Thrombosis Research 135 (2015) 9–19

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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres

Review Article

A systematic review of prothrombin complex concentrate dosing strategies to reverse vitamin K antagonist therapy☆ Nakisa Khorsand a,b,⁎, Hilde A.M. Kooistra a, Reinier M. van Hest c, Nic J.G.M. Veeger d, Karina Meijer a a

Division of Haemostasis and Thrombosis, Department of Haematology, University of Groningen, University Medical Centre Groningen, The Netherlands Central Hospital Pharmacy, The Hague, The Netherlands Department of Clinical Pharmacy, Academic Medical Centre, Amsterdam, The Netherlands d Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands b c

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 18 August 2014 Received in revised form 12 November 2014 Accepted 16 November 2014 Available online 22 November 2014

Management of patients with a major bleed while on vitamin K antagonist (VKA) is a common clinical challenge. Prothrombin Complex Concentrates (PCC) provide a rapid reversal of VKA induced coagulopathy. However, a well-defined PCC dosing strategy, especially in emergency setting, is still lacking. We performed a systematic review to describe the currently used PCC dosing strategies and to present their efficacy in terms of target INR achievement and clinical outcome. We used outcome definitions as used in the individual studies. MEDLINE and EMBASE databases were searched for studies reporting the use of PCC for emergency VKA reversal. Twenty-eight studies, including 4 randomized trials, were found. In these, fifteen different PCC dosing protocols were identified in which the PCC dose ranged from 8 to 50 IU factor IX/kg. These strategies were based on: bodyweight; bodyweight and initial INR; bodyweight and initial INR and target INR; individual doctors decision; or a fixed dose. Study quality was moderate with large variation in outcome definitions. Relatively good clinical and INR outcomes were reported with the use of any treatment protocol while less good results were reported for INR outcome when a predefined protocol was missing (doctor strategy). Lowest PCC dosages were infused in the fixed dose strategy. In emergency VKA reversal, a predefined PCC dosing protocol seems essential. We found no evidence that one dosing strategy is superior. Future studies should be designed to investigate if body weight and INR are relevant for PCC dosing. In these, we need uniform outcome definitions. © 2014 Elsevier Ltd. All rights reserved.

Keywords: Hematology (hemostasis and thrombosis) oral anticoagulants Vitamin-K dependent coagulation proteins prothrombin complex concentrates

Contents Introduction . . . . . . . Methods . . . . . . . . . Study Selection . . . Search Strategy . . . Quality Assessment . Quantitative Analyses Results . . . . . . . . . Study Selection . . . Study Characteristics Study Quality . . . . PCC Dosing Strategies Outcome Data . . .

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Abbreviations: VKA, Vitamin K Antagonist; PCC, Prothrombin Complex Concentrate; FFP, Fresh Frozen Plasma; 4 F-PCC, Four Factor PCC; 3 F-PCC, Three Factor PCC; INR, International Normalized Ratio; BW, Body Weight; INRi, Initial INR; INRt, Target INR; IU, International Unit. ☆ This manuscript has been presented as a poster at the American Society of Hematology (ASH) congress 2013, New Orleans, United States. ⁎ Corresponding author at: Escamplaan 900, 2547 EX, The Hague, The Netherlands. Tel.: +31 70 3217268; fax: +31 70 3217156. E-mail address: [email protected] (N. Khorsand).

http://dx.doi.org/10.1016/j.thromres.2014.11.019 0049-3848/© 2014 Elsevier Ltd. All rights reserved.

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N. Khorsand et al. / Thrombosis Research 135 (2015) 9–19

Discussion . . . . . . . . Conclusion . . . . . . . . Conflict of Interest Statement Acknowledgement . . . . References . . . . . . . .

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Introduction Management of patients with a major bleed while on vitamin K antagonist (VKA) therapy is a common clinical challenge. Prothrombin Complex Concentrates (PCC) provide a rapid and complete reversal of VKA induced coagulopathy. Their use is associated with several benefits when compared to Fresh Frozen Plasma (FFP) [1], which is recently confirmed in a multicenter randomized controlled trial [2]. Current guidelines [3–6] recommend the use of a four factor PCC (4 F- PCC) rather than FFP for reversal of VKA-induced coagulopathy in patients with a VKA-associated major bleeding. However, a well-defined PCC dosing strategy, especially in emergency setting, is still lacking. With the current use of PCC, efficacy is not maximal [2,7]. Even in study settings, rate of haemostatic efficacy is limited to 71% [2]. Outside clinical studies this is even lower resulting to high mortality rates [7]. Beside the efficacy of PCC, its safety has been subject to research for several decades as well. A meta-analysis reported the incidence of thromboembolic events after PCC treatment to be ±1.8% in patients receiving 4 F- PCC [8] while Sarode et al. [2] found 3.9% thrombotic events related to PCC in their randomized clinical trial. These thrombotic rate reports underscore the importance of appropriate use of PCC in acute VKA reversal. Furthermore, it is suggested that occurrence of thrombotic events may increase with higher PCC doses [9]. However, a well-defined PCC dosing strategy is, especially in emergency setting, still lacking. The aim of this systematic review is to describe the currently used PCC dosing strategies for emergency VKA reversal and to present their efficacy in terms of target INR achievement and clinical outcome.

