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Drug Profile
Four factor prothrombin complex concentrate (human): review of the pharmacology and clinical application for vitamin K antagonist reversal Expert Rev. Cardiovasc. Ther. 12(4), 417–427 (2014)
Theresa N Kinard and Ravi Sarode* Department of Pathology, Division of Transfusion Medicine and Hemostasis, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA *Author for correspondence: [email protected]
Vitamin K antagonists (VKAs) have been used for decades for the treatment and prophylaxis of thromboembolic events. Due to their wide range of therapeutic indications, they are the most prescribed oral anticoagulant worldwide. However, they are associated with bleeding complications due to their narrow therapeutic range, variability in individual dose responses and laboratory monitoring, and overdoses. Despite off-label use of 3-factor prothrombin complex concentrates and recombinant activated factor VII, until recently, vitamin K and plasma were the only recommended therapeutic options for reversing VKAs in the USA. In 2013, a 4-factor prothrombin complex concentrate (4F-PCC) was approved in the USA for VKA reversal in patients with bleeding or requiring emergency surgery and invasive procedure. Recent randomized controlled clinical trials have shown that 4F-PCC (KcentraTM ) is non-inferior for hemostatic efficacy and superior for international normalized ratio correction as compared to plasma and has a similar safety profile. KEYWORDS: bleeding • coagulopathy • KcentraTM • plasma • prothrombin complex concentrate (human) • vitamin K antagonist • warfarin
Vitamin K antagonists (VKAs) have been prescribed to patients for the past 60 years for the treatment and prophylaxis of venous and arterial thromboembolic events (TEEs). Clinical trials have demonstrated that VKAs are effective for prevention of TEE, prophylaxis against systemic emboli in patients with prosthetic heart valves, atrial fibrillation or after myocardial infarction (MI) and are effective in reducing the risk of recurrent MI and strokes [1]. Due to its wide range of therapeutic indications, it is the most prescribed oral anticoagulant worldwide and approximately 2.5 million adults and children in the USA are on VKA therapy [2]. However, clinical management is complicated by the narrow therapeutic range, variability in individual dose–response and laboratory monitoring (i.e., plasma-based laboratory testing vs whole blood point-of-care informahealthcare.com
10.1586/14779072.2014.896195
testing as well as variation in the International Sensitivity Index [ISI] of the prothrombin time [PT] reagent) and overdoses that lead to bleeding [1]. In the USA, major hemorrhage in VKA-treated patients reportedly occurs at an annual rate of 1.7–3.4% [3]. Until recently, the standard of care for VKA reversal was the administration of vitamin K and plasma. Aside from off-label use of 3 factor-prothrombin complex concentrate (3F-PCC; i.e., Bebulin, Profilnine) and recombinant factor VIIa (Novoseven), plasma had been the only source of factor replacement to reverse the effects of VKA therapy. However, plasma is not the optimal therapy for urgent VKA reversal due to time delays for ABO blood typing and thawing of frozen plasma, large volumes, long infusion times to reach the factor levels necessary to correct coagulopathy, risk of
2014 Informa UK Ltd
ISSN 1477-9072
417
Drug Profile
Kinard & Sarode
Functional factors ll, Vll, lX, X, protein C & S (carboxylated)
Nonfunctional factors ll, Vll, lX, X, protein C & S (non-carboxylated)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Gamma glutamyl carboxylase
Reduced vitamin K (KH2)
Vitamin K1 reductase
Oxidized vitamin K (vitamin K 2,3 epoxide) Inhibited by VKA Vitamin K (K1)
VKOR
Figure 1. Vitamin K-dependent factor synthesis: hepatic recycling. Vitamin K is essential for the post-translational modification of vitamin K-dependent factors. Gamma glutamyl carboxylase is a vitamin K-dependent enzyme that is responsible for the carboxylation of the N-terminal glutamic acid residues of factors II, VII, IX, X, proteins C and S. VKAs inhibit vitamin K epoxide reductase more than vitamin K1 reductase, which interferes with conversion of vitamin K 2,3 epoxide (inactive, KO, oxidized vitamin K) to vitamin KH2 (active, reduced vitamin K) and results in proteins with reduced gamma carboxylation and clotting activity. VKA: Vitamin K antagonist; VKOR : Vitamin K epoxide reductase.
