Prothrombin Complex Concentrate for Vitamin K Antagonist-Associated Intracranial Hemorrhage　― Global Evidence and the Japanese Perspective ―

Abstract

Patients receiving vitamin K antagonists (VKAs) are at increased risk of bleeding. Intracranial hemorrhage (ICH) is a major cause of morbidity and mortality in this population, and is a particular concern among Japanese clinicians, given reports of an elevated risk of this bleeding type in patients of Asian ethnicity. Patients with VKA-associated ICH require rapid international normalized ratio (INR) reversal, and treatment guidelines suggest the use of prothrombin complex concentrates (PCCs) or plasma for this purpose. Although European and US guidelines recommend PCCs for the treatment of VKA-associated major bleeding, they do not make a specific recommendation in the setting of ICH, owing to the lack of comparative evidence. In contrast, Japanese guidelines recommend the use of PCCs rather than plasma for VKA reversal in patients with ICH; however, these agents are not currently licensed in Japan for this indication. Here we review the available evidence on the use of PCCs for the treatment of VKA-associated ICH, both globally and specifically in Japanese settings. Overall, the evidence reviewed here supports the use of PCC for rapid VKA reversal in these patients.

The vitamin K antagonist (VKA) warfarin is the most commonly used anticoagulant in Japan, with more than 1 million prescriptions issued in 2015.¹ Although effective for the treatment and prophylaxis of various prothrombotic conditions, the use of VKAs is frequently associated with bleeding complications;^2,3 these events are usually minor,⁴ but may also be life threatening.

A systematic review of global studies in VKA-treated patients with atrial fibrillation indicated that the annual rate of major hemorrhage ranges from 1.3% to 7.2%; the annual rate of intracranial hemorrhage (ICH) was 0.1–2.5%.⁵ ICH is a major cause of mortality and morbidity in these patients; evidence from a large US cohort suggests that almost half of all warfarin-associated ICHs are fatal,^6,7 and that these account for almost 90% of all deaths caused by warfarin-associated bleeding.⁶

VKA-associated ICH is a particular concern among clinicians in Japan, owing to reports that Asian ethnicity is a risk factor for these events.^8–10 Although the reasons behind these observations are not fully understood, they may be partly attributed to genetic differences affecting warfarin metabolism or treatment response.^11–13

Although the incidence of ICH in Japan is high, evidence from a systematic review and meta-analysis suggests case fatalities may be lower in Japan than in other regions.¹⁴ Potential reasons for this include differences in study design, early referral to stroke units, the widespread use and availability of MRI and CT scans across Japan, and strict adherence to Japanese treatment guidelines. Nevertheless, it is important to note that the morbidity and concomitant effect on patient quality of life associated with ICH remains a major clinical problem.

Large hematoma volume and hematoma expansion have been associated with poor outcomes in ICH.¹⁵ Therefore, rapid VKA reversal is required in these patients, through prompt restoration of vitamin K-dependent coagulation factors (II, VII, IX and X). Reversal strategies are summarized in Table 1. Given that international normalized ratio (INR) reduction with vitamin K administration alone takes several hours,¹⁶ it is not recommended as a monotherapy in cases of acute major bleeding.^17,18 More rapid restoration of coagulation factors can be achieved by infusion of plasma or prothrombin complex concentrates (PCCs), concomitant with vitamin K. Despite traditionally widespread use of plasma for this purpose, its use is associated with several limitations, outlined in Table 1.^16–26 Given the advantages of PCCs over plasma, these agents are recommended for rapid VKA reversal in many treatment guidelines worldwide.^17–19

