Does Kcentra work in end-stage liver disease?

Comment by InpharmD Researcher

Evidence is both limited and conflicted as to whether four-factor prothrombin complex (4F-PCC; Kcentra®) is beneficial for patients with chronic liver disease in patients who require hemostasis. Available studies mainly reported patients with liver cirrhosis who received 4F-PCC in major hemorrhagic settings (e.g., gastrointestinal bleeding, intracranial hemorrhage, traumatic bleeding, etc.). One comparative study between liver disease and non-liver disease patients reported worse coagulopathy reversal and hemostasis in the liver disease group, resulting in higher mortality.

Background

A recent 2021 article discusses the use of prothrombin complex concentrate (PCC) in the setting of liver failure. Patients with end-stage liver disease (ESLD) are in a fragile state of rebalance where reduced procoagulant function is counterbalanced by reducing the anticoagulant activity. This balance can be easily disrupted, leading to bleeding or thromboembolism (TE). Four-factor PCC (4F-PCC) has been utilized in scenarios where patients have a high model for end-stage liver disease (MELD) score as an alternative to frozen plasma (FP) for correcting the hypercoagulation state. The primary argument for utilizing 4F-PCC is to reduce the risk of consequences related to FP including FP-associated immunomodulation, transfusion-related acute lung injury, or transfusion-associated circulatory overload (TACO). However, the concern for thromboembolism has prevented the widespread use of 4F-PCC in patients with liver disease. The use of 4F-PCC is mainly observed as prophylaxis prior to surgery or for active bleeding and are typically used in combination with other blood products. 4F-PCC is sometimes used to correct elevated international normalized ratio (INR) with a target INR of <1.5 commonly utilized, but an optimal hemostatic endpoint has not been established in liver failure. The authors conclude that the evidence seems promising but requires further study to determine optimal dosing and thrombotic potential, especially with repeat dosing. [1]