pathogen transmission, transfusion-related acute lung injury and transfusion-associated circulatory overload [4–7]. VKA is briefly discussed followed by the pharmacology and clinical application of the newly approved 4F-prothrombin complex concentrate (4F-PCC; Kcentra ) for VKA reversal in bleeding patients and in patients requiring urgent surgery or other invasive procedure. TM
Vitamin K
Vitamin K is essential for the post-translational modification of specific proteins produced by the liver: factors II, VII, IX, X, proteins C and S (FII, FVII, FIX, FX, PC, PS). Gamma glutamyl carboxylase is a vitamin K-dependent enzyme that is responsible for the carboxylation of the N-terminal glutamic acid residues of vitamin K-dependent factors (VKDFs) and proteins. The carboxylation renders these factors functional by allowing their interaction with calcium and phospholipids in the formation of coagulation complexes important to the generation of thrombin (FIGURE 1). Dietary sources of vitamin K (phylloquinone) are yellow and green plants; the daily requirement is approximately 1 mg/ kg. Although less easily absorbed, an additional source of vitamin K (menaquinone-n) is from the intestinal flora [8]. Vitamin K is fat soluble and is absorbed in the terminal intestine; therefore, any condition that inhibits or prevents absorption, particularly absorption of fats, will impact the production of functional VKDF [9]. The half-life of vitamin K is 36 h [10]. 418
Vitamin K antagonists
In the early 1900s, a coumarin derivative was isolated from moldy sweetclover contaminated hay, which was responsible for the hemorrhagic deaths of cattle in the USA and Canada in the 1920s [11]. This compound evolved to warfarin (named after the Wisconsin Alumni Research Foundation), a VKA, which was initially marketed as a rodenticide in 1948. By 1954, warfarin was used as an anticoagulant in humans. Although a misnomer, the mechanism of action of VKAs is not on vitamin K itself, but on its inhibition of the gamma carboxylation of glutamic acid residues of the VKDFs. VKAs inhibit vitamin K epoxide reductase and vitamin K1 reductase, which interferes with conversion of vitamin K 2,3 epoxide to vitamin KH2 and results in proteins with reduced gamma carboxylation and clotting activity (FIGURE 1) [12–17]. Although VKAs affect both procoagulant and anticoagulant VKDFs, procoagulant inhibition is more dominant. The biologic effects of warfarin are not apparent until the functional VKDFs (especially FII and FX) are reduced to 6 are at greater risk of developing any type of major bleeding compared with patients in the therapeutic range [28]. The risk of intracranial hemorrhage increases when INR is greater than 4 [29]. Fluctuation in the INR is an indicator of poor management of warfarin Expert Rev. Cardiovasc. Ther. 12(4), (2014)
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Four factor prothrombin complex concentrate (human)
Drug Profile
therapy and increases bleeding risk [29,30]. These hemorrhagic complications require an effective and rapid antidote for VKA reversal [31].
Table 1. Elimination half lives of vitamin K-dependent factors and proteins. Protein
Half-life (h)
Reversal of VKA
Factor II (prothrombin)
42–72
Prior to the availability of 3F-PCC and 4F-PCC, the standard of care for reversing VKA effect and bleeding was plasma transfusion. However, plasma requires ABO blood typing, long preparation time, a large volume and slow infusion rate. Additionally, transfusion of plasma also has the potential for allergic reactions, transfusion-related acute lung injury, transfusionassociated circulatory overload and a risk of infectious disease transmission [4–7]. Currently, several published guidelines are available for the reversal of supratherapeutic INR with or without bleeding (TABLE 2) [26,27]. These therapies include withholding warfarin and administration of vitamin K and PCC for active bleeding.
Factor VII
4–6
Factor IX
21–30
Factor X
27–48
Protein C
3
Protein S
60
Market overview
Two types of prothrombin complex concentrates are available: activated PCC and nonactivated PCC. Activated PCC (antiinhibitor coagulant complex, Factor VIII Inhibitor Bypass Activity, FEIBA, Baxter, Deerfield, IL, USA) is licensed for the treatment of hemophilia A and B patients with inhibitors and is not used for reversal of VKAs. Nonactivated PCCs can be classified as 3F-PCC or 4F-PCC (TABLE 3). 3F-PCCs are known as FIX concentrates because they were developed to treat hemophilia B patients and contain very low concentrations of FVII and probably no PC or PS. The 4F-PCCs contain clinically adequate amounts of all VKDF including PC and PS. Although not licensed for the reversal of VKAs, 3F-PCCs have been used for VKA-associated bleeding management [26,27,32–43]. The result, unless FVII is supplemented with plasma or recombinant FVIIa, is suboptimal VKA reversal [44–46]. 4F-PCC (Kcentra -USA, CSL Behring GmbH, Marburg, Germany) is currently the only US FDA approved factor derivative for the urgent reversal of VKA in patients with acute major bleeding or who require emergency surgery or invasive TM
procedure. 4F-PCCs have been available and used in many countries under the trade names Beriplex P/N, Confidex (CSL Behring GmbH, Marburg, Germany) and Octaplex (Octapharma, Lachen, Switzerland). These have been used in Europe for VKA reversal, factor deficiencies associated with liver disease and treatment of acquired bleeding [31]. Octaplex is under FDA review at this time. Introduction to 4F-PCC
4F-PCC (Kcentra) is a purified, heat-treated, nanofiltered and lyophilized nonactivated concentrate of FII, FVII, FIX and FX, PC and PS, which is manufactured from US source human plasma (TABLE 3). Additionally, it also contains antithrombin, albumin, heparin, sodium chloride and sodium citrate. Potency is defined by the FIX concentration, which ranges from 400 to 620 IU/vial. This 4F-PCC is well balanced in the procoagulant factors with no activated clotting factors and contains more PC and PS than other PCC preparations currently available. The actual concentrations of each factor and protein are listed with each carton. The dosage is based on FIX concentration, which is the only factor concentration identified on the vial. On average, this 4F-PCC contains 42% therapeutic protein, proving that it is one of the most pure formulations of 4F-PCC, that is, of all the components in Kcentra, 42% are the VKDF and proteins [47]. It can be stored at room temperature, does not
Table 2. Vitamin K antagonist reversal guidelines. American college of chest physicians evidence-based clinical practice guidelines – 9th edition [26]
British guidelines on oral anticoagulation with warfarin – 4th edition [27]
Recommendation
INR 4.5–10 with no bleeding
INR >5–8 with no bleeding
Hold VKA dose(s)
INR >10 with no bleeding
INR >8 with no bleeding
Give oral vitamin K
Any major bleeding
Any bleeding irrespective of INR
4F-PCC‡ and intravenous vitamin K§
INR >5.0 but 20 (range 15.8 to >20) and after treatment was 1.1. All patients achieved an INR £1.3 30 min after the start of infusion. Factor levels demonstrated variable increases in plasma, but all began decreasing by 48 h which reflected in increasing median INR (1.6). Cessation of bleeding occurred within 8 h of treatment in all subjects. No adverse events were reported including any thromboembolic complications. Endogenous Expert Rev. Cardiovasc. Ther. 12(4), (2014)
Four factor prothrombin complex concentrate (human)
Drug Profile
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Table 5. Pharmacokinetics of 4-factor prothrombin complex concentrate proteins in healthy volunteers. Parameter
Maximum % increase†
Half-life (h)
IVR (%/IU/kg)
MRT (h)
VD (ml/kg)
Cl (mg/kg/h)
Factor II
122
59.7
2.11
81.7
71.0
0.97
Factor VII
62
4.2
2.43
6.1
41.8
7.06
Factor IX
73
16.7
1.57
21.6
92.4
3.63
Factor X
158
30.7
2.08
44.3
56.1
1.25
Protein C
149
47.2
2.76
57.0
62.9
1.10
Protein S
59
49.1
2.02
69.2
76.6
1.11
†
5 min after infusion. Cl: Clearance; IU: International units; IVR: In vivo recovery; MRT: Mean residence time; VD: Volume of distribution at steady state. Data taken from [49].
