of two Cochrane reviews”. Clin Pharmacol Ther. 2016;102:21–4.CrossRef
81.
Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008;61:763–9.CrossRef
82.
Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L, et al. Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? Int J Epidemiol. 2009;38:276–86.CrossRef
83.
Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manusal for trial sequential analysis (TSA). Denmark: Copenhagen Trial Unit; 2011. Available from http://​www.​ctu.​dk
84.
Wetterslev J, Jakobsen JC, Gluud C. Trial sequential analysis in systematic reviews with meta-analysis. BMC Med Res Methodol. 2017;17:39.CrossRef
85.
Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008;61:64–75.CrossRef
86.
Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009;9:86.CrossRef
87.
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care. 2003;41:582–92.
88.
Goodman SN. Toward evidence-based medical statistics. 2: the Bayes factor. Ann Intern Med. 1999;130:1005–13.CrossRef
89.
Goodman SN. Introduction to Bayesian methods I: measuring the strength of evidence. Clin Trials. 2005;2:282–90 discussion 301–284, 364–278.CrossRef
90.
Jakobsen JC, Gluud C, Winkel P, Lange T, Wetterslev J. The thresholds for statistical and clinical significance - a five-step procedure for evaluation of intervention effects in randomised clinical trials. BMC Med Res Methodol. 2014;14:34.CrossRef
91.
Nguyen TL, Collins GS, Lamy A, Devereaux PJ, Daures JP, Landais P, et al. Simple randomization did not protect against bias in smaller trials. J Clin Epidemiol. 2017;84:105–13.CrossRef
92.
Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol. 2017;17:162.CrossRef
93.
Mavridis D, Chaimani A, Efthimiou O, Leucht S, Salanti G. Addressing missing outcome data in meta-analysis. Evid Based Ment Health. 2014;17:85–9.CrossRef
94.
investigators GUSTO. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673–82.CrossRef
95.
Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114:774–82.CrossRef
96.
97.
Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273:408–12.CrossRef
98.
Savovic J, Jones HE, Altman DG, Harris RJ, Juni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med. 2012;157:429–38.CrossRef
99.
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–6.CrossRef
100.
Home PD. Validity of meta-analysis in diabetes: we need to be aware of its limitations. Diabetes Care. 2013;36:3361–7.CrossRef
101.
Bennetts M, Whalen E, Ahadieh S, Cappelleri JC. An appraisal of meta-analysis guidelines: how do they relate to safety outcomes? Res Synth Methods. 2017;8:64–78.CrossRef
102.
Hernandez AV, Walker E, Ioannidis JP, Kattan MW. Challenges in meta-analysis of randomized clinical trials for rare harmful cardiovascular events: the case of rosiglitazone. Am Heart J. 2008;156:23–30.CrossRef
Metadata
Title
Prothrombin complex concentrate versus placebo, no intervention, or other interventions in critically bleeding patients associated with oral anticoagulant administration: a protocol for a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis
Authors
Christian Ovesen
Jan Purrucker
Christian Gluud
Janus Christian Jakobsen
Hanne Christensen
Thorsten Steiner
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Systematic Reviews / Issue 1/2018
Electronic ISSN: 2046-4053
DOI
https://doi.org/10.1186/s13643-018-0838-y

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