A 2020 abstract poster reported the outcomes of patients with liver disease who received four-factor prothrombin complex concentrate (Kcentra) for management of major/life-threatening hemorrhage or need for emergent surgery that failed to respond to blood products or cannot tolerate fresh frozen plasma (FFP). From a total of 52 patients receiving 72 doses of Kcentra, 67% of patients presented with liver failure secondary to cirrhosis, and 28% had acute liver failure. Kcentra was mostly used for gastrointestinal bleeding followed by use prior to surgery. Hemostasis was achieved in 27.6% of patients. Adverse events within 30 days include venous thromboemboli (7.8%), line-related thrombosis (3.1%), myocardial infarction (1.6%), and other (3.1%). At discharge, 53.1% of patients perished and 4.6% went to hospice while the rest were discharged. The authors noted the adverse events reported were higher than package insert (7-8%) while only helping a quarter of hepatic impaired patients achieve hemostasis. [2]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the evidence of using Kcentra for coagulopathy of chronic liver disease? Should it be used in life threatening or potentially life threatening bleeding for these patients?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Prothrombin Complex Concentrates for Coagulopathy in Liver Disease: Single-Center, Clinical Experience in 105 Patients
Design	Retrospective, single‐center audit/service evaluation N= 105 (194 episodes of Prothrombin complex concentrates [PCC] administration)
Objective	To evaluate the indications for PCC use and the correction of PT/INR at each administration
Study Groups	All (N= 105)
Inclusion Criteria	Patients with acute or chronic liver disease who received PCC
Exclusion Criteria	Hepatectomy, episodes that required coadministration of rFVIIa
Methods	The effect of PCC on coagulation was analyzed in patients for whom coagulation results were available 7 hours before and after PCC. Data on thromboembolic events and mortality within 4 weeks of PCC administration were captured.
Duration	Between January 2008 and June 2012
Outcome Measures	Primary: categorization of indications for PCC administration, the ability of PCC to correct PT/INR at each administration, potential relation to the dose administered Secondary: assessment of coadministration of other hemostatic products
Baseline Characteristics		All (N= 105)
	Age, years ≤ 40 41‐50 51‐60 61‐70 > 70	25 (24%) 27 (26%) 32 (30%) 14 (13%) 7 (7%)
	Female	69 (66%)
	Type of liver failure Chronic liver disease Acute liver failure	81 (77%) 24 (23%)
	Chronic liver disease etiology* ALD PBC/PSC/AI Viral NASH CCF HCC Other	44 (42%) 10 (10%) 25 (24%) 5 (5%) 4 (4%) 11 (10%) 15 (14%)
	Severity of liver disease at admission (Child‐Pugh grade)† < 7 = A 7-9 = B > 9 = C	4 (6%) 27 (38%) 40 (56%)
	Severity of liver disease at admission (MELD)† ≤ 9 10-19 20-29 30-39 ≥ 40	4 (5%) 42 (53%) 22 (28%) 10 (13%) 2 (3%)
	Acute liver failure etiology Acetaminophen overdose Viral/HBV Other	11 (46%) 4 (17%) 9 (38%)
	Patients undergoing OLT Chronic liver disease Acute liver failure	18 (17%) 6 (6%)
	^*Patients may have more than one etiology. Percentage values will add up to more than 100%. ^†Figures based on patients with chronic liver disease only. Percentages are of those patients with available data. Abbreviations: AI, adrenal insufficiency; ALD, acute liver disease; CCF, congestive cardiac failure; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; MELD, Model for End‐Stage Liver Disease; NASH, nonalcoholic steatohepatitis; OLT, orthotopic liver transplantation; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.
Results	Variable	No Fibronogen or Cryoprecipitate				Concurrent Administration of Fibrinogen or Cryoprecipitate
	Variable	N	Pre-PCC Median (interquartile range [IQR])	Post-PCC Median (IQR)	p-Value	N	Pre-PCC Median (IQR)	Post-PCC Median (IQR)	p-Value
	PT	46	27 (23, 34)	23 (20, 26)	<0.001	43	30 (23, 54)	21 (18, 28)	<0.001
	INR	49	2.3 (1.9, 2.9)	1.8 (1.6, 2.1)	<0.001	52	3.1 (2.0, 7.0)	1.9 (1.5, 2.8)	<0.001
	INR ≤ 1.5	49	6%	22%	0.005	52	4%	25%	<0.001
	aPTT	46	46 (38, 63)	45 (39, 56)	0.06	28	56 (45, 67)	46 (40, 66)	0.09
	Fibrinogen	28	1.6 (1.2, 2.3)	1.7 (1.2, 2.3)	0.37	22	1.0 (0.6, 1.4)	1.6 (1.1, 2.1)	<0.001
	Hemoglobin	39	8.4 (7.8, 8.8)	8.3 (7.9, 8.8)	0.75	31	8.1 (7.3, 9.3)	8.3 (7.2, 9.5)	0.36
	Indications for PCC were preprocedure prophylaxis and treatment for active/recent bleeding in 48% and 52% of 194 treatment episodes, respectively. The median dose of PCC administered was 22 IU/kg (IQR, 16‐29 IU/kg).
Adverse Events	No cardiovascular or cerebrovascular adverse events. Forty-six patients died of causes unrelated to PCC treatment.
Study Author Conclusions	In patients with liver disease, PCC therapy was effective in improving coagulation test results without an excess of thrombotic events. Further assessment of PCC as hemostatic therapy in this setting is required.
InpharmD Researcher Critique	Most patients (77%) had chronic liver disease. The study lacks a comparator (patient who did not receive PCC) and is subject to the limitations inherent to a retrospective analysis. Other hemostatic agents were used in addition to PCC which limits the interpretation of the results in terms of PCC use. The authors noted substantial heterogeneity across included patients.

References:

Drebes A, de Vos M, Gill S, et al. Prothrombin complex concentrates for coagulopathy in liver disease: single-center, clinical experience in 105 patients. Hepatol Commun. 2019;3(4):513-524. doi:10.1002/hep4.1293