thrombin potential >110% was used as a surrogate marker for hypercoagulability and was seen in one patient 30 min after treatment. A Phase IIIb multicenter RCT by Sarode et al. was the first to compare 4F-PCC against plasma for urgent VKA reversal in patients presenting with acute major bleeding (TABLE 7) [48]. A total of 202 intent-to-treat subjects were randomized to the receive 4F-PCC (Beriplex P/N, n = 98) or plasma (n = 104) based on the patient’s pretreatment INR and weight (4F-PCC dosing TABLE 4, plasma dosing: INR 2–4: 10 ml/kg, INR 4–6:12 ml/kg, INR >6: 15 ml/kg, maximum 1500 ml plasma for maximum total weight of 100 kg). Most patients also received 5–10 mg iv. vitamin K. There were four exceptions in the 4F-PCC group and two in the plasma group that received no vitamin K and eight in the 4F-PCC group and three in the plasma group that received nonintravenous vitamin K. Primary endpoint was determined by hemostatic efficacy at 24 h from the start of infusion and INR reduction (£1.3) at 30 min after the end of infusion. Secondary endpoint measurements were plasma levels of FII, FVII, FIX, FX, PC and PS and time to INR correction. Serious adverse events of interest were TEE, deaths and late bleeding. Hemostatic efficacy, TEE and late bleeding were reviewed by blinded efficacy adjudication and safety adjudication boards, respectively. Median baseline INR for 4F-PCC group was 3.9 (range 1.8–20.0) and 3.6 (range 1.9–38.9) in the plasma group. Effective hemostasis was achieved in 72% of the 4F-PCC group compared with 65% in plasma group. A subset analysis stratified by type of bleed did not show statistically significant differences between the treatment groups by type of bleed; however, visible and musculoskeletal bleeding were found to have significantly better effective hemostasis in the 4F-PCC group than the plasma group (p = 0.02). INR reduction at 30 min was achieved in 62% of the 4F-PCC group and 10% of the plasma group. The mean VKDF and protein levels were similar prior to treatment between the treatment groups, but were significantly higher in the 4F-PCC group than the plasma group 30 min to 6 h after the start of infusion (p < 0.05), except FVII (p = 0.19). Hemostatic factors levels in both groups were reached by informahealthcare.com
24 h. Median volume and infusion time were longer in the plasma group (813.5 ml plasma vs 99.4 ml 4F-PCC, 148 min for plasma vs 17 min for 4F-PCC). Thromboembolic adverse events occurred similarly in both groups (eight in the 4F-PCC group and seven in the plasma group), whereas volume overload was more common in plasma group compared with 4F-PCC. VKA reversal with 4F-PCC in patients with bleeding or requiring urgent surgery
A study by Preston et al. examined 4F-PCC (Beriplex P/N) for urgent reversal of VKAs in patients (n = 42) with bleeding or who required emergency surgery [40]. Dosing was based on patient’s pretreatment INR and weight (TABLE 4). All subjects also received 2–5 mg iv. vitamin K. INR and plasma levels of the VKDF, PC, antithrombin, fibrinogen, D-dimer and platelet count were measured at 20, 60 and 120 min after 4F-PCC treatment. The median pretreatment INR was 3.98 (range 2.0– 27.6). The target INR of £1.3 was achieved in 33 patients (79%) within 20 min of 4F-PCC. The other patients achieved INRs of 1.3–1.9. Changes in thrombogenicity markers antithrombin, D-dimer and fibrinogen did not correlate with clinically observed TEE. Clinical efficacy was not assessed. Eight patients died within 7 days of 4F-PCC treatment; one death was due to a thrombotic stroke 48 h after PCC administration in a patient with severe sepsis as well as cardiac and renal failure. This death could not be ruled out as unrelated to 4F-PCC treatment. A prospective, open-label, uncontrolled, multicenter Phase III study by Pabinger et al. involved 43 patients who received 4F-PCC (Beriplex P/N), required VKA reversal for major bleeding (n = 17) or emergency surgery (n = 26) [38]. 4F-PCC was administered according to pretreatment INR and patient weight (TABLE 4) and 88% of patients also received iv. (n = 33), oral (n = 4) or subcutaneous (n = 1) vitamin K. Median baseline INR was 3.3 (range 2 to >17). Median INR 30 min after infusion was 1.18 and 93% of patients achieved an INR £1.3. INR values remained within the normal range throughout the study period. Clinical efficacy was rated as satisfactory (delayed cessation of bleeding and/or a decrease in INR 421
Drug Profile
Kinard & Sarode
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Table 6. Summary of clinical efficacy results of supportive studies and published clinical trials. Ref.