Table 1. VKA Reversal Strategies

Strategy / Key attributes
Interruption of VKA treatment
• May be sufficient in asymptomatic patients with an elevated INR and a low risk of bleeding16
• Not sufficient in emergency bleeding situations
Vitamin K
• Reversal can take several hours16
• Not recommended as a monotherapy in cases of major bleeding17,18
• Should be administered concomitantly with plasma or PCCs for urgent reversal17,18
FFP
• Contains all the vitamin K-dependent coagulation factors, but large volumes are required for INR reversal (risk of volume overload)16,17
• Delays related to blood typing and thawing; long infusion times16
• Potential for pathogen transmission and TRALI16,17
PCCs
• Virally inactivated concentrates of vitamin K-dependent coagulation factors16
• Can be administered in smaller volumes and over shorter infusion times than FFP16
• Preferred over plasma in many treatment guidelines17–19
4F-PCCs
• Contain all 4 vitamin K-dependent coagulation factors (non-activated FII, FVII, FIX and FX)
• Licensed for VKA reversal* (not in Japan)
3F-PCCs
• Contain clinically relevant quantities of non-activated FII, FIX and FX
• Evidence suggests that INR reversal with 3F-PCCs is suboptimal20,21
• Apart from Uman Complex,22 these products are not licensed for VKA reversal: indicated for the treatment and prophylaxis of bleeding events in patients with hemophilia B23,24
• Not available in Japan
Activated PCC
• Contains non-activated FII, FIX and FX and activated FVII
• Activated coagulation factors may be associated with increased risk of thrombosis25
• Not licensed for VKA reversal: indicated for the treatment of hemophilia A or B with inhibitors26

*The 4F-PCC available in Japan (PPSB-HT Nichiyaku) is licensed for the treatment of hemophilia B and not for VKA reversal. F, factor; FFP, fresh frozen plasma; INR, international normalized ratio; PCC, prothrombin complex concentrate; TRALI, transfusion-related acute lung injury.

Although PCCs are preferred over plasma for VKA reversal in cases of major bleeding,^17–19 European treatment guidelines for VKA-associated ICH state that no specific recommendation can be made, given the lack of evidence from randomized controlled trials (RCTs) in this setting at the time of publication.²⁷ US guidelines also do not make a strong recommendation, but propose that PCCs may be considered over plasma, based on the lower complication rate and more rapid INR reduction time.²⁸ Conversely, Japanese guidelines suggest the use of PCC rather than plasma for the treatment of patients experiencing ICH during warfarin therapy;²⁹ however, none of the non-activated 4-factor PCCs (4F-PCCs) are currently licensed for VKA reversal in Japan. We review the current evidence on the use of PCCs for the reversal of VKA-associated ICH, with a focus on Japan. The literature search strategy is described in Supplementary Methods.

Review of the Evidence

Global Studies

PCC vs. Plasma Several studies have compared PCC and plasma for VKA reversal in patients with ICH (Table 2).^30–41 Overall, use of PCC rather than plasma was associated with more rapid INR reduction^31,38,41 or greater proportions of patients achieving the INR target,^{30,33,34,38,39} although statistical comparisons between groups were not always made. Evidence suggests that rapid INR reversal is important to prevent hematoma expansion.^39,42,43 Because INR reversal can be achieved more rapidly with PCC than with plasma, lower rates of hematoma expansion would be expected in patients treated with PCC. In line with this, studies that reported hematoma expansion outcomes generally favored the use of PCC over plasma,^31,33,39 or showed no signficant difference between groups.³²

Table 2. Comparative Studies Evaluating PCC for VKA Reversal in Patients With Intracranial Hemorrhage, 2008–2016

