Learning Objective
  • To compare the efficacy and adverse effects of prothrombin complex concentrate and plasma for rapid correction of vitamin K antagonist-associated hemorrhagic emergency

Clinical vignette

A 78-year-old female presents to the emergency department with brisk hematochezia, fatigue, and tachycardia. She is receiving chronic oral anticoagulant therapy with warfarin as thromboprophylaxis for a mechanical mitral valve. International normalized ratio (INR) is 4.2. Red blood cell transfusion is ordered, and 10 mg of intravenous vitamin K is given. You are asked whether plasma or prothrombin complex concentrate is more effective for emergent reversal of her warfarin-associated coagulopathy.

Warfarin is a vitamin K antagonist (VKA) that has been the mainstay of oral anticoagulant therapy for the prevention and treatment of thromboembolism. Bleeding is the major complication of anticoagulant therapy with rates of major warfarin-related bleeding up to 7% reported depending on the indication for anticoagulation and study design.1-5  Warfarin use increases the risk of major bleeding by 0.3%-0.5%/year and intracranial hemorrhage (ICH) by 0.2%/year compared to controls in clinical trials.1  Despite the availability of warfarin-reversal agents, warfarin-associated bleeding leads to significant morbidity and mortality, with case fatality rates of 8%-13%.5-8  Death in hospital or within 7 days of discharge has been reported in 18% of warfarin-treated atrial fibrillation patients presenting with major bleeding.9  In patients presenting with warfarin-associated ICH, high mortality rates of 54% and 64% have been reported at 30 days and 6 months, respectively.10 

Although direct oral anticoagulants (DOACs) are now approved for several indications, warfarin use is expected to continue for patients who are stably managed on long-term warfarin therapy, conditions in which DOACs are not proven (eg, antiphospholipid antibody syndrome, mechanical heart valves), patients with severe renal failure (creatinine clearance <30 mL/min), and patients for whom DOACs are cost prohibitive.

Warfarin-associated major bleeding complications require urgent reversal of coagulopathy. When given intravenously, the effect of vitamin K on warfarin coagulopathy is evident within 6 hours. Plasma contains all coagulation factors and will correct coagulation factor deficiency attributable to inadequate synthesis. Time to thaw frozen plasma (FP) may in some circumstances be a limitation, but large blood banks typically have a continuous stock of thawed plasma. The infusion time depends on vascular access and volume status of the patient. Fluid overload and mild allergic reactions are the most common adverse reactions to plasma (∼1 in 100 transfusions). Serious allergic and transfusion-related acute lung injury reactions are rare (∼1 in 10 000 transfusions).11-16 

Prothrombin complex concentrates (PCCs) are plasma-derived products containing vitamin K-dependent factors II, VII, IX, and X (4-factor PCC) or II, IX, and X (3-factor PCC), with some formulations also containing proteins C and S and heparin. PCC is stored as a lyophilized powder at room temperature, does not require blood group determination, can be administered by rapid infusion, and undergoes viral inactivation.17  PCC has a higher product cost and has been associated with thromboembolic complications when used to reverse VKA coagulopathy.18 

We conducted a systematic review to evaluate the current best evidence regarding the comparative efficacy and safety of PCC or plasma for warfarin reversal in the setting of major bleeding. Using standard systematic review methodology, we conducted a search of OVID Medline from inception to June 18, 2015. Studies were eligible for inclusion if they were randomized controlled trials (RCTs) or observational studies comparing treatment with PCC or plasma for warfarin-associated bleeding in adult patients (aged ≥18 years) and written in English. Pediatric studies, animal studies, abstracts, articles lacking original data, non-English studies, noncomparative studies, and studies using plasma/PCC for indications other than major bleeding were excluded. The search strategy used Medical Subject Headings (MeSH) and keyword searches as shown in Figure 1.

Figure 1.

Search strategy.

Figure 1.

Search strategy.