Study (year)
Study description
Patients receiving 4F-PCC (n)
Pretreatment INR of subjects receiving 4F-PCC median (range)
INR correction 8 and major bleeding. Patients received 30 IU/kg 4F-PCC and 5 mg iv. vitamin K
n = 10
>20 (15.8 to >20)
100†
[34]
Preston et al. (2002)
Nonrandomized study examining VKA reversal in patients with bleeding or requiring emergency surgery with 4F-PCC§ and 2–5 mg iv. vitamin K
n = 42
3.98 (2–27.6)
79‡
[40]
Pabinger et al. (2008)
Phase III single-arm, uncontrolled, multicenter study examining VKA reversal to control bleeding or prior to emergency surgery with 4F-PCC§ and most patients received iv. vitamin K
n = 43
3.3 (2 to >17)
93†
[38]
Sarode et al. (2013)
Phase IIIb RCT comparing 4F-PCC§ versus plasma (pretreatment INR 2–4:10 ml/kg, INR 4–6: 12 ml/kg, INR >6: 15 ml/kg, maximum 1500 ml) for VKA reversal to control major bleeding. Most patients received vitamin K
n = 98
3.9 (1.8–20)
62†
[48]
Refaai et al. (2013)
Phase IIIb RCT comparing 4F-PCC§ versus plasma (pretreatment INR 2–4: 10 ml/kg, INR 4–6: 12 ml/kg, INR >6: 15 ml/kg, maximum 1500 ml) for VKA reversal in patients requiring emergency surgery or invasive procedure
n = 87
2.9 (2.0–17.0)
55.2†
[50]
†
30 min after the start of infusion. 20 min after the start of infusion. 4F-PCC dosing according to TABLE 4. 4F-PCC: Four factor prothrombin complex concentrate; INR: International normalized ratio; iv.: Intravenous; RCT: Randomized controlled trial; VKA: Vitamin K antagonist. ‡ §
within 1–2 h or mildly abnormal hemostasis during surgery) or very good (prompt cessation of bleeding and/or rapid fall in INR to £1.3 or normal hemostasis during surgery) in 98% of the subjects. All factor levels increased rapidly after administration and were sustained throughout the study period. A total of 51 adverse events in 25 patients were reported including 2 suspected thromboembolic complications. Eight serious adverse events unrelated to treatment occurred in six patients, three of whom died. A total of five deaths were reported during the follow-up period. Death occurred in one patient who received additional PCC outside of protocol, and the incident was considered possibly treatment related. Transient changes in thrombogenicity markers did not correlate with clinically observed TEE. There were no reports of hepatitis A virus, HBV, HIV or parvovirus B19 infection transmission at 3-month follow-up. 4F-PCC versus plasma for VKA reversal in patients requiring emergency surgery or invasive procedures
In a recently completed prospective, randomized, multicenter, Phase IIIb study, 4F-PCC (Beriplex P/N/Kcentra) or plasma was administered to patients on VKAs who required rapid reversal prior to urgent surgery or invasive procedure to compare clinical and hemostatic efficacy and safety [50]. One hundred sixty-eight patients were enrolled: 87 patients received 422
4F-PCC and 81 patients received plasma (4F-PCC dosing TABLE 4, plasma dosing: INR 2–4: 10 ml/kg, INR 4–6: 12 ml/kg, INR >6: 15 ml/kg, maximum 1500 ml plasma for maximum total weight of 100 kg). The primary endpoints included hemostatic efficacy for the time period from the start of infusion of 4F-PCC or plasma until the end of the urgent surgery/invasive procedure, and clinical efficacy was defined as INR of £1.3 at 30 min after the end of infusion of 4F-PCC or plasma. Baseline INR for the 4F-PCC group was 2.9 (2.0–17.0) and 2.9 (2.0–26.7) in the plasma group. Unpublished observations showed that 4F-PCC was superior to plasma in achieving effective hemostasis (89.7% 4F-PCC vs 75.3% plasma) and INR reduction to £1.3 at 30 min after the end of infusion (55.2% 4F-PCC vs 9.9% plasma). The study also found that 4F-PCC was well tolerated and had a similar safety profile to plasma. Additionally, fluid overload occurred more frequently in the plasma group than in the 4F-PCC group (9.1% difference). These data are anticipated to be published soon. Postmarket surveillance
Pharmacovigilance data, which are maintained by CSL Behring, are available for the first 15 years of clinical use of PCC in Europe [31]. A review of several studies showed that 4F-PCC has been administered for rapid correction of INR with
Expert Rev. Cardiovasc. Ther. 12(4), (2014)
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Four factor prothrombin complex concentrate (human)
cessation of bleeding in patients using VKA, factor supplementation in liver disease and treatment of trauma-related bleeding. The data collection also showed a low risk of thrombotic events possibly related to 4F-PCC administration (