Citation	Study location	Study design (n)	PCC used	No. of patients in each treatment group		Key efficacy results	Key outcomes	Key safety results
				PCC	Comparator
4F-PCC
Huhtakangas et al35	Finland	Retrospective case series (n=181)	4F-PCC	41	No PCC: 140 (included FFP and/or vitamin K or no reversal agent)	• Not reported	• 3-month mortality rates were 37% and 69% for the PCC and no PCC groups, respectively • 1-year survival was significantly higher in the PCC group compared with the no PCC group (P<0.001)	• Not reported
Kuwashiro et al42	Japan	Review of medical records (n=50)	4F-PCC	22	Standard of care (no PCC): 28	• After 2 h and 24 h, INR values were significantly lower in the PCC group vs. the control group	• Among those with an INR >2.0 at admission, rates of hematoma enlargement (P=0.017), poor outcome (P=0.045) and in-hospital mortality (P=0.042) were significantly lower in the PCC vs. control groups	• Not reported
Majeed et al36	Canada, Sweden, the Netherlands	Retrospective, multicenter trial (n=135)	4F-PCC	100	Plasma: 35	• Not reported	• 38% of patients died within 30 days of follow-up, 54% and 32% of those in the plasma and PCC groups, respectively. After adjusting for covariates, there was no significant difference in mortality rates between treatment groups	• Not reported
Steiner et al39	Germany	Multicenter, prospective, open-label, randomized, blinded-endpoint study (n=50)	4F-PCC	27	FFP: 23	• INR decreased to ≤1.2 within 3 h in 9% and 67% of patients in the FFP and PCC groups, respectively	• Hematoma expansion at 3 h was greater in the FFP group compared with the PCC group (23.7 vs. 9.7 mL; P=0.023) • 90-day mortality rates were 35% and 19% for the FFP and PCC groups, respectively (P=NS) • No significant between-group differences observed for neurological outcomes	• 6 SAEs were judged to be FFP-related (hematoma expansion, n=4; anaphylactic reaction, n=1; ischemic stroke, n=1) and 2 PCC-related (ischemic stroke and pulmonary embolism) • 1 TEE was reported in the FFP group, 7 TEEs were reported in the PCC group and 1 further TEE was reported in a patient who received PCC after FFP
Yanamadala et al41	USA	Prospective, observational study (n=33)	4F-PCC	5	FFP: 28	• Time to INR reversal (<1.6) was significantly shorter in the PCC group vs. the FFP group (65 vs. 256 min; P<0.05)	• Not reported	• Not reported
3F-PCCs
Edavettal et al31	USA	Retrospective comparison between PCC and historical controls (n=60)	3F-PCC	28	FFP: 32	• INR <1.5 achieved more rapidly in the PCC group than in the control group (P=0.033) • Significantly fewer units of FFP administered in PCC group vs. control (P<0.001)	• Significantly lower proportion of patients experienced hematoma expansion in the PCC vs. FFP group (P=0.031) • Lower mortality rate in the PCC group vs. control (6.9% vs. 14.7%; P=NS) • Lower amount of neurosurgical intervention in the PCC group vs. control (10.3% vs. 25.5%)	• Not reported
Fong et al32	Hong Kong	Retrospective historical cohort study (n=85)	3F-PCC	23*	FFP: 33*	• Mean INR decreased from 2.81 to 1.21 within 24 h following PCC infusion; 87.9% of patients achieved INR ≤1.4 within 24 h (INR data not available for FFP group)	• Hematoma expansion was observed in 15.8% of those in the PCC group vs. 40.0% in the FFP group (P=NS) • Neurological deterioration was significantly lower in patients administered PCC vs. FFP (P=0.027) • No significant difference between mortality rates in PCC and FFP groups	• 1 TEE was reported in patients receiving PCC
Frontera et al33	USA	Prospective observational study (n=64)	3F-PCC	16	FFP: 25 PCC+FFP: 23	• Target INR <1.4 achieved in 88%, 84% and 70% of patients treated with PCC, FFP and PCC+FFP, respectively; mean post-reversal INR was 1.2, 1.3 and 1.3, respectively	• After adjustment, PCC was associated with lower risk of death/severe disability at 3 months (OR: 0.02), while FFP was associated with a higher risk (OR: 51.6) • New/expanded hemorrhage occurred more often in the FFP alone vs. other treatment groups (28% vs. 0% and 17% in the PCC alone and PCC+FFP groups, respectively; P=0.020)	• Treatment-related complications occurred in 19%, 28% and 17% of patients treated with PCC, FFP and PCC+FFP, respectively (P=NS); thrombotic complications occurred in 12.5%, 16% and 9%, respectively (P=NS)
Hanger et al34	New Zealand	Retrospective review (n=88)	3F-PCC	22†	No PCC: 39† (FFP with no PCC: 21)	• Within 24 h, INR ≤1.2 was achieved in 20/23 patients who received PCC • In the FFP with no PCC group, 12/21 patients achieved INR ≤1.2 within 24 h	• Earlier treatment with PCC was associated with improved survival • Surviving patients had greater gains in functional independence when treated with PCC compared with non-PCC treatment	• Not reported
Pinner et al47	USA	Retrospective chart review (n=24)	3F-PCC	9	rFVIIa: 15	• INR ≤1.3 within 1 h achieved by 5/6 (83%) patients in rFVIIa group and by 1/5 (20%) patients in the PCC group (note that not all patients received concomitant vitamin K)	• Hematoma expansion occurred in 20% of patients in the rFVIIa group, compared with 11% in the PCC group • 34% of patients died in each group	• Thrombotic complications occurred in 3 patients (rFVIIa, n=1; PCC, n=2)
Siddiq et al38	USA	Retrospective chart review (n=19)	3F-PCC	10 (also received FFP)	FFP: 9	• Mean INR reduced from 2.44 to 1.34 and 1.84 to 1.34 in the PCC and no PCC groups, respectively • 80% and 33% of patients achieved INR ≤1.4 3–4 h post treatment in the PCC and no PCC groups, respectively • Change in INR/h was significantly higher in the PCC group (0.27) vs. the no PCC group (0.06; P<0.005)	• 90% and 66% achieved a good recovery (GCS 14–15) at the time of discharge in the PCC and no PCC groups, respectively (P=NS) • 1 and 2 patients died in the PCC and no PCC groups, respectively	• No AEs reported in either group
Woo et al40	USA	Retrospective chart review (n=63)	3F-PCC	8	FFP: 46 rFVIIa: 9	• Time to INR reversal was more rapid with PCC or rFVIIa than with FFP • INR rebound occurred more frequently with rFVIIa than with FFP or PCC	• 24%, 22% and 0% of patients died before discharge in the FFP, rFVIIa and PCC groups, respectively	• 3 patients had potential complications (FFP, n=1; rFVIIa, n=2)
Unspecified or both 3F- and 4F-PCCs used
Alonso de Leciñana et al30	Spain	Observational study of cohorts from prospective multicenter registries (n=71)	Not specified	50	FFP: 6 Vitamin K only: 3 No reversal: 12	• INR <1.5 was achieved in 64%, 50% and 33% of those treated with PCC, FFP and vitamin K monotherapy, respectively	• Not reported by treatment	• No TEEs reported during hospital stay
Parry-Jones et al37	Argentina, Australia, Finland, France, Germany, Italy, the Netherlands, UK and USA	Observational, retrospective pooled analysis of 16 registries (n=1,547)	Not specified (3F-PCC or 4F-PCC)	585	FFP: 377 FFP+PCC: 131 No reversal: 454	• Not reported	• No significant difference in risk of death between PCC and FFP; lowest case fatality with PCC+FFP	• Not reported