The literature search yielded 1504 potentially eligible studies. An additional 6 studies were identified from a manual review of reference lists. One study was included after the initial search strategy was conducted. Therefore, 17 studies were included in the final review (Table 1). Only 2 studies were RCTs, with the remainder being observational studies. In general, the studies had small sample sizes (range of 12-1547 patients). Eleven studies (65%) included <100 total patients. Patient populations were heterogeneous; the majority of studies included patients with warfarin-associated ICH (n = 12, 71%), followed by major bleeding (n = 3, 18%), gastrointestinal (GI) bleeding (n = 1, 6%), and trauma (n = 1, 6%). Individual studies also varied with respect to treatment protocols, PCC dosing, and additional interventions, such as vitamin K. Except for the RCT by Sarode et al,19  the studies were of low methodologic quality and subject to bias.

Table 1.

Comparative studies evaluating PCC and plasma for reversal of warfarin-associated major bleeding

Comparative studies evaluating PCC and plasma for reversal of warfarin-associated major bleeding
Comparative studies evaluating PCC and plasma for reversal of warfarin-associated major bleeding
Comparative studies evaluating PCC and plasma for reversal of warfarin-associated major bleeding
Comparative studies evaluating PCC and plasma for reversal of warfarin-associated major bleeding

ED indicates emergency department; FIM, functional independence measure; GCS, Glasgow coma score; IHD, ischemic heart disease; LOS, length of stay; NR, not reported; PRBC, packed RBCs; rFVIIa, recombinant factor VIIa; RLS, reaction level scale; RR, relative risk; SD, standard deviation; TE, thromboembolic; VK, vitamin K; VTE, venous thromboembolism.

* p ≤ 0.05, statistically significant.

** 4-Factor PCC was superior to plasma.

In the no-PCC group, 16 of 18 patients received FFP.

†† In the no-PCC group, 29 of 39 patients received FFP.

Thirteen patients received 3-factor PCC plus factor VII concentrate, and 16 patients received 4-factor PCC.

Hemostatic efficacy was evaluated in one non-inferiority RCT by a blinded external adjudication committee using a hemostatic efficacy scale.19  The proportion of patients experiencing effective hemostasis defined as “excellent or good” over 24 hours was similar between the PCC and plasma groups [72.4%; 95% confidence interval (CI), 63.6%-81.3%; and 65.4%, 95% CI, 56.2%-74.5%; p = 0.0045 for non-inferiority].

Of 11 studies reporting mortality, 2 observational studies showed differences between treatment groups. After adjusting for differences in baseline patient characteristics, Parry-Jones et al showed a similar risk of death with PCC and plasma [hazard ratio (HR), 1.075; 95% CI, 0.874-1.323; p = 0.492].20  There were statistically significant increased risks of death with no reversal (HR, 2.540; 95% CI, 1.784-3.616; p < 0.001) and use of PCC alone (HR, 1.445; 95% CI, 1.014-2.058) compared with reversal with both plasma and PCC. Patients receiving 4-factor PCC had a higher risk of death than those receiving 3-factor PCC (HR, 1.441; 95% CI, 1.041-1.995; p = 0.027). The study by Sjoblom et al21  did not adjust for baseline imbalance in prognostic features (higher proportion of PCC patients had intraventricular blood present on imaging) and showed a statistically significant difference in mortality in favor of the plasma group (11.5% versus 39.1%; p < 0.05). In the Sarode et al19  non-inferiority RCT, the adjusted odds ratio (OR) for death with PCC versus plasma was 0.49 (95% CI, 0.19-1.24). The remainder of studies showed no difference in mortality, although they were likely underpowered to detect differences.19,22-28 

There were no differences in the duration of hospital admission in 3 studies reporting this outcome.22,23,29  One study showed an improvement in functional gains in patients receiving PCC versus plasma after warfarin-associated ICH as measured by the functional independence measure.30  Of 3 studies evaluating red blood cell (RBC) transfusion, only the study by Hickey et al showed a reduction in the mean units of RBCs transfused.19,22,29  Adverse events were included infrequently as study outcomes (n = 4 studies), but there were fewer total events with PCC and no difference in thrombotic rates in 3 studies.19,22,25,26 