Drug Profile
Four factor prothrombin complex concentrate (human): review of the pharmacology and clinical application for vitamin K antagonist reversal Expert Rev. Cardiovasc. Ther. 12(4), 417–427 (2014)
Theresa N Kinard and Ravi Sarode* Department of Pathology, Division of Transfusion Medicine and Hemostasis, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA *Author for correspondence: [email protected]
Vitamin K antagonists (VKAs) have been used for decades for the treatment and prophylaxis of thromboembolic events. Due to their wide range of therapeutic indications, they are the most prescribed oral anticoagulant worldwide. However, they are associated with bleeding complications due to their narrow therapeutic range, variability in individual dose responses and laboratory monitoring, and overdoses. Despite off-label use of 3-factor prothrombin complex concentrates and recombinant activated factor VII, until recently, vitamin K and plasma were the only recommended therapeutic options for reversing VKAs in the USA. In 2013, a 4-factor prothrombin complex concentrate (4F-PCC) was approved in the USA for VKA reversal in patients with bleeding or requiring emergency surgery and invasive procedure. Recent randomized controlled clinical trials have shown that 4F-PCC (KcentraTM ) is non-inferior for hemostatic efficacy and superior for international normalized ratio correction as compared to plasma and has a similar safety profile. KEYWORDS: bleeding • coagulopathy • KcentraTM • plasma • prothrombin complex concentrate (human) • vitamin K antagonist • warfarin
Vitamin K antagonists (VKAs) have been prescribed to patients for the past 60 years for the treatment and prophylaxis of venous and arterial thromboembolic events (TEEs). Clinical trials have demonstrated that VKAs are effective for prevention of TEE, prophylaxis against systemic emboli in patients with prosthetic heart valves, atrial fibrillation or after myocardial infarction (MI) and are effective in reducing the risk of recurrent MI and strokes [1]. Due to its wide range of therapeutic indications, it is the most prescribed oral anticoagulant worldwide and approximately 2.5 million adults and children in the USA are on VKA therapy [2]. However, clinical management is complicated by the narrow therapeutic range, variability in individual dose–response and laboratory monitoring (i.e., plasma-based laboratory testing vs whole blood point-of-care informahealthcare.com
10.1586/14779072.2014.896195
testing as well as variation in the International Sensitivity Index [ISI] of the prothrombin time [PT] reagent) and overdoses that lead to bleeding [1]. In the USA, major hemorrhage in VKA-treated patients reportedly occurs at an annual rate of 1.7–3.4% [3]. Until recently, the standard of care for VKA reversal was the administration of vitamin K and plasma. Aside from off-label use of 3 factor-prothrombin complex concentrate (3F-PCC; i.e., Bebulin, Profilnine) and recombinant factor VIIa (Novoseven), plasma had been the only source of factor replacement to reverse the effects of VKA therapy. However, plasma is not the optimal therapy for urgent VKA reversal due to time delays for ABO blood typing and thawing of frozen plasma, large volumes, long infusion times to reach the factor levels necessary to correct coagulopathy, risk of
2014 Informa UK Ltd
ISSN 1477-9072
417
Drug Profile
Kinard & Sarode
Functional factors ll, Vll, lX, X, protein C & S (carboxylated)
Nonfunctional factors ll, Vll, lX, X, protein C & S (non-carboxylated)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Gamma glutamyl carboxylase
Reduced vitamin K (KH2)
Vitamin K1 reductase
Oxidized vitamin K (vitamin K 2,3 epoxide) Inhibited by VKA Vitamin K (K1)
VKOR
Figure 1. Vitamin K-dependent factor synthesis: hepatic recycling. Vitamin K is essential for the post-translational modification of vitamin K-dependent factors. Gamma glutamyl carboxylase is a vitamin K-dependent enzyme that is responsible for the carboxylation of the N-terminal glutamic acid residues of factors II, VII, IX, X, proteins C and S. VKAs inhibit vitamin K epoxide reductase more than vitamin K1 reductase, which interferes with conversion of vitamin K 2,3 epoxide (inactive, KO, oxidized vitamin K) to vitamin KH2 (active, reduced vitamin K) and results in proteins with reduced gamma carboxylation and clotting activity. VKA: Vitamin K antagonist; VKOR : Vitamin K epoxide reductase.