*After exclusion of patients with GCS ≤8/immediately intubated/scheduled for operation on presentation; ^†after exclusion of palliated patients. AE, adverse event; GCS, Glasgow coma scale; OR, odds ratio; rFVIIa, recombinant activated factor VII; SAE, serious adverse event; TEE, thromboembolic event. Other abbreviations as in Table 1.

Overall, there is currently a lack of comparative evidence from RCTs in this population, with only 1 recent RCT conducted in patients with VKA-associated ICH.³⁹ Although other controlled comparisons of PCC and plasma have been conducted for urgent VKA reversal in cases of major bleeding⁴⁴ or prior to urgent surgical procedures,⁴⁵ these studies included few patients with ICH. Of the 202 patients included in the major bleeding study, 24 presented with ICH (4F-PCC, n=12; plasma, n=12).⁴⁴ No significant between-group differences were observed in terms of hemostatic efficacy; however, the small number of patients in this category may have resulted in insufficient power to detect any differences.

In contrast, data from the study by Steiner et al, which was conducted exclusively in patients with ICH, favors the use of 4F-PCC over FFP for rapid INR reversal: significantly more patients in the 4F-PCC group achieved the primary endpoint (INR ≤1.2 within 3 h of treatment) than in the plasma group (18/27 [67%] vs 2/23 [9%]; P=0.0003).³⁹ This rapid INR reduction was associated with less extensive hematoma expansion with 4F-PCC vs. FFP. Although these observations may not have translated into a clinical benefit (no significant between-group differences were observed for clinical outcome measures, such as deaths, modified Rankin Scale (mRS) and extended Glasgow Outcome Scale scores at day 90), the study was not powered for these endpoints. Of note, there were 5 deaths from hematoma expansion in the FFP group, and no fatal hematoma expansions among patients treated with 4F-PCC.

A large systematic review and meta-analysis comparing PCCs and FFP for warfarin reversal in various settings demonstrated a significant reduction in 30-day all-cause mortality with PCC vs. FFP (P=0.006).⁴⁶ This meta-analysis included 13 studies, 6 of which were conducted exclusively in patients with ICH. Subgroup analyses by bleeding site were also conducted; administration of PCC significantly reduced all-cause mortality compared with FFP in patients with intracranial bleeding (P=0.04), but not in those with extracranial bleeding (P=0.18).