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16 18 18 18 18

Uman[TIAB] OR PPSB[tiab] OR “factor IX concentrate”[tiab] OR Prothromplex[tiab] OR Autoplex[tiab]) AND ("Vitamin K/antagonists and inhibitors"[Mesh] OR "vitamin K antagonist"[tiab] OR "vitamin K antagonists"[tiab] OR warfarin[tiab] OR acenocoumarol[tiab] OR phenprocoumon[tiab] OR Anticoagula*[tiab] OR "Anticoagulants"[Mesh: NoExp] OR "coumarins"[MeSH Terms] OR coumarin*[tiab] OR VKA[tiab] OR anti-coagula*[tiab]) Furthermore, the EMBASE database (1980 to January 2014) was searched. The titles and abstracts of the studies were read by two assessors (NK and HAMK) to judge whether the study was potentially eligible. The full article was retrieved when the information in the title or abstract appeared to meet the inclusion criteria. The eligibility of all full text articles was then assessed independently by the two investigators. Disagreement between the two was resolved by consensus or by a third reviewer (KM) if consensus was not reached. Quality Assessment Quality assessment was performed by two assessors (NK and HAMK) using two quality assessment tools of Downs and Thomas [13, 14]. According to an extensive evaluation by Deeks et al., these are the most adequate tools to assess methodological quality and the risk of bias for randomized, non-randomized and observational studies [15]. Disagreement between the two assessors was resolved by consensus or by discussion with a third reviewer (KM). For the presentation of the quality of the studies we adopted the method as applied by Siegal et al. [16], in which we also added the total Downs (total number of favorable answers out of a total score of 27) and Thomas score (strong/moderate/weak).

Methods

Quantitative Analyses

This review was performed utilizing the methodology from the PRISMA Statement [10] and Moose reporting recommendations [11]. A protocol for this review was prospectively developed and registered in PROSPERO (Registration number: CRD42013003803) [12].

Quantitative data are primarily presented with the use of descriptive statistics. Where feasible, analysis on pooled data was performed. For all analyses, commercially available computer software (IBM SPSS Statistics version 19) was used. PCC dosages were predominantly described as presented in the original studies. However, for the quantitative analyses, all dosages were expressed as International Units of factor IX per kg bodyweight (IU F IX/kg). If the original study only reported on dosage per patient, a bodyweight of 75 kg was adopted to convert the PCC dosage. Efficacy parameters used to describe the outcome of the quantitative data are the proportion of patients that met the successful target INR or clinical outcome definition in each dosing strategy. For this we scored whether clinical outcome or INR targets were reached according to the pre-defined definitions of INR and/or clinical endpoint used in the concerning individual studies, irrespective of these outcomes were part of the primary or secondary endpoint of the individual study. Safety endpoints (i.e. thromboembolic events) were not included in the quantitative analysis.

Study Selection Studies were included if they reported the use of PCC for emergency reversal of VKA therapy. Additional inclusion criteria were the reporting of PCC dosing strategy, and results presented as achieving target INR or any haemostatic/clinical outcome parameter, and a prospective enrollment of patients, and the availability of a full text publication in English, Dutch, German or French language. All PCC studies in non-VKA patients, case-reports (N b 5), duplicates and studies on activated PCC were excluded. Furthermore, to minimize inclusion of studies without a pre-defined dosing strategy, we excluded retrospective studies. Search Strategy

Results We searched the MEDLINE (1966 to January 2014) electronic database using the following strategy: ((prothrombin[tiab] AND complex[tiab] AND concentrate*[tiab]) OR "prothrombin complex concentrates" [Supplementary Concept] OR Beriplex[TIAB] OR Prothrombinex[TIAB] OR Octaplex[TIAB] OR Bebulin [TIAB] OR Cofact[TIAB] OR PROPLEX[TIAB] OR Profilnine[TIAB] OR

Study Selection A total of 1,510 citations (411 MEDLINE, 1,099 EMBASE) were identified by our search strategy (Fig. 1). Of these, 333 studies were duplicates. After screening of the title and abstract using the predefined

