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Three Part Question

In [patients using vitamin K antagonists and with acute, life-threatening bleeding] do [prothrombin complex concentrates] improve [mortality, morbidity and INR]?

Clinical Scenario

A 72 year old woman is brought in to Emergency by the paramedics after a fall from her own height at home. She slipped and hit her head on the edge of the bathroom sink and presents with a hematoma above her left eye. Her current Glasgow Coma Scale is 11 (E3M3V5), and she is only oriented to person (not place or time). She is on warfarin for atrial fibrillation and her other medications include metformin, gliclazide, ramipril, atorvastatin, metoprolol, nitroglycerin patch and furosemide. Urgent CT of her head reveals a left sided subdural hematoma. You want to reverse her anticoagulation with a prothrombin complex concentrate, but you are unsure of the evidence around their efficacy.

Search Strategy

OvidSP MEDLINE 1950 to May Week 2 2009. [exp. Recombinant Proteins/ or Prothrombin/ or Blood Coagulation Factors] AND [exp. Hemorrhage {all subheadings}]. Limit to Abstracts and English language and Humans and Study Type (case reports or clinical trial, all or comparative study or controlled clinical trial or meta analysis or randomized controlled trial).
The Cochrane Library 2nd Quarter 2009. [exp. Recombinant Proteins/ or Prothrombin/ or Blood Coagulation Factors] AND [exp. Hemorrhage {all subheadings}]. Limit to Abstracts and English language and Humans and Study Type (case reports or clinical trial, all or comparative study or controlled clinical trial or meta analysis or randomized controlled trial).

Several review articles were also hand searched for relevant references.

Search Outcome

A total of 367 papers was found in MEDLINE, of which 360 were either irrelevant or of insufficient quality for inclusion. The seven remaining papers, plus three papers found through a hand search, are included below in Table 1.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Pabinger et al 2008 Austria/Germany/Israel/Hungary	44 Patients with an INR > 2 and requiring either i)emergency surigcal or urgent invasive diagnostic intervention or ii)INR normalization as a result of acute bleeding	Prospective study, open label.	INR decline to	Clinical hemostatic efficacy classified as very good in 40 patients (93%).	Non-randomized, non-blinded, non-concealed study. No control group for comparison. No reporting of the effect of PCC infusion on patient mortality.
Riess HB et al 2007 Germany	60 Patients requiring reversal of oral anticoagulation for i) acute invasive procedures or ii) control of hemorrhage	Prospective, open label.	52/59 (88%) of patients obtained target INR	Three events in 3 patients felt to be related to PCC infusion.	Non-randomized, non-blinded, non-concealed study. No control group for comparison. No reporting of the effect of PCC infusion on patient mortality.
van Aart et al. 2006 The Netherlands	93 Patients requiring reversal of oral anticoagulation (INR > 2.2) for i) urgent intervention ii) acute hemorrhage.	Comparison of individualized versus standard dose PCC for reversal of oral anticoagulation. Open, prospective, randomized controlled trial.	89% of 'Individualized' dose patients reacehed target INR < 15 minutes vs 43% of standard dose patients	2 serious adverse events related to PCC	Non-blinded, non-concealed study. No control group for comparison. No reporting of the effect of PCC infusion on patient mortality.
Lubetsky A 2004 Israel	20 Patients requiring reversal of oral anticoagulation (INR 6.1 +/- 2) for i) surgical procedures or ii) acute hemorrhage	Prospective, open label	Mean INR declined to 1.5 +/- 0.3 within 10 minutes.	Clinical response graded as good in 85% of patients	Small sample size. Non-randomized, non-blinded, non-concealed study. No control group for comparison. No reporting of the effect of PCC infusion on patient mortality.
Evans et al 2001 UK	10 Patients requiring reversal of oral anticoagulation for acute hemorrhage and INR > 14.	Prospective, open label.	Median INR was 20 pretreatment, and 1.1 post treatment	All patients had immediate cessation of bleeding	Small sample size. Non-randomized, non-blinded, non-concealed study. No control group for comparison.
Makris et al 1997 UK/The Netherlands	41 Patients requiring reversal of oral anticoagulation for i) acute hemorrhage or ii) urgent surgical procedures.	Retrospective comparison of FFP and PCC	Mean INR in FFP group 2.3 (1.6-3.8); Mean INR in PCC group 1.3 (0.9-3.8)		Retrospective study. No indication of clinical hemostatic response or comparison of mortality.
Preston et al. 2001 UK	42 Patients requiring immediate reverals of oral anticoagulation therapy.	Prospective, open label.	Meadin INR pre-PCC 3.98 (2.0-27.6); 33/42 (79%) of patients had INR < 1.3 within 20 minutes of infusion	1 thrombotic adverse event	Non-randomized, non-blinded, non-concealed study. No control group for comparison. No reporting of the effect of PCC infusion on patient mortality.
Cartmill et al. 2000 UK	12 Patients with life-threatening intracranial hemorrhage.	Pre-post implementation comparison of PCC vs FFP.	Mean post-PCC INR 1.32 (1.09-1.49); Mean post-FFP INR 2.30 (1.30-2.30)	Mean PCC INR correction time 41 minutes (30-60); Mean FFP correction time 115 minutes (60-180)	Small sample size. Not truly prospective. Only data on PCC patients collected prospectively. No comparison of mortality between patient groups.
Fredriksson et al. 1992 Sweden	151 Patients with oral anticoagulation-related intracranial hemorrhage.	Retrospective analysis	11% mortality in FFP group; 39% mortality in PCC group		Retrospective study. Multiple centers involved in study with non-uniform criteria for use of various treatments. Only 3/18 FFP patients had interventricular blood compared to 10/23 in PCC group.
Lankiewicz et al. 2006 USA	58 Patients with INR > 2 requiring reversal of oral anticoagulation for i) immediate surgical intervention or ii) acute hemorrhage	Prospective, open label	Mean INR post PCC 1.4 (0.9-5.7)	4 patients with possible PCC related thrombotic complications	50% of patients also received FFP as part of treatment. Non-randomized, non-blinded, non-concealed study. No control group for comparison.

