Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex)

Indications

Reversal of Apixaban (Eliquis)-Associated Coagulopathy (see Apixaban) (Biomed Res Int, 2014) [MEDLINE]

Clinical Efficacy

xxxxx

Reversal of Coagulopathy in Patients with Critical Illnesses Involving Deficiency of Vitamin K-Dependent Coagulation Factors

Clinical Efficacy

xxxxx

Reversal of Coagulopathy of Liver Disease (see Cirrhosis)

Clinical Efficacy

xxxxx

Reversal of Coumadin-Associated Coagulopathy (see Coumadin)

Clinical Efficacy

Trial Comparing Prothrombin Complex Concentrate-4 Factor to Fresh Frozen Plasma in the Correction of INR in Coumadin-Associated Hemorrhage (Circulation, 2013) [MEDLINE]
- Prothrombin Complex Concentrate-4 Factor was Superior to Fresh Frozen Plasma in Terms of Achieving Rapid INR Correction
Randomized, Non-Inferiority Trial Comparing Prothrombin Complex Concentrate-4 Factor vs Fresh Frozen Plasma in Reversing Coumadin (Lancet, 2015) [MEDLINE]
- Prothrombin Complex Concentrate-4 Factor Achieved Effective Hemostasis in 90% of Subjects, as Compared to 75% in the Plasma Group
- Safety Profile (Thromboembolic Events, Fluid Overload, and Late Bleeding Events) were Similar in the Two Groups
Review of Prothrombin Complex Concentrate to Reverse Coumadin Anticoagulation in the Setting of Bleeding or the Need for an Invasive Procedure (Ann Intern Med, 2016) [MEDLINE]: review of 5 randomized controlled trials and 8 observational studies
- Prothrombin Complex Concentrate Decreased the Mortality Rate in Reversing Coumadin Anticoagulation, as Compared to Fresh Frozen Plasma

Recommendations (Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]

For Coumadin Anticoagulation with Associated Major Hemorrhage, Prothrombin Complex Concentrate-4 Factor is Recommended Over Fresh Frozen Plasma* (Grade 2C Recommendation)
- Intravenous Vitamin K (5-10 mg IV) is Also Recommended: see below

Recommendations (Neurocritical Care Society and Society of Critical Care Medicine Guidelines for Reversal of Antithrombotics in the Setting of Intracranial Hemorrhage, 2016) [MEDLINE]

Vitamin K (10 mg IV) is Recommended
Prothrombin Complex Concentrate-3 Factor or Prothrombin Complex Concentrate-3 Factor are Recommended Over FFP or Factor VIIa (Conditional Recommendation, Low Quality Evidence)
- Prothrombin Complex Concentrate-4 Factor is Recommended Over Prothrombin Complex Concentrate-3 Factor (Conditional Recommendation, Low Quality Evidence)

Reversal of Rivaroxaban (Xarelto)-Associated Coagulopathy (see Rivaroxaban) (Biomed Res Int, 2014) [MEDLINE]

Clinical Efficacy
- xxxxx

Contraindications

Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation)
- Importantly Kcentra Has Not Been Studied in Patients Who Had a Thromboembolic Event, Disseminated Intravascular Coagulation, Transient Ischemic Attack/Cerebrovascular Accident (CVA), Unstable Angina Pectoris/Myocardial Infarction, or Severe Peripheral Vascular Disease within the Prior 3 Months
History of Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia)
- Kcentra Contains Heparin
History of Thromboembolic Events within the Prior 3 Months
- Importantly Kcentra Has Not Been Studied in Patients Who Had a Thromboembolic Event, Disseminated Intravascular Coagulation, Transient Ischemic Attack/Cerebrovascular Accident (CVA), Unstable Angina Pectoris/Myocardial Infarction, or Severe Peripheral Vascular Disease within the Prior 3 Months
Known Anaphylactic or Severe Systemic Reactions to Kcentra or Any of its Components, Including the Following
- Heparin (see Heparin)
- Factors II, VII, IX, or X
- Proteins C or S
- Antithrombin III
- Human Albumin (see Albumin)