N. Khorsand et al. / Thrombosis Research 135 (2015) 9–19

11

Fig. 1. Flow chart of study inclusion. 1Exclusion based on title and abstract screening. 2Reason for exclusion was: abstract only: 71, no original data: 57, no VKA patients/healthy volunteers/in-vitro: 3, case reports (N b 5): 6, retrospective study: 7, neither clinical outcome nor INR outcome parameter: 9, No PCC cohort: 1, duplicate PCC data in other paper with different outcome parameter: 2.

inclusion and exclusion criteria, 184 were retrieved for more detailed evaluation. Of these 71 were excluded because only a congress abstract was available, as well as 57 because they did not contain (original) data (letters, editorials, reviews). An additional 28 studies were excluded for other reasons (e.g. Non-VKA patients, in-vitro studies, retrospective studies). Thus, a total of 28 studies was included in our systematic review. Study identification and selection are summarized in Fig. 1. Of the 184 citations that were retrieved for more detailed evaluation, the assessors agreed on the eligibility of 175 (95%) studies, reached consensus on 4 (2.2%) other studies, and consulted the third reviewer for consensus on 5 (2.7%) studies. Study Characteristics Study characteristics are provided in Table 1. Eleven different brands of PCC were used of which 3 were 3 F-PCC. A total of 431 patients were treated with 3 F-PCC (N = 6 studies) while 2,132 patients were treated with 4 F-PCC (N = 22 studies). The total number of included patients in the 28 included studies was 2,563, ranging from 6 to 686 patients per study. PCC was indicated in a total of 1,996 patients because of a major bleed, in 342 because of emergency surgery, and in 90 VKA-patients for other reasons. For 135 patients we could not trace back the indication to major bleed or emergency surgery. In the 28 included studies a very large heterogeneity in study outcome parameters was observed with six different primary endpoints. These were the proportion of patients reaching a target INR in 16 studies (57%), INR decrease in 4 (14%), incidence of thromboembolic complications in 2 (7%), clinical response in 3 (11%), ‘appropriate PCC treatment’ in 2 studies (7%) and 1 study with co-primary endpoints existing of clinical response and reaching target INR (4%). In addition, twelve different definitions were used for the above mentioned primary endpoints. Firstly, target INR as a primary endpoint was 1.5 in 6 studies, 1.3 in three studies, 3.5 and 2 in one study each or it was differentiated in two or more target INRs (e.g. partial or complete reversal) in 6 studies. Secondly, incidence of thromboembolic events as a primary endpoint was either reported as occurrence of thromboembolism within 7 or within 30 days after PCC administration. Thirdly, ‘appropriate PCC treatment’ was defined as adherence to a national

guideline in one study and defined by the authors in another study. Lastly, clinical response definition ranged from cessation of bleed in one study, intracranial hematoma enlargement in another study to no further bleeding complications in the third study. In the fourth study in which clinical response counted as a co-primary endpoint, a hemostatic efficacy scale was developed in discussion with the Food and Drug Administration. Secondary outcome parameters included mainly a mixture of above mentioned parameters. Additional secondary parameters included the impact of concomitant FFP use, INR and/or coagulation factor changes over a period up to 96 hours after PCC, time to PCC infusion, and time to emergency surgery. The efficacy outcome definitions as used for the quantitative analyses for this review are as reported in the individual studies for clinical outcome and target INR achievement (Table 1). Study Quality As shown in Table 2, study quality was moderate with potential for biased comparisons. Four studies used a randomized design. The majority of the included studies was single arm (N = 18, 64%), and open label (N = 28, 100%). Five studies reported on PCC as part of a comparative study with FFP [2,17–19] or vitamin K [20] and five studies compared different PCC dosing strategies [21–25]. For this review, only the prospective PCC cohorts are included. The remaining studies (N = 18) reported on the effectiveness or the safety of PCC in a single arm setting [26–43]. PCC Dosing Strategies Fifteen different PCC protocols were identified. As shown in Table 3, these dosing protocols were based on five main strategies, namely based on bodyweight (‘BW’), bodyweight and initial INR (‘BW + INRi’), bodyweight and initial INR and target INR (‘BW + INRi + INRt’), individual doctors decision (‘doctor’) or a fixed dose strategy (‘fixed’). The most studied strategy was the BW + INRi + INRt strategy (N = 1,219 patients in 9 studies). The BW strategy (307 patients in 7 studies), fixed strategy (418 patients in 7 studies), BW + INRi (309 patients in 4

12

Table 1 baseline characteristics of the included studies. PCC brand

Study design

Clinical outcome

INR outcome

Study N (PCC population cohort)

Bobbitt [26]

PTX-VF

None

Target INR b1.5

All

173

Cartmill [18]

9A-BPL

None

Target INR b1.5

ICH

6

Demeyere [17]

Cofact

None

Target INR b1.5

Surg

20

Desmettre [27]

Octaplex

Bleeding control (not further defined)

Target INR b1.5

ICH, ECH

686

Desmettre [28]