Three of the studies identified in our search were included in the meta-analysis. In a few further studies we reviewed, significantly higher survival rates were demonstrated in patients treated with PCC vs. patients in comparator groups; however, it should be noted that management of patients in the latter groups varied, with patients receiving plasma, vitamin K or no reversal agent.^33–35,42 In other studies, mortality rates were lower in the PCC group than in the plasma group, but statistical signficance was not reached.^31,32,36

PCC vs. rFVIIa Another treatment option that has been investigated for VKA reversal in patients with ICH is recombinant activated factor VII (rFVIIa).^40,47 Two retrospective chart reviews compared 3-factor PCC (3F-PCC) and rFVIIa for this purpose (Table 2).^40,47 In one of these studies, there was no difference in time to INR reversal with 3F-PCC or rFVIIa; however, there was an increased risk of INR rebound with rFVIIa.⁴⁰ Conversely, in the other study, INR ≤1.3 within 1 h was achieved by 5/6 (83%) evaluable patients treated with rFVIIa, compared with 1/5 (20%) of those treated with 3F-PCC, although this did not translate into a clinical benefit; hematoma expansion occurred in 3/15 (20%) and 1/9 (11%) of those treated with rFVIIa and 3F-PCC, respectively.⁴⁷

It should be noted that both these studies compared rFVIIa with 3F-PCC, and evidence from ICH and other settings suggests that VKA reversal with 3F-PCC is suboptimal.^20,21 Direct comparisons of 3F- and 4F-PCCs for this purpose are only reported in a few retrospective studies,^48–51 mostly conducted in patients requiring VKA reversal owing to major bleeding, including ICH. In all studies, a greater proportion of patients achieved INR targets (varied by study, ranging from ≤1.3 to ≤1.5) in the 4F-PCC vs. the 3F-PCC group, reaching statistical significance in 2 of the 4 studies.^48,51 Interestingly, in the recent meta-analysis described earlier, a mortality benefit over FFP was demonstrated with 4F-PCCs (P=0.005), but not with 3F-PCCs (P=0.47).⁴⁶

Safety

Historically, there has been concern over the potential association of PCCs with thromboembolic events (TEEs), which resulted from observations in patients with hemophilia treated with high, repeat doses of activated PCCs.⁵² However, most modern PCC formulations contain non-activated factors and antithrombotic components (such as protein C and protein S), reducing the risk of TEEs. A systematic review and meta-analysis of 27 studies in patients treated with PCC for VKA reversal in various settings (including ICH) estimated that the risk of these complications is low (1.4%).⁵³

In our search, TEE rates in PCC-treated patients varied widely from 0% to 25.9%, which may, at least in part, be attributed to differences in study design, safety monitoring strategies and sample size. When drawing conclusions from these data, it is critical to consider the low patient numbers included in many of the studies, the high levels of comorbidities, the generally poor prognosis of patients with ICH and, most importantly, the underlying risk of TEEs in populations receiving VKAs.

Conclusions regarding the relative safety of different reversal agents should also be made with caution, given the lack of comparative studies that adequately standardize patient population selection; treatment options such as PCCs may be administered in patients with the poorest prognoses, resulting in selection bias. One study comparing PCC with plasma in patients with VKA-associated ICH showed no significant difference in the proportion of patients experiencing TEEs,³³ while in the only RCT in the ICH population, no statistical comparison was made for this endpoint, and conclusions were limited by small sample sizes.³⁹ TEEs occurred in 7/27 patients in the PCC group, and 2/23 patients in the FFP group (one of these patients also received PCC because of inadequate INR reduction at 3 h).

Further complicating interpretation of safety data, once the VKA has been reversed, the underlying risk of TEEs in these patients is restored. As such, TEEs may occur because of the underlying condition and potential delay in reinitiating VKA therapy,⁵⁴ independently of the reversal strategy used. In support of this hypothesis, in the RCT described above, most of the TEEs (6/9) occurred at least 1 week after study treatment and in patients who had not restarted anticoagulation; only 1 patient (FFP group) had resumed VKA therapy at the time of the event. In the large meta-analysis comparing PCC and FFP for VKA reversal in a range of settings, the risk of TEEs was similar between groups (TEEs occurred in 15/358 [4.2%] and 17/349 [4.8%] of patients who received PCC and FFP, respectively).⁴⁶ In addition, an integrated analysis of the 2 largest RCTs comparing a 4F-PCC and plasma^44,45 showed no increased risk of TEEs with 4F-PCC in patients requiring VKA reversal owing to major hemorrhage or prior to urgent surgical procedures.⁵⁵