Comment(s)

There are multiple prospective, open label studies demonstrating that PCC leads to a more rapid and more effective reversal of INR and clinical hemostasis in patients with acute hemorrhage or requiring urgent surgical procedures compared to patients treated with FFP. At present, there is no well designed study that answers the question of whether patient outcomes such as morbidity or mortality are improved with the administration of PCC compared to FFP.

Editor Comment

There are currently 3 prospective, randomized controlled trials recruiting patients that are examining the safety and efficacy of PCC vs FFP. Clinicaltrials.gov : NCT00618098, NCT00708435, NCT00803101.

Clinical Bottom Line

The use of PCC rapidly reverses oral anticoagulation (INR) and improves clinical hemostasis. Currently there is insufficient evidence to conclude that PCC is superior to FFP for the improvement of patient outcomes.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, OStermann H for the Beriplex P/N Anticoagulation Reversal Study Group. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. Journal of Thrombosis and Haemostasis 2008;622-31
2. Riess HB, Meier-Hellmann A, Motsch J, Elias M, Kursten FW, Dempfle CE Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thrombosis Research 2007;9-16.
3. van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk ME, Schouten TJ, Ploeger B, Strengers PFW Individualized dosing regimen for prothrombin complex concentrate more effective than standard treatment in the reversal of oral anticoagulant therapy: An open, prospective randomized controlled trial Thrombosis Research 2006;313-20.
4. Lubetsky A, Hoffman R, Zimlichman R, Eldor A, Zvi J, Kostenko V, Brenner B. Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation. Thrombosis Research 2004;371-8.
5. Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding. British Journal of Haematology 2001;998-1001.
6. Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thrombosis and Haemostasis 1997;477-80.
7. Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. British Journal of Haematology 2001;619-24.
8. Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. British Journal of Neurosurgery 2000;458-61.
9. Sjoblom L, Hardemark HG, Lindgren A, Norrving B, Fahlen M, Samuelsson M, Stigendal L, Stockelberg D, Taghavi A, Wallrup L, Wallvik J. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study Stroke 2001;2567-2574
10. Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatts PM Urgent reversal of warfarin with prothrombin complex concentrate Thrombosis and Haemostasis 2006;967-70.