Octaplex Kaskadil

None

None

All

252

Dowlatshahi [29]

Octaplex

None

Target INR b1.5

ICH

141

Evans [30]

Beriplex

Clinical response (not further defined) over a period of 48 hours

Target INR b1.3

ECH

10

Fischer [31]

None

All

39

Haghpanah [32]

Partieller Prothrombin Komplex Uman

Observational, single-arm study: to determine the incidence of thromboembolic events within 30 days after PCC treatment Non-randomized, comparative study: PCC cohort compared to historic FFP-treated controls in ICH patients needing urgent neurosurgery RCT: PCC versus FFP before urgent cardio pulmonary bypass surgery Observational, multicenter, single-arm study: to assess management of acute VKA reversal with PCC in France Observational, multicenter, single-arm study: to assess acute VKA reversal with PCC while indication and dosage of its use are at the discretion of the physician Multicenter, observational single-arm study: to study the efficacy of PCC to correct the INR and its efficacy Observational single-arm cohort study: to assess efficacy and safety in patients with initial INR N 8 and indication for PCC Observational, single-arm study: to report on the usage of PCC for acute VKA reversal

Target INR b3.5

ECH

37

Imberti [33]

Uman

Target INR b1.5

ICH, ECH

126

Kerebel [21]

Octaplex

ICH

29 -30

Khorsand [23]

Cofact

Mean INR at 10 minutes after PCC infusion. In this patients who reached target INR b1.5 are reported Target INR b2

ECH, Surg

35

Khorsand [22]

Cofact

Target INR b2

ECH

101 139

Urgent surgery: no intra or post operative bleeding complications. In emergent bleeding: bleeding control and no further complications Non-randomized, pre-post intervention study: to None evaluate the efficacy of PCC Multicenter, observational single-arm cohort None study: to evaluate the efficacy and safety of PCC Multicenter RCT: ICH patients receiving 25 IU/kg Overall clinical response- verbal rating scale at 48 hours (cohort 1) or 40 IU/kg PCC (cohort 2) Successful clinical outcome as specified for invasive Non-randomized, comparative pre-post cohort procedures, visual and non-visual major bleeds study: PCC cohort (1000 IU/patient, cohort 1) after fixed dose protocol introduction compared with a retrospective variable dosing cohort (cohort 2) Successful clinical outcome as specified for invasive Non-randomized, comparative, two-cohort study: bleeding emergencies treated with a fixed procedures, visual and non-visual major bleeds PCC dose (1000 IU/patient. cohort 1) versus a variable PCC dosing regimen (cohort 2)

N. Khorsand et al. / Thrombosis Research 135 (2015) 9–19

Author

Kuwashiro [19]

PPSB-HT NICHIYAKU

Lavenne-Pardonge PPSB-SD [34] Beriplex

Lubetsky [36]

Octaplex

Majeed [37]

Pabinger [38]

Prothromplex Octaplex Beriplex Beriplex

Preston [39]

Beriplex

Riess [40]

Octaplex

Roodheuvel [25]

Cofact

Sarode [2]

Beriplex

Tran [41]

PTX-VF

Van Aart [24]

Cofact

Vigue [42]

Kaskadil

Yasaka [20]

PPSB-HT NICHIYAKU

Yasaka [43]

PPSB-HT NICHIYAKU

Multinational, single-arm cohort study: to evaluate the efficacy and safety of PCC Multicenter, single-arm study: to evaluate efficacy and safety of PCC Multinational, single-arm cohort study: to determine PCC efficacy Observational study comparing a PCC protocol in two target INR cohorts with usage of no PCC-protocol in these two target INR cohorts Multinational, Phase IIIB RCT: major bleeding patients were randomly allocated either PCC or FFP to reverse VKA therapy Single-arm, cohort study: to determine PCC efficacy when used without FFP RCT: acute VKA reversal by a low fixed dose regimen (500 IU/patient. arm 1) versus a variable dosing regimen (arm 2) Observational, single-arm cohort study: to report on the use of a bolus infusion of PCC after which neurosurgery started without waiting for INR results Cohort study: bleeding emergencies were treated with PCC only, vitamin K or a combination of PCC and vitamin K Single-arm cohort study: to evaluate PCC efficacy

Occurrence of hematoma enlargement after PCC infusion

None

ICH

22

Bleeding control (not further defined)

Target INR b 1.5 or target INR b2 for partial or complete reversal

ICH, ECH

14

Cessation of bleed or in case of invasive procedures: prevention of intra and postprocedural bleeding Clinical response as graded by investigators (not further defined) Evidence of continuous bleeding as clinical, visual or radiologicalevidence. In case of invasive procedure: assessment of bleeding complications by surgeon Clinical hemostatic efficacy rated by physician based on a prompt cessation of bleed. Cessation of bleed not further defined. None