Dosing

Although treatment guidelines do not recommend a specific PCC dose to be used for VKA reversal in patients with ICH, the European Stroke Organisation guidelines report an example dose of 25–40 IU/kg to prevent hematoma expansion.²⁷ Most PCC manufacturers use a general dosing regimen based on body weight and pretreatment INR. For example, recommended doses of one 4F-PCC (Beriplex^®/Kcentra^®) range from 25 IU/kg for an INR of 2.0–3.9 up to 50 IU/kg for an INR >6.⁵⁶ The doses used in the studies reviewed here varied, but were generally consistent with these ranges; however, lower doses were sometimes administered.^35,42 Inadequate dosing of PCC has been suggested as a potential reason for failure to achieve INR reversal,^30,57 but no particular recommendations on more appropriate dosing regimens were made.

Three studies compared the efficacy of different PCC dosing strategies in patients with VKA-related ICH.^58–60 Abdoellakhan and colleagues⁵⁸ retrospectively assessed the effect of a change in protocol at their center in the Netherlands. A variable 4F-PCC dosing regimen (based on body weight, initial and target INR, according to manufacturer’s instructions; median dose 23 IU/kg) was compared with a fixed dosing schedule (1,000 IU followed by another 500 IU if the target INR ≤1.5 was not achieved) in patients with either traumatic or spontaneous bleeds. Though a fixed dosing regimen may have several advantages (e.g., no need to calculate dose and therefore a quicker administration time), this analysis demonstrated that fewer patients on this regimen achieved INR ≤1.5 after the first infusion compared with the variable dose group (68% vs. 96%; P=0.013). The authors concluded that the dose (1,000 IU; approximately 14 IU/kg for a 70-kg person) may have been too low. Although conclusions from this study were limited by its retrospective nature, use of a higher dose of PCC is also supported by results from a phase 3 randomized study of 4F-PCC use in patients with VKA-associated ICH,⁵⁹ and in a retrospective study of 3F-PCC use in patients receiving warfarin and presenting with traumatic brain injury.⁶⁰ In the phase 3 study, both doses of 4F-PCC (25 IU/kg and 40 IU/kg) were effective in reducing INR to ≤1.5. However, the higher dose reduced INR to a greater extent than the lower dose (INR ≤1.2 was achieved in 76.0% and 44.5% of patients receiving 40 IU/kg and 25 IU/kg, respectively), with no increase in the incidence of TEEs or death.⁵⁹ Although no effect on clinical outcomes was demonstrated, the benefit of using a higher dose of PCC should be evaluated in further studies.

Treatment of VKA-Associated ICH in Japan

As mentioned before, Japanese guidelines recommend the use of PCCs over FFP for the treatment of patients who develop ICH during anticoagulant therapy. Although these agents are not currently licensed for VKA reversal in Japan, off-label use of PCCs has been reported in some studies (Table 3).

Table 3. Evidence From Japan on the Use of PCCs in Patients With VKA-Associated Intracranial Hemorrhage