For the remainder of the studies, efficacy was evaluated predominantly using surrogate outcomes, such as INR correction, which is a known poor predictor of clinical hemostasis. In 7 studies, administration of PCC was associated with reduced time to INR correction (as defined in individual studies) compared with plasma.22-28  Two studies showed reduced time from product administration to laboratory testing with PCC compared with plasma.31,32  In 3 of 6 studies, the mean posttreatment INR was reduced significantly in patients receiving PCC compared with plasma.27,29,31-34  The proportion of patients achieving INR correction (as defined in individual studies) was significantly greater in patients receiving PCC compared with plasma in all 5 studies reporting this outcome.26,27,29,30,35 

Reversal of warfarin anticoagulation for major bleeding requires administration of vitamin K to reestablish the activity of vitamin K-dependent coagulation factors, an effect seen at least 6 hours after intravenous administration. Adjunctive replacement of coagulation factors with PCC or plasma contribute to the rapid normalization of hemostasis desired in the setting of major bleeding. Together, the results of this review suggest that, when compared with plasma, PCCs result in faster INR correction; however, the effect on clinical outcomes, such as mortality and thromboembolic events, is unclear because of the low methodologic quality of available studies. There was only one high-quality RCT that found PCC to be non-inferior with respect to hemostatic efficacy, mortality, and adverse events.19  Given the morbidity and mortality associated with warfarin-related bleeding complications, especially ICH, high-quality studies evaluating patient-important clinical outcomes are needed.

Conclusion

There is grade 2B evidence that supports using PCCs or fresh frozen plasma (FFP) as a supplement to vitamin K for urgent reversal of VKA-associated hemorrhage (weak recommendation, moderate-quality evidence). The patient in the clinical scenario received intravenous vitamin K and 35 IU (factor IX)/kg 4-factor PCC in addition to the vitamin K. INR was 1.9 at the first measurement 1 hour after infusion. Hematochezia stopped within 24 hours, and the patient proceeded to endoscopy to guide additional management. Despite the rapid INR reversal, current evidence does not clearly inform whether the outcome at 24 hours would have been meaningfully different after vitamin K and FFP infusion or after intravenous vitamin K alone.

Correspondence

Dr Deborah M. Siegal, Division of Hematology and Thromboembolism, McMaster University, 50 Charlton Avenue East, L-208, Hamilton, ON L8N 4A6, Canada; Phone: 905-521-6024; Fax: 905-540-6568; e-mail: deborah.siegal@medportal.ca.

References

References
1
Schulman
 
S
Beyth
 
RJ
Kearon
 
C
Levine
 
MN
American College of Chest P
Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Ed. 8
Chest
2008
, vol. 
133
 
Suppl. 6
(pg. 
257S
-
2598S
)
2
Hylek
 
EM
Complications of oral anticoagulant therapy: bleeding and nonbleeding, rates and risk factors
Semin Vasc Med
2003
, vol. 
3
 
3
(pg. 
271
-
278
)
3
Hylek
 
EM
Evans-Molina
 
C
Shea
 
C
Henault
 
LE
Regan
 
S
Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation
Circulation
2007
, vol. 
115
 
21
(pg. 
2689
-
2696
)
4
Linkins
 
L
O'Donnell
 
M
Julian
 
JA
Kearon
 
C
Intracranial and fatal bleeding according to indication for long-term oral anticoagulant therapy
J Thromb Haemost
2010
, vol. 
8
 
10
(pg. 
2201
-
2207
)
5
Linkins
 
LA
Choi
 
PT
Douketis
 
JD
Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis
Ann Intern Med
2003
, vol. 
139
 