Pharmacology

Prothrombin Complex Concentrate-4 Factor is Human Plasma-Derived

Factor II (Approximately 25x More Concentrated than is Present in Plasma): procoagulant, vitamin K-dependent
Factor VII (Approximately 25x More Concentrated than is Present in Plasma): procoagulant, vitamin K-dependent
Factor IX (Approximately 25x More Concentrated than is Present in Plasma): procoagulant, vitamin K-dependent
Factor X (Approximately 25x More Concentrated than is Present in Plasma): procoagulant, vitamin K-dependent
Protein C: anticoagulant, vitamin K-dependent
Protein S: anticoagulant, vitamin K-dependent

Clinical Effect

A Single Kcentra Infusion Produces a Rapid and Sustained Increase in Plasma Concentration of Factors II, VII, IX, and X within 30 min

Administration

Intravenous (IV)

Dose
- Mean infusion time with Kcentra is 7x faster than with fresh frozen plasma (mean duration 24 min vs almost 3 hrs)
- Requires 87% less volume than fresh frozen plasma
- Does not require thawing or blood-type matching

Dose Adjustment

Hepatic: XXX
Renal: XXX

Use in Pregnancy (see Pregnancy)

Should Only Be Used in Pregnancy When Clearly Indicated

Use During Breast Feeding

Should Only Be Used During Breast Feeding When Clearly Indicated

Adverse Effects

Allergic/Immunologic Adverse Effects

Anaphylaxis (see xxxx)

Epidemiology
- Anaphylaxis Has Been Reported

Cardiovascular Adverse Effects

Hypotension (see Hypotension)

Epidemiology
- XXXX

Neurologic Adverse Effects

Headache (see Headache)

Epidemiology
- XXXX

Gastrointestinal Adverse Effects

Nausea/Vomiting (see Nausea and Vomiting)

Epidemiology
- XXXX

Hematologic Adverse Effects

Thromboembolic Events

Epidemiology
- Importantly Kcentra Has Not Been Studied in Patients Who Had a Thromboembolic Event, Disseminated Intravascular Coagulation, Transient Ischemic Attack/Cerebrovascular Accident (CVA), Unstable Angina Pectoris/Myocardial Infarction, or Severe Peripheral Vascular Disease within the Prior 3 Months
Clinical
- Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident)
- Venous Thromboembolism
  - Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis)
  - Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism)

Infectious Adverse Effects

Transmission of Infectious Agents

Epidemiology
- XXXX
Physiology
- Kcentra is Derived from Human Plasma
- Risk of Transmission of Infectious Agents (Including Viruses, Such as Creutzfeldt-Jakob Disease Agent) Cannot Be Completely Eliminated

Rheumatologic Adverse Effects

Arthralgias (see Arthralgias)

Epidemiology
- XXXX

References

Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma- controlled, phase IIIb study. Circulation. 2013;128:1234–43 [MEDLINE]
Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation. 2013 Jul 23;128(4):360-4. doi: 10.1161/CIRCULATIONAHA.113.001875. Epub 2013 Jun 14 [MEDLINE]
Management of the bleeding patient receiving new oral anticoagulants: a role for prothrombin complex concentrates. BioMed Res Int. 2014; Article ID 583794 [MEDLINE]
Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet 2015 May 23;385(9982):2077-87. doi: 10.1016/S0140-6736(14)61685-8. Epub 2015 Feb 27 [MEDLINE]
Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7 [MEDLINE]
Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016 Feb;24(1):6-46. doi: 10.1007/s12028-015-0222-x [MEDLINE]
Review: For warfarin reversal, prothrombin complex concentrates reduce mortality compared with fresh frozen plasma. Ann Intern Med. 2016 Dec 20;165(12):JC65. doi: 10.7326/ACPJC-2016-165-12-065 [MEDLINE]