Any changes in INR with a target INR of 1

ICH, Surg

8

INR decrease in 10 minutes (no pre defined target INR) None

ECH, Surg

20

All

160

Target INR b1.3

All

43

Target INR b1.3

All

42

Surg

56

All

60

Clinical efficacy as three-point-verbal rating scale for bleeding Target INR b1.3 and target INR b2.1 for partial or control (not further defined) complete reversal None Target INR b1.5 or target INR b2.1 for partial or complete reversal Hemostatic efficacy scale over a period of 24 hours as predefined for each bleeding time

Target INR b1.3

ECH, ICH

98

Achievement of haemostasis (not further defined) and no bleeding complications Bleeding control (not further defined) and the need for repeating PCC

Target INR b1.4 and target INR b2 for partial or complete reversal Target INR b1.5 or target INR b2.1 for partial or complete reversal

Ech, Surg

50

All

47 -46

Glasgow Outcome Scale at 6 months after PCC treatment

Target INR b1.5

ICH

18

Clinical deterioration or haematoma enlargement

INR decrease over a period of time without a predefined target INR

ICH, ECH

13

None

Target INR b1.5

All

42

N. Khorsand et al. / Thrombosis Research 135 (2015) 9–19

Lorenz [35]

Non-randomized, comparative study: cohort 1 PCC added to standard therapy, cohort 2 standard therapy for ICH Observational, single-arm cohort study: to corroborate efficacy results obtained by van Aart et al. [24] Observational, single-arm cohort study: to evaluate the effectiveness and safety of PCC Multicenter, single-arm phase II study: to assess the efficacy of PCC Multicenter, observational, single-arm cohort study: to investigate the safety of PCC

RCT = Randomized Controlled Trial, Surg = urgent surgery, ICH = intracranial hemorrhage, ECH = extracranial major hemorrhage, All = indication is ECH, ICH and/or Surg

13

14

Table 2 Study Quality Assessment. Randomized Controlled Trials

Observational Studies

Random Allocation Blinding allocation conceal-ment

Appropriate Loss to follow-up outcome reported analyses

Score

Author

Consecutive Analyses protocol enrollment in place before enrollment

Intervention/ control setting similar (if applicable)

Intervention /control time frame similar (if applicable)

Blinded assessment of outcome

Loss to follow-up reported

Score

Demeyere [17]

Yes

Yes

Yes

Yes

S-22

Kerebel [21]

Yes

NR

Yes

Yes

M-20

Bobbitt [26] Cartmill [18] Desmettre, [27] Desmettre, [28] Dowlatshahi [29] Evans [30] Fischer [31]

Yes No Yes Yes Yes No No

Yes NR No Yes Yes Yes No

NA NA NA NA Yes NA NA

NA NA NA NA Yes NA NA

No No No No No No No

No Yes Yes No No No Yes

W-19 M-11 M-19 M-19 W-21 W-11 W-12

Sarode [2]

Yes

Yes

Participants: Yes Outcome assessors: Yes Participants: NR Outcome assessors: NR Participants: NR Outcome assessors: Yes

Yes

Yes

S-21

Van Aart [24]

NR

Yes

Participants: No Outcome assessors: No

No

Yes

No No Yes Yes No No No Yes No No No No No No Yes No NR

Yes Yes Yes Yes Yes No Yes Yes Yes Yes No Yes No Yes No No No

Yes NA NA No NA Yes NA NA Yes NA NA NA Yes Yes NA NA Yes

No NA NA Yes Yes Yes NA NA Yes NA NA NA Yes Yes NA NA Yes

No No No No No No No No No No No No NR No No No No

Yes No No Yes No No No Yes Yes Yes No Yes Yes No Yes Yes Yes

W-11 W-12 M-19 M-20 W-16 W-14 W-14 M-18 M-20 M-17 W-15 M-16 M-15 W-13 M-16 W-10 M-15

Haghpanah [32] Imberti [33] Khorsand [23] Khorsand [22] Kuwashiro [19] W-18 Lavenne-Pardonge [34] Lorenz [35] Lubetsky [36] Majeed [37] Pabinger [38] Preston [39] Riess [40] Roodheuvel [25] Tran [41] Vigue [42] Yasaka [20] Yasaka [43]

NR: not reported, NA: not applicable, scores as gained by “Thomas” (S = strong, M = moderate, W = weak) and “Downs” checklists (numeric score out of 27) [13,14]

N. Khorsand et al. / Thrombosis Research 135 (2015) 9–19

Author

Table 3 Study dosing strategy and outcome. PCC brand

4 F-PCC or 3 F-PCC

Protocol Dose

Target INR reached N / total

Target INR reached %

Time to INR measurement (minutes after PCC)†

Positive clinical response N / total

Positive clinical response %

BW BW BW BW BW BW BW BW BW BW BW BW BW BW BW BW BW

PTX-VF 9A-BPL Beriplex Uman Octaplex Octaplex Octaplex Kaskadil Uman Beriplex Beriplex Beriplex Cofact Octaplex Cofact PPSB-SD Prothromplex Octaplex Beriplex Octaplex Cofact