11
(pg. 
893
-
900
)
6
Guerrouij
 
M
Uppal
 
CS
Alklabi
 
A
Douketis
 
JD
The clinical impact of bleeding during oral anticoagulant therapy: assessment of morbidity, mortality and post-bleed anticoagulant management
J Thromb Thrombolysis
2011
, vol. 
31
 
4
(pg. 
419
-
423
)
7
Majeed
 
A
Hwang
 
HG
Connolly
 
SJ
, et al. 
Management and outcomes of major bleeding during treatment with dabigatran or warfarin
Circulation
2013
, vol. 
128
 
21
(pg. 
2325
-
2332
)
8
Witt
 
DM
Delate
 
T
Garcia
 
DA
, et al. 
Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding
Arch Intern Med
2012
, vol. 
172
 
19
(pg. 
1484
-
1491
)
9
Gomes
 
T
Mamdani
 
MM
Holbrook
 
AM
Paterson
 
JM
Hellings
 
C
Juurlink
 
DN
Rates of hemorrhage during warfarin therapy for atrial fibrillation
CMAJ
2013
, vol. 
185
 
2
(pg. 
E121
-
E127
)
10
Sjoblom
 
L
Hardemark
 
HG
Lindgren
 
A
, et al. 
Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study
Stroke
2001
, vol. 
32
 
11
(pg. 
2567
-
2574
)
11
Refaai
 
MA
Goldstein
 
JN
Lee
 
ML
Durn
 
BL
Milling
 
TJ
Sarode
 
R
Increased risk of volume overload with plasma compared with four-factor prothrombin complex concentrate for urgent vitamin K antagonist reversal
Transfusion
 
Published online ahead of print July 1, 2015. doi: 10.1111/trf.13191
12
Stainsby
 
D
Jones
 
H
Asher
 
D
, et al. 
Serious hazards of transfusion: a decade of hemovigilance in the UK
Transfus Med Rev
2006
, vol. 
20
 
4
(pg. 
273
-
282
)
13
Narick
 
C
Triulzi
 
DJ
Yazer
 
MH
Transfusion-associated circulatory overload after plasma transfusion
Transfusion
2012
, vol. 
52
 
1
(pg. 
160
-
165
)
14
Pandey
 
S
Vyas
 
GN
Adverse effects of plasma transfusion
Transfusion
2012
, vol. 
52
 
Suppl. 1
(pg. 
65S
-
79S
)
15
Toy
 
P
Gajic
 
O
Bacchetti
 
P
, et al. 
Transfusion-related acute lung injury: incidence and risk factors
Blood
2012
, vol. 
119
 
7
(pg. 
1757
-
1767
)
16
Robillard
 
P
Nawej
 
KI
Jochem
 
K
The Quebec hemovigilance system: description and results from the first two years
Transfus Apher Sci
2004
, vol. 
31
 
2
(pg. 
111
-
122
)
17
Goldstein
 
JN
Refaai
 
MA
Milling
 
TJ
, 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
, vol. 
385
 
9982
(pg. 
2077
-
2087
)
18
Dentali
 
F
Marchesi
 
C
Pierfranceschi
 
MG
, et al. 
Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis
Thromb Haemost
2011
, vol. 
106
 
3
(pg. 
429
-
438
)
19
Sarode
 
R
Milling
 
TJ
Refaai
 
MA
, 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
, vol. 
128
 
11
(pg. 
1234
-
1243
)
20
Parry-Jones
 
AR
Di Napoli
 
M
Goldstein
 
JN
, et al. 
Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage
Ann Neurol
2015
, vol. 
78
 
1
(pg. 
54
-
62
)
21
Sjoblom
 
LH
Hårdemark
 
HG
Lindgren
 
A
, et al. 
Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study
Stroke
2001
, vol. 
32
 
11
(pg. 
2567
-
2574
)
22
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
, vol. 
128
 