pathogen transmission, transfusion-related acute lung injury and transfusion-associated circulatory overload [4–7]. VKA is briefly discussed followed by the pharmacology and clinical application of the newly approved 4F-prothrombin complex concentrate (4F-PCC; Kcentra ) for VKA reversal in bleeding patients and in patients requiring urgent surgery or other invasive procedure. TM
Vitamin K
Vitamin K is essential for the post-translational modification of specific proteins produced by the liver: factors II, VII, IX, X, proteins C and S (FII, FVII, FIX, FX, PC, PS). Gamma glutamyl carboxylase is a vitamin K-dependent enzyme that is responsible for the carboxylation of the N-terminal glutamic acid residues of vitamin K-dependent factors (VKDFs) and proteins. The carboxylation renders these factors functional by allowing their interaction with calcium and phospholipids in the formation of coagulation complexes important to the generation of thrombin (FIGURE 1). Dietary sources of vitamin K (phylloquinone) are yellow and green plants; the daily requirement is approximately 1 mg/ kg. Although less easily absorbed, an additional source of vitamin K (menaquinone-n) is from the intestinal flora [8]. Vitamin K is fat soluble and is absorbed in the terminal intestine; therefore, any condition that inhibits or prevents absorption, particularly absorption of fats, will impact the production of functional VKDF [9]. The half-life of vitamin K is 36 h [10]. 418
Vitamin K antagonists
In the early 1900s, a coumarin derivative was isolated from moldy sweetclover contaminated hay, which was responsible for the hemorrhagic deaths of cattle in the USA and Canada in the 1920s [11]. This compound evolved to warfarin (named after the Wisconsin Alumni Research Foundation), a VKA, which was initially marketed as a rodenticide in 1948. By 1954, warfarin was used as an anticoagulant in humans. Although a misnomer, the mechanism of action of VKAs is not on vitamin K itself, but on its inhibition of the gamma carboxylation of glutamic acid residues of the VKDFs. VKAs inhibit vitamin K epoxide reductase and vitamin K1 reductase, which interferes with conversion of vitamin K 2,3 epoxide to vitamin KH2 and results in proteins with reduced gamma carboxylation and clotting activity (FIGURE 1) [12–17]. Although VKAs affect both procoagulant and anticoagulant VKDFs, procoagulant inhibition is more dominant. The biologic effects of warfarin are not apparent until the functional VKDFs (especially FII and FX) are reduced to 6 are at greater risk of developing any type of major bleeding compared with patients in the therapeutic range [28]. The risk of intracranial hemorrhage increases when INR is greater than 4 [29]. Fluctuation in the INR is an indicator of poor management of warfarin Expert Rev. Cardiovasc. Ther. 12(4), (2014)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Four factor prothrombin complex concentrate (human)
Drug Profile
therapy and increases bleeding risk [29,30]. These hemorrhagic complications require an effective and rapid antidote for VKA reversal [31].
Table 1. Elimination half lives of vitamin K-dependent factors and proteins. Protein
Half-life (h)
Reversal of VKA
Factor II (prothrombin)
42–72
Prior to the availability of 3F-PCC and 4F-PCC, the standard of care for reversing VKA effect and bleeding was plasma transfusion. However, plasma requires ABO blood typing, long preparation time, a large volume and slow infusion rate. Additionally, transfusion of plasma also has the potential for allergic reactions, transfusion-related acute lung injury, transfusionassociated circulatory overload and a risk of infectious disease transmission [4–7]. Currently, several published guidelines are available for the reversal of supratherapeutic INR with or without bleeding (TABLE 2) [26,27]. These therapies include withholding warfarin and administration of vitamin K and PCC for active bleeding.
Factor VII
4–6
Factor IX
21–30
Factor X
27–48
Protein C
3
Protein S
60
Market overview
Two types of prothrombin complex concentrates are available: activated PCC and nonactivated PCC. Activated PCC (antiinhibitor coagulant complex, Factor VIII Inhibitor Bypass Activity, FEIBA, Baxter, Deerfield, IL, USA) is licensed for the treatment of hemophilia A and B patients with inhibitors and is not used for reversal of VKAs. Nonactivated PCCs can be classified as 3F-PCC or 4F-PCC (TABLE 3). 3F-PCCs are known as FIX concentrates because they were developed to treat hemophilia B patients and contain very low concentrations of FVII and probably no PC or PS. The 4F-PCCs contain clinically adequate amounts of all VKDF including PC and PS. Although not licensed for the reversal of VKAs, 3F-PCCs have been used for VKA-associated bleeding management [26,27,32–43]. The result, unless FVII is supplemented with plasma or recombinant FVIIa, is suboptimal VKA reversal [44–46]. 4F-PCC (Kcentra -USA, CSL Behring GmbH, Marburg, Germany) is currently the only US FDA approved factor derivative for the urgent reversal of VKA in patients with acute major bleeding or who require emergency surgery or invasive TM
procedure. 4F-PCCs have been available and used in many countries under the trade names Beriplex P/N, Confidex (CSL Behring GmbH, Marburg, Germany) and Octaplex (Octapharma, Lachen, Switzerland). These have been used in Europe for VKA reversal, factor deficiencies associated with liver disease and treatment of acquired bleeding [31]. Octaplex is under FDA review at this time. Introduction to 4F-PCC
4F-PCC (Kcentra) is a purified, heat-treated, nanofiltered and lyophilized nonactivated concentrate of FII, FVII, FIX and FX, PC and PS, which is manufactured from US source human plasma (TABLE 3). Additionally, it also contains antithrombin, albumin, heparin, sodium chloride and sodium citrate. Potency is defined by the FIX concentration, which ranges from 400 to 620 IU/vial. This 4F-PCC is well balanced in the procoagulant factors with no activated clotting factors and contains more PC and PS than other PCC preparations currently available. The actual concentrations of each factor and protein are listed with each carton. The dosage is based on FIX concentration, which is the only factor concentration identified on the vial. On average, this 4F-PCC contains 42% therapeutic protein, proving that it is one of the most pure formulations of 4F-PCC, that is, of all the components in Kcentra, 42% are the VKDF and proteins [47]. It can be stored at room temperature, does not
Table 2. Vitamin K antagonist reversal guidelines. American college of chest physicians evidence-based clinical practice guidelines – 9th edition [26]
British guidelines on oral anticoagulation with warfarin – 4th edition [27]
Recommendation
INR 4.5–10 with no bleeding
INR >5–8 with no bleeding
Hold VKA dose(s)
INR >10 with no bleeding
INR >8 with no bleeding
Give oral vitamin K
Any major bleeding
Any bleeding irrespective of INR
4F-PCC‡ and intravenous vitamin K§
INR >5.0 but 20 (range 15.8 to >20) and after treatment was 1.1. All patients achieved an INR £1.3 30 min after the start of infusion. Factor levels demonstrated variable increases in plasma, but all began decreasing by 48 h which reflected in increasing median INR (1.6). Cessation of bleeding occurred within 8 h of treatment in all subjects. No adverse events were reported including any thromboembolic complications. Endogenous Expert Rev. Cardiovasc. Ther. 12(4), (2014)
Four factor prothrombin complex concentrate (human)
Drug Profile
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Table 5. Pharmacokinetics of 4-factor prothrombin complex concentrate proteins in healthy volunteers. Parameter
Maximum % increase†
Half-life (h)
IVR (%/IU/kg)
MRT (h)
VD (ml/kg)
Cl (mg/kg/h)
Factor II
122
59.7
2.11
81.7
71.0
0.97
Factor VII
62
4.2
2.43
6.1
41.8
7.06
Factor IX
73
16.7
1.57
21.6
92.4
3.63
Factor X
158
30.7
2.08
44.3
56.1
1.25
Protein C
149
47.2
2.76
57.0
62.9
1.10
Protein S
59
49.1
2.02
69.2
76.6
1.11
†
5 min after infusion. Cl: Clearance; IU: International units; IVR: In vivo recovery; MRT: Mean residence time; VD: Volume of distribution at steady state. Data taken from [49].