Citation	Study design	No. of patients	PCC used	Comparator?	Key efficacy results	Key outcomes	Key safety results
Kuwashiro et al42	Review of medical records	50 (PCC, n=22; control, n=28)	4F-PCC	Standard of care (no PCC)	• After 2 h and 24 h, INR values were significantly lower in the PCC group vs. the control group	• Among those with an INR >2.0 at admission, rates of hematoma enlargement (P=0.017), poor outcome (P=0.045) and in-hospital mortality (P=0.042) were significantly lower in the PCC vs. control groups	• Not reported
Takahashi et al61	Review of medical records	38 (PCC, n=24; FFP, n=14)	4F-PCC	FFP	• Initial INR values were not different between groups; however, INR values were significantly lower after treatment with PCC vs. FFP (P=0.004) • Time required for INR reduction was significantly shorter with PCC vs. plasma (P<0.0001)	• Survival rate was significantly higher in the PCC vs. FFP group (P=0.016)	• Not reported
Yasaka et al62	Review of medical records	42*	4F-PCC	NA	• INR <1.5 achieved after PCC administration in 96% patients with an initial INR 2.0–4.9 • 500 IU optimal for rapid INR correction if initial INR <5.0, but inadequate in those with a higher INR • Administration of concomitant vitamin K may allow for rapid INR correction and maintain this reduction for 12–24 h	• No hematoma expansion or deterioration of symptoms in 25/27 patients with cerebral hemorrhage	• No AEs, including TEEs, were observed in any patient
Yasaka et al63	Review of medical records	17† (PCC, n=13; vitamin K, n=4)	4F-PCC	Vitamin K only	• PCC administration with or without vitamin K was more effective in correcting INR than vitamin K alone • In those treated with PCC+vitamin K, INR decreased from 2.70 to a median of 1.13 at 10 min, and remained low at 12–24 h • INR in those treated with PCC without vitamin K decreased from 6.23 to 1.36 at 10 min, but then increased to 2.07 at 12–24 h • INR decreased slowly in those who received vitamin K only	• Cerebral hematoma expansion was seen in 2/11 patients treated with PCC (1 did not receive concomitant vitamin K and had an INR re-increase) • 2 patients treated with PCC died • 1/4 patients treated with vitamin K only died; the other 3 had small hematomas at the start of treatment and there was no clinical deterioration	• No TEEs during hospitalization (2–54 days)
Osaki et al64	Prospective observational study	50 (vitamin K monotherapy, n=22; vitamin K+PCC, n=18; vitamin K+PCC+FFP, n=2; vitamin K+FFP, n=1; no reversal, n=7)	4F-PCC	NA	• Not reported	• Hematoma expansion was documented in 2/7 (29%) patients who did not receive reversal therapy, 7/22 (32%) treated with vitamin K alone, and 4/21 (19%) treated with vitamin K+PCC and/or FFP	11 patients experienced TEEs, including 3 patients treated with vitamin K+PCC

*Only 35 with intracranial hemorrhage: cerebral hemorrhage, n=27; acute epidural hemorrhage, n=7; acute subdural hemorrhage, n=1; ^†only 15 with intracranial hemorrhage: cerebral hemorrhage, n=13; acute epidural hemorrhage, n=1; acute subdural hemorrhage, n=1. NA, not applicable. Other abbreviations as in Tables 1,2.

Use of PCC and FFP for VKA reversal was compared in a single-center retrospective analysis of 38 patients with left ventricular assist devices who developed ICH.⁶¹ As in the global studies reviewed earlier, INR reduction was more effective with PCC than with FFP, with INR values decreasing more quickly, and to a greater extent, in the PCC group. Furthermore, survival rates were also significantly greater in those treated with PCC compared with patients in the FFP group (P=0.016).

The efficacy of PCCs for VKA reversal in Japanese patients with ICH has also been evaluated in other small, medical record review studies.^42,62,63 The largest of these studies compared outcomes in 50 patients treated with (n=22) or without (n=28) PCC.⁴² Rapid INR reversal with PCC was more effective in preventing hematoma expansion, poor outcomes and in-hospital mortality, with lower rates for each outcome observed in those treated with PCC vs. control (P=0.017, P=0.045 and P=0.042, respectively).

As in Western populations, the optimal dose of PCC to use in Japanese patients with VKA-associated ICH has not been established. One study of 42 patients (including 35 with ICH) showed rapid INR reduction to <1.5 was achieved in 25/26 (96%) patients with an initial INR <5.0 with a dose of 500 IU (6.0–17.9 IU/kg); however, this dose was inadequate in those with an initial INR >5.0.⁶² Doses used in the studies conducted in Japan tended to be lower than doses used in studies of Western populations, which might be related to the lower body weight of Japanese patients. Another reason could be that physicians in Japan take a cautious approach to dosing in order to avoid thrombotic complications, as PCCs are not licensed in Japan for VKA reversal. No TEEs occurred in 2 of the Japanese studies that reported safety outcomes.^62,63 In a prospective, observational cohort analysis of treatment regimens for warfarin reversal in patients with ICH, 3/11 TEEs occurred in patients treated with PCC.⁶⁴ In 1 case, the TEE occurred >90 days after the ICH and the patient had been re-anticoagulated; VKA therapy had not been resumed in the other 2 patients at the time of the TEE. The remaining 8 TEEs occurred in patients treated with vitamin K alone, or who were not receiving any reversal agent. These findings highlight the importance of restarting anticoagulation in a timely manner because, as mentioned earlier, the reversal of anticoagulation exposes the patient to the thrombotic risk for which the anticoagulant was originally prescribed.