4
(pg. 
360
-
364
)
23
Kalina
 
M
Tinkoff
 
G
Gbadebo
 
A
Veneri
 
P
Fulda
 
G
A protocol for the rapid normalization of INR in trauma patients with intracranial hemorrhage on prescribed warfarin therapy
Am Surg
2008
, vol. 
74
 
9
(pg. 
858
-
861
)
24
Majeed
 
A
Meijer
 
K
Larrazabal
 
R
, et al. 
Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate
Thromb Haemost
2014
, vol. 
111
 
2
(pg. 
233
-
239
)
25
Boulis
 
NM
Bobek
 
MP
Schmaier
 
A
Hoff
 
JT
Use of factor IX complex in warfarin-related intracranial hemorrhage
Neurosurgery
1999
, vol. 
45
 
5
(pg. 
1113
-
1118
discussion 8-9
26
Chapman
 
SA
Irwin
 
ED
Beal
 
AL
Kulinski
 
NM
Hutson
 
KE
Thorson
 
MA
Prothrombin complex concentrate versus standard therapies for INR reversal in trauma patients receiving warfarin
Ann Pharmacother
2011
, vol. 
45
 
7-8
(pg. 
869
-
875
)
27
Siddiq
 
F
Jalil
 
A
McDaniel
 
C
, et al. 
Effectiveness of Factor IX complex concentrate in reversing warfarin associated coagulopathy for intracerebral hemorrhage
Neurocrit Care
2008
, vol. 
8
 
1
(pg. 
36
-
41
)
28
Woo
 
CH
Patel
 
N
Conell
 
C
, 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
, vol. 
81
 
1
(pg. 
110
-
115
)
29
Karaca
 
MA
Erbil
 
B
Ozmen
 
MM
Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in gastrointestinal hemorrhage due to warfarin usage in the ED
Am J Emerg Med
2014
, vol. 
32
 
6
(pg. 
660
-
664
)
30
Hanger
 
HC
Geddes
 
JA
Wilkinson
 
TJ
Lee
 
M
Baker
 
AE
Warfarin-related intracerebral haemorrhage: better outcomes when reversal includes prothrombin complex concentrates
Int Med J
2013
, vol. 
43
 
3
(pg. 
308
-
316
)
31
Cartmill
 
M
Dolan
 
G
Byrne
 
JL
Byrne
 
PO
Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies
Br J Neurosurg
2000
, vol. 
14
 
5
(pg. 
458
-
461
)
32
Sarode
 
R
Matevosyan
 
K
Bhagat
 
R
Rutherford
 
C
Madden
 
C
Beshay
 
JE
Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage
J Neurosurg
2012
, vol. 
116
 
3
(pg. 
491
-
497
)
33
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
Thromb Haemost
1997
, vol. 
77
 
3
(pg. 
477
-
480
)
34
Fredriksson
 
K
Norrving
 
B
Stromblad
 
LG
Emergency reversal of anticoagulation after intracerebral hemorrhage
Stroke
1992
, vol. 
23
 
7
(pg. 
972
-
977
)
35
Huttner
 
HB
Schellinger
 
PD
Hartmann
 
M
, 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
, vol. 
37
 
6
(pg. 
1465
-
1470
)
36
Sarode
 
R
Matevosyan
 
K
Bhagat
 
R
Rutherford
 
C
Madden
 
C
Beshay
 
JE
Rapid warfarin reversal: a 3-factor prothrombin complex concentrate and recombinant factor VIIa cocktail for intracerebral hemorrhage
J Neurosurg
2012
, vol. 
116
 
3
(pg. 
491
-
497
)

Competing Interests

Conflict-of-interest disclosures: D.M.S. has participated in advisory boards for Boerhinger Ingelheim, Portola Pharmaceuticals, and Daiichi Sankyo and has developed educational material for Interactive Forums. W.J.S. has received research funding from Fresenius-Kabi and has consulted for Momenta Pharmaceuticals.

Author notes

Off-label drug use: None disclosed.