thrombin potential >110% was used as a surrogate marker for hypercoagulability and was seen in one patient 30 min after treatment. A Phase IIIb multicenter RCT by Sarode et al. was the first to compare 4F-PCC against plasma for urgent VKA reversal in patients presenting with acute major bleeding (TABLE 7) [48]. A total of 202 intent-to-treat subjects were randomized to the receive 4F-PCC (Beriplex P/N, n = 98) or plasma (n = 104) based on the patient’s pretreatment INR and weight (4F-PCC dosing TABLE 4, plasma dosing: INR 2–4: 10 ml/kg, INR 4–6:12 ml/kg, INR >6: 15 ml/kg, maximum 1500 ml plasma for maximum total weight of 100 kg). Most patients also received 5–10 mg iv. vitamin K. There were four exceptions in the 4F-PCC group and two in the plasma group that received no vitamin K and eight in the 4F-PCC group and three in the plasma group that received nonintravenous vitamin K. Primary endpoint was determined by hemostatic efficacy at 24 h from the start of infusion and INR reduction (£1.3) at 30 min after the end of infusion. Secondary endpoint measurements were plasma levels of FII, FVII, FIX, FX, PC and PS and time to INR correction. Serious adverse events of interest were TEE, deaths and late bleeding. Hemostatic efficacy, TEE and late bleeding were reviewed by blinded efficacy adjudication and safety adjudication boards, respectively. Median baseline INR for 4F-PCC group was 3.9 (range 1.8–20.0) and 3.6 (range 1.9–38.9) in the plasma group. Effective hemostasis was achieved in 72% of the 4F-PCC group compared with 65% in plasma group. A subset analysis stratified by type of bleed did not show statistically significant differences between the treatment groups by type of bleed; however, visible and musculoskeletal bleeding were found to have significantly better effective hemostasis in the 4F-PCC group than the plasma group (p = 0.02). INR reduction at 30 min was achieved in 62% of the 4F-PCC group and 10% of the plasma group. The mean VKDF and protein levels were similar prior to treatment between the treatment groups, but were significantly higher in the 4F-PCC group than the plasma group 30 min to 6 h after the start of infusion (p < 0.05), except FVII (p = 0.19). Hemostatic factors levels in both groups were reached by informahealthcare.com
24 h. Median volume and infusion time were longer in the plasma group (813.5 ml plasma vs 99.4 ml 4F-PCC, 148 min for plasma vs 17 min for 4F-PCC). Thromboembolic adverse events occurred similarly in both groups (eight in the 4F-PCC group and seven in the plasma group), whereas volume overload was more common in plasma group compared with 4F-PCC. VKA reversal with 4F-PCC in patients with bleeding or requiring urgent surgery
A study by Preston et al. examined 4F-PCC (Beriplex P/N) for urgent reversal of VKAs in patients (n = 42) with bleeding or who required emergency surgery [40]. Dosing was based on patient’s pretreatment INR and weight (TABLE 4). All subjects also received 2–5 mg iv. vitamin K. INR and plasma levels of the VKDF, PC, antithrombin, fibrinogen, D-dimer and platelet count were measured at 20, 60 and 120 min after 4F-PCC treatment. The median pretreatment INR was 3.98 (range 2.0– 27.6). The target INR of £1.3 was achieved in 33 patients (79%) within 20 min of 4F-PCC. The other patients achieved INRs of 1.3–1.9. Changes in thrombogenicity markers antithrombin, D-dimer and fibrinogen did not correlate with clinically observed TEE. Clinical efficacy was not assessed. Eight patients died within 7 days of 4F-PCC treatment; one death was due to a thrombotic stroke 48 h after PCC administration in a patient with severe sepsis as well as cardiac and renal failure. This death could not be ruled out as unrelated to 4F-PCC treatment. A prospective, open-label, uncontrolled, multicenter Phase III study by Pabinger et al. involved 43 patients who received 4F-PCC (Beriplex P/N), required VKA reversal for major bleeding (n = 17) or emergency surgery (n = 26) [38]. 4F-PCC was administered according to pretreatment INR and patient weight (TABLE 4) and 88% of patients also received iv. (n = 33), oral (n = 4) or subcutaneous (n = 1) vitamin K. Median baseline INR was 3.3 (range 2 to >17). Median INR 30 min after infusion was 1.18 and 93% of patients achieved an INR £1.3. INR values remained within the normal range throughout the study period. Clinical efficacy was rated as satisfactory (delayed cessation of bleeding and/or a decrease in INR 421
Drug Profile
Kinard & Sarode
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Table 6. Summary of clinical efficacy results of supportive studies and published clinical trials. Ref.