3 3 4 3 4 4 4 4 3 4 4 4 4 4 4 4 4

25-50 IU/kg 50 IU/kg 30 IU/kg 10-50 IU/kg 25 IU/kg 40 IU/kg 25-50 IU/kg 20 IU/kg 35-50 IU/kg 25-50 IU/kg 25-50 IU/kg 25-50 IU/kg 8-33 IU/kg 10-30 IU/kg 8-33 IU/kg 8-33 IU/kg NR

137 / 173 6/6 10 / 10 31 / 37 29 / 29 30 / 30 NR 18 / 18 94 / 126 40 / 43 33 / 42 61/98 7 / 20 539 / 686 124 / 131 12 / 14 91 / 160

79 100 100 84 100 100 NR 100 75 93 79 62 35 79 95 86 57

23 hours 15 30 30 10 10 10 3 30 30 20 30 15 minutes after surgery 240 15 60 NR

NR NR 10 / 10 NR 17 / 25 19 / 28 17 / 20 13 / 18 NR 40 / 43 NR 71/98 NR 542 / 686 122 / 139 14 / 14 150 / 160

NR NR 100 NR 68 68 85 73 NR 93 NR 72 NR 79 88 100 94

4F 4F

NR 1650 IU

51 / 56 31/45

91 69

10 NR

56 / 56 NR

100 NR

PTX-VF Cofact Octaplex Kaskadil PPSB-HT NICHIYAKU Beriplex Cofact

3F 4F 4F

25-50 IU/kg 8-33 IU/kg NR

46 / 50 41 / 46 137 / 252

92 89 54

30 15 NR

50 / 50 43 / 46 NR

100 93 NR

4F 4F 4F

NR NR 1125 IU

NR 8/8 10/15

NR 100 67

NR 10 NR

12 / 22 8/8 NR

55 100 NR

Octaplex Partieller Prothrombin Komplex Cofact Cofact Cofact PPSB-HT NICHIYAKU PPSB-HT NICHIYAKU

4 3 4 4 4 4 4

1000 IU 1000 IU 1040 IU 1040 IU 500 IU 500 or 1,000 IU 200, 500, 1,000 or 1,500

56 / 78 NR 21 / 30 88 / 96 20 / 47 NR 33 / 42

72 NR 70 92 43 NR 79

60 NR 15 15 15 NR 60

NR 39 / 39 32 / 35 97 / 101 27 / 47 9 / 11 NR

NR 100 91 96 57 82 NR

+ + + + + + + + +

INRi INRi INRi INRi INRi INRi INRi INRi INRi

+ + + + +

INRt INRt INRt INRt INRt

BW + INRi + INRt BW + INRi + INRt BW + INRi + INRt BW + INRi + INRt Doctor Doctor Doctor Doctor Fixed Fixed Fixed Fixed Fixed Fixed Fixed

Bobbit [26] Cartmill† [18] Evans [30] Haghpanah [32] Kerebel-cohort 1 [21] Kerebel- cohort 2 [21] Lubetsky [36] Vigue [42] Imberti [33] Pabinger [38] Preston [39] Sarode [2] Demeyere† [17] Desmettre, [27] Khorsand-cohort 2 [22] Lavenne-Pardonge [34] Majeed [37]

Riess [40] Roodheuvel strategy 1[25] Tran [41] van Aart- cohort 2 [24] Desmettre [28] Kuwashiro† [19] Lorenz [35] Roodheuvel strategy 2[25] Dowlatshahi [29] Fischer [31] Khorsand⁎ [23] Khorsand-cohort 1 [22] van Aart- cohort 1 [24] Yasaka† [20] Yasaka [43]

F F F F F F F F F F F F F F F F F

F F F F F F F

N. Khorsand et al. / Thrombosis Research 135 (2015) 9–19

PCC protocol based on:⁎ Author

⁎ Only the prospective cohort is included,† Only the PCC cohort is included, NR: information not reported, 3 F: 3factor PCC, 4 F: 4factor PCC, BW: based on body weight, BW + INRi: based on bodyweight and initial INR, BW + INRi + INRt: based on bodyweight, initial INR and target INR, Doctor: at the discretion of the treating physician, Fixed: fixed dose ⁎ PCC protocol based on:

