Efficacy and safety of prothrombin complex concentrate for vitamin K antagonist-associated intracranial hemorrhage: a systematic review and meta-analysis
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Prothrombin complex concentrate (PCC) is the treatment of choice in vitamin K antagonist-associated intracranial hemorrhage (VKA-ICH). However, the efficiency and safety associated with their use remain unclear.
This study aimed to assess the current evidence of the clinical outcomes in patients with VKA-ICH treated with or without PCC.
Summary of review
A meta-analysis was conducted. Two randomized controlled trials and 19 observational studies were included. PCC use demonstrated a significant increased likelihood of international normalized ratio (INR) normalization (OR = 3.76; 95% CI 1.74–8.12), shortened time to INR correction (MD = − 1.30; 95% CI − 2.08 to − 0.53) and reduction of hematoma expansion (HE) rate (OR = 0.37; 95% CI 0.23–0.60). Although PCC use revealed a statistical reduction at 30-day mortality (OR = 0.62; 95% CI 0.50–0.78), the result was inconsistent with mortality at discharge (OR = 1.03; 95% CI 0.68–1.57) and 90-day follow-up (OR = 0.50; 95% CI 0.24–1.07), both of which yielded no significant difference. When subgroup analyses were performed focus on PCC only treatment with FFP, no statistically significant difference was observed in 30-day mortality (OR = 0.43; 95% CI 0.11–1.71) as well. Besides, significant difference was not found in neurologic improvement at discharge (OR = 1.85; 95% CI 0.32–10.75), 30-day follow-up (OR = 3.00; 95% CI 0.93–9.70), or 90-day follow-up (OR = 1.55; 95% CI 0.84–2.86). No statistically significant difference was noted in the risk of thromboembolism following PCC administration (OR = 0.61; 95% CI 0.23–1.63).
PCC use for VKA-ICH reversal was associated with a significant reduction in INR and HE rate, without an increased risk of thromboembolic events. However, this reduction was not associated with improvement in neurologic deficits or overall survival. Well-designed randomized trials with special considerations to the aspect are necessary.
KeywordsIntracranial hemorrhage Vitamin K antagonists Prothrombin complex concentrate Meta-analysis
The work was supported by the National Key R&D Program of China (2017YFC1307500, 2017YFC1307504) and Science and Technology Project of Huizhou City (2017C0416032).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Lip GY, Andreotti F, Fauchier L et al (2011) Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace 13:723–746CrossRefPubMedGoogle Scholar
- 4.Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G (2012) Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141:e44S–e88SCrossRefPubMedPubMedCentralGoogle Scholar
- 11.Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012CrossRefGoogle Scholar
- 12.Steiner T, Poli S, Griebe M, Hüsing J, Hajda J, Freiberger A, Bendszus M, Bösel J, Christensen H, Dohmen C, Hennerici M, Kollmer J, Stetefeld H, Wartenberg KE, Weimar C, Hacke W, Veltkamp R (2016) Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol 15:566–573CrossRefPubMedGoogle Scholar
- 15.Frontera JA, Gordon E, Zach V, Jovine M, Uchino K, Hussain MS, Aledort L (2014) Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage. Neurocrit Care 21:397–406CrossRefPubMedGoogle Scholar
- 21.Kuwashiro T, Yasaka M, Itabashi R, Nakagaki H, Miyashita F, Naritomi H, Minematsu K (2011) Effect of prothrombin complex concentrate on hematoma enlargement and clinical outcome in patients with anticoagulant-associated intracerebral hemorrhage. Cerebrovasc Dis 31:170–176CrossRefPubMedGoogle Scholar
- 22.Woo CH, Patel N, Conell C, Rao VA, Faigeles BS, Patel MC, Pombra J, Akins PT, Axelrod YK, Ge IY, Sheridan WF, Flint AC (2014) Rapid warfarin reversal in the setting of intracranial hemorrhage: a comparison of plasma, recombinant activated factor VII, and prothrombin complex concentrate. World Neurosurg 81:110–115CrossRefPubMedGoogle Scholar
- 26.Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, Flechsenhar J, Neugebauer H, Jüttler E, Grau A, Palm F, Röther J, Michels P, Hamann GF, Hüwel J, Hagemann G, Barber B, Terborg C, Trostdorf F, Bäzner H, Roth A, Wöhrle J, Keller M, Schwarz M, Reimann G, Volkmann J, Müllges W, Kraft P, Classen J, Hobohm C, Horn M, Milewski A, Reichmann H, Schneider H, Schimmel E, Fink GR, Dohmen C, Stetefeld H, Witte O, Günther A, Neumann-Haefelin T, Racs AE, Nueckel M, Erbguth F, Kloska SP, Dörfler A, Köhrmann M, Schwab S, Huttner HB (2015) Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 313:824–836CrossRefPubMedGoogle Scholar
- 28.Takahashi A, Kato TS, Oda N, Komamura K, Kanzaki H, Asakura M, Hashimura K, Niwaya K, Funatsu T, Nakatani T, Kobayashi J, Kitamura S, Shishido T, Miyata S, Takahashi JC, Iihara K, Kitakaze M (2010) Prothrombin complex concentrate for rapid reversal of warfarin-induced anticoagulation and intracerebral hemorrhage in patients supported by a left ventricular assist device. Int J Gerontol 4:143–147CrossRefGoogle Scholar
- 32.Lihai S, Feng Z (2010) Clinical treatment of intracranial hemorrhage due to oral warfarin therapy in 27 patients [in Chinese]. Chin J Neuromed 9:1262–1264Google Scholar
- 37.Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, de Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GYH, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K (2016) 2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS. Eur Heart J 37:2893–2962CrossRefPubMedGoogle Scholar
- 40.Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R (2009) Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion 49:1171–1177CrossRefPubMedGoogle Scholar