Study (year)
Study description
Patients receiving 4F-PCC (n)
Pretreatment INR of subjects receiving 4F-PCC median (range)
INR correction 8 and major bleeding. Patients received 30 IU/kg 4F-PCC and 5 mg iv. vitamin K
n = 10
>20 (15.8 to >20)
100†
[34]
Preston et al. (2002)
Nonrandomized study examining VKA reversal in patients with bleeding or requiring emergency surgery with 4F-PCC§ and 2–5 mg iv. vitamin K
n = 42
3.98 (2–27.6)
79‡
[40]
Pabinger et al. (2008)
Phase III single-arm, uncontrolled, multicenter study examining VKA reversal to control bleeding or prior to emergency surgery with 4F-PCC§ and most patients received iv. vitamin K
n = 43
3.3 (2 to >17)
93†
[38]
Sarode et al. (2013)
Phase IIIb RCT comparing 4F-PCC§ versus plasma (pretreatment INR 2–4:10 ml/kg, INR 4–6: 12 ml/kg, INR >6: 15 ml/kg, maximum 1500 ml) for VKA reversal to control major bleeding. Most patients received vitamin K
n = 98
3.9 (1.8–20)
62†
[48]
Refaai et al. (2013)
Phase IIIb RCT comparing 4F-PCC§ versus plasma (pretreatment INR 2–4: 10 ml/kg, INR 4–6: 12 ml/kg, INR >6: 15 ml/kg, maximum 1500 ml) for VKA reversal in patients requiring emergency surgery or invasive procedure
n = 87
2.9 (2.0–17.0)
55.2†
[50]
†
30 min after the start of infusion. 20 min after the start of infusion. 4F-PCC dosing according to TABLE 4. 4F-PCC: Four factor prothrombin complex concentrate; INR: International normalized ratio; iv.: Intravenous; RCT: Randomized controlled trial; VKA: Vitamin K antagonist. ‡ §
within 1–2 h or mildly abnormal hemostasis during surgery) or very good (prompt cessation of bleeding and/or rapid fall in INR to £1.3 or normal hemostasis during surgery) in 98% of the subjects. All factor levels increased rapidly after administration and were sustained throughout the study period. A total of 51 adverse events in 25 patients were reported including 2 suspected thromboembolic complications. Eight serious adverse events unrelated to treatment occurred in six patients, three of whom died. A total of five deaths were reported during the follow-up period. Death occurred in one patient who received additional PCC outside of protocol, and the incident was considered possibly treatment related. Transient changes in thrombogenicity markers did not correlate with clinically observed TEE. There were no reports of hepatitis A virus, HBV, HIV or parvovirus B19 infection transmission at 3-month follow-up. 4F-PCC versus plasma for VKA reversal in patients requiring emergency surgery or invasive procedures
In a recently completed prospective, randomized, multicenter, Phase IIIb study, 4F-PCC (Beriplex P/N/Kcentra) or plasma was administered to patients on VKAs who required rapid reversal prior to urgent surgery or invasive procedure to compare clinical and hemostatic efficacy and safety [50]. One hundred sixty-eight patients were enrolled: 87 patients received 422
4F-PCC and 81 patients received plasma (4F-PCC dosing TABLE 4, plasma dosing: INR 2–4: 10 ml/kg, INR 4–6: 12 ml/kg, INR >6: 15 ml/kg, maximum 1500 ml plasma for maximum total weight of 100 kg). The primary endpoints included hemostatic efficacy for the time period from the start of infusion of 4F-PCC or plasma until the end of the urgent surgery/invasive procedure, and clinical efficacy was defined as INR of £1.3 at 30 min after the end of infusion of 4F-PCC or plasma. Baseline INR for the 4F-PCC group was 2.9 (2.0–17.0) and 2.9 (2.0–26.7) in the plasma group. Unpublished observations showed that 4F-PCC was superior to plasma in achieving effective hemostasis (89.7% 4F-PCC vs 75.3% plasma) and INR reduction to £1.3 at 30 min after the end of infusion (55.2% 4F-PCC vs 9.9% plasma). The study also found that 4F-PCC was well tolerated and had a similar safety profile to plasma. Additionally, fluid overload occurred more frequently in the plasma group than in the 4F-PCC group (9.1% difference). These data are anticipated to be published soon. Postmarket surveillance
Pharmacovigilance data, which are maintained by CSL Behring, are available for the first 15 years of clinical use of PCC in Europe [31]. A review of several studies showed that 4F-PCC has been administered for rapid correction of INR with
Expert Rev. Cardiovasc. Ther. 12(4), (2014)
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Four factor prothrombin complex concentrate (human)
cessation of bleeding in patients using VKA, factor supplementation in liver disease and treatment of trauma-related bleeding. The data collection also showed a low risk of thrombotic events possibly related to 4F-PCC administration (