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N. Khorsand et al. / Thrombosis Research 135 (2015) 9–19

studies), and doctor strategy (282 patients in 3 studies) were less studied. The planned PCC dose ranged from 8 to 50 IU of factor IX/kg body weight, including fixed dose protocols of 200, 500, 1,000, or 1,500 IU of factor IX/patient. The median actual infused dosage of PCC was reported in 26 studies for a total of 2,547 patients and ranged from 3 to 57 IU/kg. In this, the actual infused PCC dosage was lowest for the fixed dose strategy (Fig. 2). Outcome Data Data on target INR achievement and successful clinical outcome are depicted in Fig. 3A and B. Time to INR measurement in each study as well as results on target INR and clinical outcome are shown in Table 3. Target INR achievement was reported in 24 (86%) studies for a total of 2,406 out of 2,563 patients (94%) (Table 3 and Fig. 3a). In these studies a wide range of proportions of patients who reached the target INR is reported. For the BW strategy, INR data are available in 6 studies with a total number of 303 patients. All studies are relatively small (range 6–173 patients). In all studies, the large majority of patients have a positive outcome (range 79-100%). For BW + INRi strategy, INR data for four studies with a total of 309 patients are available. Positive INR outcome ranges from 62 to 93% of patients in these studies, with the lowest success rates in the two larger studies (62% [2] and 75% [33]). For BW + INRi + INRt strategy, 9 studies are available with a total of 1,208 patients. Target INR is reported to have been reached in 35-95% of

patients. The single largest study (686 patients [27]) reported 79%. An explanation for the low target INR achievement in the small study by Demeyere et al. [17] could be the fact that the calculated dose was given to the patient in two parts (half before and half after the surgery). INR was measured 15 minutes after administration of the second half of PCC dosage. For doctor strategy two very small studies [25,35] and one large (n = 252, [28]) study are available. The small studies report good outcomes, but the large study had only 54% success in reaching the target INR. This could in part be caused by the fact that there was a long time window from diagnosis to infusion of PCC in this study. For the fixed strategy, five studies with a total of 293 patients were available. Positive INR outcome ranged from 43 to 92%. Van Aart et al. [24] report a low proportion of patients reaching the target INR after infusion of a very low fixed dose of 500 IU factor IX per patients. In that study, authors conclude the low fixed dosage of PCC to be insufficient to reach the predefined target INR. Clinical outcome was reported in 19 (68%) studies for 1,656 patients out of a total 2,563 patients (65%). Generally, outcome was good, ranging from 55 to 100%. Data were most robust for the BW + INRi + INRt strategy, including 1,151 patients in 7 studies, with a reported range of successful clinical outcome from 79 to 100%. Results were more or less similar for BW, BW + INRi and fixed. For all three strategies, the number of studies was relatively low and most studies were small. For doctor strategy, only two very small [19,35]studies reported clinical outcome. Due to large heterogeneity, individual study results are not pooled over the different strategies, but presented individually (Fig. 3A and B). As results on target INR for patients treated with a 3 F-PCC are reported for only 12% (392/2,563) of the studied population and for clinical outcome in only 3% (89/2,563), data are not further stratified for this parameter. However, patients treated with a 3 F-PCC are not equally distributed among all strategies and mainly influence the BW strategy (216 out of the 307 (70%) patients in the BW strategy are treated with a 3 FPCC). Discussion

Fig. 2. Median PCC dosage per study (cohort) (IU/kg). Actual median dose infused in each study (arm). Dots represent the included studies (cohorts) with large, average, and small amount of included patients. Actual median dose infused was unknown in two studies (Evans, N = 10,[30] strategy BW. Cartmill, N = 6, [18] strategy BW). For these studies the protocol dosage is depicted (30 IU/kg and 50 IU/kg respectively) instead of the actual infused dosage.

In our systematic review, we included 28 prospective PCC studies in which the dosing strategy was based on bodyweight, bodyweight and initial INR, bodyweight and initial INR and target INR, doctors decision, or a fixed dose strategy in predominantly small, single-arm and openlabel studies with at most moderately robust study designs. Our review shows a great diversity in dosing protocols (15 different dosing protocols). Moreover, many different definitions for assessing the outcome of PCC treatment are used hampering a meta-analysis and powerful statement on the best dosing strategy. Despite the heterogeneity, data collected from the included studies provide a valuable opportunity to better understand and improve urgent VKA reversal with PCC. Firstly, although one small study which included 8 patients reported good INR and clinical outcome results with the doctor strategy, less good results on reaching target INR and clinical outcome seem to be seen for this strategy compared to individual reports with other strategies. This suggests that it is important to have a dosing protocol available to guide PCC dosing in emergency setting. However, due to the wide range in reported data, results should be interpreted with caution. Secondly, comparison between infused doses per strategy show that a lower dosage of PCC is used when a fixed dose protocol is applied with no difference in overall results on target INR achievement and clinical outcome. Taking into account the low but still quantifiable incidence of 1.8% thromboembolic complications after PCC treatment [8] and the suggestion that the risk of thromboembolic events may increase with higher doses [9], a low fixed PCC dosing strategy seems to be the most simple though effective and safe strategy. However, the quality of the included studies, which is not optimal, should be kept in mind along with the heterogeneity of the included data and the limited number of