There is wide variation in preferred treatment strategies among physicians in Japan. In a nationwide survey, 295/315 respondents indicated that they aimed to normalize INR on admission of anticoagulated patients with ICH.⁶⁵ Of 315 respondents, 31 (9.8%) specified PCC as their first-choice reversal agent, although PCCs are not licensed for this indication in Japan, as mentioned earlier. Vitamin K was the preferred reversal agent for the majority of clinicians (199/315; 63.2%), followed by FFP (64/315; 20.3%). Vitamin K monotherapy was also the most common regimen in a more recent prospective, observational study of the choice of treatment options used for warfarin-associated ICH.⁶⁴ Of the 50 patients included in the study, 22 (44%) were treated with vitamin K only, 18 (36%) with concomitant PCC and vitamin K, 2 (4%) with a combination of PCC, FFP and vitamin K, and 1 patient with concomitant FFP and vitamin K.

The frequent use of vitamin K monotherapy for VKA reversal in these situations may be considered surprising as this strategy is not recommended for the treatment of major bleeding or ICH in Japan or elsewhere. In a chart review study of 17 patients presenting with hemorrhagic complications (15 with ICH), vitamin K monotherapy was less effective for rapid INR reversal than PCC with or without concomitant vitamin K.⁶³ Vitamin K monotherapy may be considered in certain clinical scenarios, such as in patients with left ventricular assist devices, where continuous anticoagulation is required. However, if more rapid INR reduction is required, as is very often the case, coadministration of PCC and vitamin K would be more appropriate. Administration of PCC without vitamin K was associated with increases in INR after the initial decrease, whereas INR reductions in those receiving PCC with vitamin K were sustained for 24 h. This, along with evidence from another study by the same authors,⁶² demonstrates that these treatments should be administered concomitantly.

The overall body of evidence on the use of PCCs in Japanese settings is promising, indicating that PCCs are more effective than plasma or vitamin K monotherapy for VKA reversal in patients with ICH. However, as much of the data currently available comes from small reviews of medical records, there remains a need for additional evidence on clinical outcomes to further strengthen the support for PCC use in this setting and to optimize dosing.

Beyond VKA Reversal

Prior to the advent of specific reversal agents, use of PCCs for the treatment of ICH associated with non-VKA oral anticoagulants (NOACs) was investigated in several studies and incorporated in clinical practice guidelines.^66–68 In a retrospective review, favorable outcomes were observed in 6/18 (33%) patients with rivaroxaban- or apixaban-associated ICH who were treated with 4F-PCC.⁶⁹ Now that specific NOAC reversal agents are available, or are in development, the future role of PCCs in this setting is unclear.

Conclusions and Summary

In summary, we can draw the following conclusions from the existing literature on the use of PCCs for the treatment of VKA-associated ICH.

• Overall, the studies reviewed here supported the use of PCC for rapid INR reduction in patients with VKA-associated ICH.

• Although there is a general lack of comparative evidence from RCTs, a recent RCT provides good-quality evidence supporting the use of 4F-PCCs over plasma for the treatment of VKA-associated ICH. Further investigation into potential clinical benefits of 4F-PCC, in terms of neurological outcome and mortality, may be warranted.

• The relative efficacy of rFVIIa vs. PCCs is unclear; only 2 retrospective studies have compared rFVIIa with a 3F-PCC for the treatment of VKA-associated ICH, and there are data available indicating that INR reversal with 3F-PCCs is suboptimal.

• TEE data should be interpreted in the context of a population at high risk for these events. With this in mind, it is important that anticoagulation is reinitiated in patients once the risk of thrombosis outweighs the risk of bleeding.

• Data from Japanese populations suggest that 4F-PCC (concomitant with vitamin K) is more effective for INR reversal than plasma or vitamin K monotherapy. However, data suggest that 4F-PCCs are underused in Japan, which may, in part, be because PCCs are not licensed for VKA reversal. There is a need for further data on the use of PCCs in Japanese patients, particularly from clinical practice settings.

Acknowledgments

Medical writing assistance was provided by Leanne Regan, PhD, of Fishawack Communications Ltd, funded by CSL Behring.

Conflicts of Interest

M.Y. has received honorarium from Bayer, BMS, Boehringer Ingelheim and Daiichi Sankyo, and grants from Boehringer Ingelheim and Sanofi. A.B. is an employee of CSL Behring. K.T. has received honorarium from Bayer, BMS, Boehringer Ingelheim and Daiichi Sankyo.

Supplementary Files

Supplementary File 1

Supplementary Methods

Figure S1. Literature search strategy.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-0428

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