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a)

b)

Fig. 3. A. Target INR reached per study. B. Successful clinical outcome per study. The proportion of patients who reached target INR and those who had a successful clinical outcome after PCC treatment are depicted for each included study. In this, the 95% CI is shown by vertical lines. * indicates studies that applied a 3 F-PCC.

patients in some of the strategy sub-groups. Furthermore, target INR and clinical outcome data show that a very low fixed dose of 500 IU factor IX per patient is insufficient for a successful treatment. While our review shows a great diversity on PCC dosing strategies among published data, the same applies to the current state of PCC guidelines in which the ACCP [4] leaves the dosing to the discretion of the physician (doctor strategy), the French guidelines [5] recommend a bodyweight adjusted dosing regardless of the INR (BW), the Canadian

guidelines [44] recommend three different fixed doses stratified by initial INR (a derived type of fixed dose strategy and BW + INRi strategy) and the Australian [6] and British guidelines [3] recommend a range of bodyweight adjusted dosing from which the physician decides (a derived type of BW strategy and doctor strategy). Remarkably, the most studied strategy (BW + INRi + INRt strategy) and the dosing used in the recently published study with strongest design (BW + INRi) [2] are not part of the above mentioned guidelines.

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Apart from the different dosing strategies, considerable heterogeneity in assessing the impact of PCC treatment is noticed indicating the lack of consensus regarding different aspects of emergency reversal of VKA treatment e.g. optimal target INR, and clinical outcome definition. Furthermore, PCC is predominantly studied in small, single-arm and open label settings using the INR to measure its effect rather than clinical outcome. For future studies, standardization in reporting outcome of PCC treatment is essential. While clinical outcome is the most important parameter for evaluating treatment effects, only 4 included studies assessed this parameter as a (co) primary endpoint. Most studies used INR as a more direct measure of reversal of VKA, as it is objective and easier to determine. However, also a variety in defining the target INR exists while it remains unclear whether one needs to achieve a (very) low INR in order to stop clinical bleeding or that a higher target INR may also be sufficient. Facing these dilemmas, recently Sarode et al. [2] took an important step forward by developing a hemostatic efficacy scale in discussion with the Food and Drug Administration. Our systematic review has potential limitations. Firstly, to minimize the risk of including outcome obtained without a pre-defined dosing strategy, we excluded retrospective studies. In this, we might have missed some retrospectively performed but still highly informative and reliable data. Secondly, as the heterogeneity in all aspects of included studies was one of our main results, we refrained from pooling the data. Furthermore, heterogeneity also existed for reporting on vitamin K dosage and usage in included patients. Data were insufficient to be taken into consideration. Our quality assessment (Table 2) helps to understand and characterize the gained evidence. Lastly, we disregarded differences in PCC products. Many different brands of PCC are currently available which are, historically, all standardized based on factor IX levels. However, compositional differences are inevitable and their impact on clinical outcome remains unknown [45]. Moreover, some PCC contain a significantly lower amount of factor VII, the so-called 3 F-PCC. These 3 F-PCC are considered to be less potent, although the extent of the evidence is limited [46]. The majority of patients treated by the BW strategy received a 3 F-PCC. Therefore, data gained by this strategy could be less robust.

Conclusion Studies reporting on the usage of PCC in emergency VKA reversal vary greatly in many aspects hampering a meta-analysis on the optimal dosing strategy. More standardization in terms of e.g. optimal target INR and definition of clinical outcome is needed. PCC dosing strategies are based on 5 main principals using bodyweight, bodyweight and initial INR, bodyweight and initial INR and target INR, doctors decision, or a fixed dose strategy. Our review shows that relatively good outcome results are obtained with the use of any treatment protocol while less good results are reported for INR outcome when a predefined protocol is missing (doctor strategy). This suggests that it is important to have a dosing protocol available to guide PCC dosing as absence of a predefined protocol could delay start of PCC treatment and hence worsen outcome results. In future, studies should be designed to test whether body weight and INR are relevant for PCC dosing or whether a simple, low fixed dose regimen is adequately effective in an emergency reversal setting. In these future studies, we need uniform outcome definitions.

Conflict of Interest Statement This work is supported by an unrestricted grant from Sanquin BV (Amsterdam, The Netherlands; manufacturer of Cofact®). N. Khorsand received speakers fee from Sanquin BV. All other authors report no conflicts.

Acknowledgement The authors would like to thank Mrs. M.A.E. Mol (Clinical Librarian) for her help with defining the database search strategy.

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