Four-Factor Prothrombin Complex Concentrate for Coagulopathy Reversal in Patients With Liver Disease
Design	Single-center, retrospective, observational study N= 85
Objective	To analyze the efficacy and safety of 4-factor prothrombin complex concentrate (4F-PCC) in patients with and without liver disease (LD) when used for the treatment or prophylaxis of significant bleeding.
Study Groups	Liver disease (LD group) (n= 31) Without liver disease (non-LD group) (n= 54)
Inclusion Criteria	Received at least 1 dose of 4F-PCC, had at least 1 international normalized ratio (INR) prior to 4F-PCC administration (pre-INR) and at least 1 INR after 4F-PCC administration (post-INR) both obtained within 48 hours of 4F-PCC administration.
Exclusion Criteria	Age < 18 years, documented congenital factor deficiency, pregnancy
Methods	Patient data with documented LD based on the international classification of disease (ICD-9) codes, type of bleeding, and indication for 4F-PCC administration were collected for analysis. For warfarin reversal, patients received 4F-PCC 25 to 50 units/kg based on patient INR and body weight. For use prior to surgery, fixed low-dose 4F-PCC (approximately 500 units) was administered for INR reversal in nonbleeding coagulopathic patients. Concurrent use of blood products including fresh frozen plasma (FFP), packed red blood cells, platelets, and cryoprecipitate were allowed.
Duration	Data collection period: July 1, 2013 to April 20, 2014
Outcome Measures	Primary: coagulopathy reversal defined as post-INR < 1.5 collected at least 30 minutes after 4F-PCC Secondary: Hemostasis at 48 hours defined as the composite endpoint of all three of the following: achieved and maintained hemoglobin ≥ 7 g/dL for 48 hours after 4F-PCC administration, discontinuation of all blood products, and physician documented assessment of hemostasis in the electronic medical record within 48 hours of 4F-PCC administration.
Baseline Characteristics		LD group (n= 31)	Non-LD group (n= 54)	p-Value
	Age, years (interquartile range [IQR])	58 (50 to 62)	70 (60 to 82)	<0.01
	Male	17 (54.8%)	36 (66.7%)	0.35
	Body mass index, kg/m² (IQR)	23 (22 to 24)	23 (21 to 27)
	Type of bleeding Procedural associated Intracranial hemorrhage Gastrointestinal bleed Other trauma bleed Other bleed No bleed	5 (16.1%) 5 (16.1%) 10 (32.3%) 0 3 (9.7%) 8 (25.8%)	3 (5.6%) 23 (42.6%) 8 (14.8%) 4 (7.4%) 5 (9.3%) 11 (20.4%)	0.73
	Etiology of liver disease Hepatitis C cirrhosis Alcoholic cirrhosis Acute hepatitis, liver injury, liver failure Nonalcoholic steatohepatitis Isoniazid-induced hepatitis Crypotgenic cirrhosis Cardiac cirrhosis Sarcoidosis Unknown	10 (32.3%) 8 (25.8%) 4 (12.9%) 2 (6.5%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 3 (9.7%)	-	-
	Severity of liver disease Child-Pugh A Child-Pugh B Child-Pugh C Model for End-Stage Liver Disease (MELD) score (IQR)	1 (3.2%) 6 (19.4%) 24 (77.4%) 29 (21 to 40)	-	-
	Antiplatelet use prior to 4F-PCC None Aspirin Clopidogrel Other	27 (87.1%) 3 (9.7%) 0 1 (3.2%)	33 (61.1%) 18 (33.3%) 1 (1.9%) 2 (3.7%)	-
	Anticoagulant use None Warfarin Dabigatran Rivaroxaban Edoxaban	25 (80.7%) 4 (12.9%) 0 1 (3.2%) 1 (3.2%)	10 (18.5%) 40 (74%) 1 (1.9%) 2 (3.7%) 1 (1.9%)	-
	Concurrent use of packed red blood cells Concurrent use of fresh frozen plasma	22 (70.1%) 26 (83.9%)	20 (37.0%) 23 (42.6%)	<0.01 <0.01
	Median dose of 4F-PCC, units	1638 (537 to 2220)	2146 (1608 to 2785)
Results	Endpoint	LD group (n= 31)	Non-LD group (n= 54)	p-Value
	Coagulopathy reversal	6 (19.4%)	44 (81.5%)	<0.01
	Hemostasis at 48 hours	6 (19.4%)	23 (42.6%)	0.03
	Thrombotic events	1 (3.2%)	8 (14.8%)	0.15
	Mortality	51.6%	18.5%	<0.01
Study Author Conclusions	In conclusion, 4F-PCC appears to be safe in patients with liver disease when administered judiciously; however, further studies are necessary to optimize its use and elucidate its hemostatic potential in this patient population.
InpharmD Researcher Critique	The majority of patients also received additional blood products along with the 4F-PCC, making it difficult to assess the pro-coagulation effects of 4F-PCC.

References:

Huang WT, Cang WC, Derry KL, Lane JR, von Drygalski A. Four-Factor Prothrombin Complex Concentrate for Coagulopathy Reversal in Patients With Liver Disease. Clin Appl Thromb Hemost. 2017;23(8):1028-1035. doi:10.1177/1076029616668406

The Use of Kcentra® in the Reversal of Coagulopathy of Chronic Liver Disease
Design	Case reports
Case presentation 1	A 55-year-old male presented with a history of nonalcoholic steatohepatitis cirrhosis, coronary artery disease, and end-stage renal disease on dialysis to be treated for non-healing heel ulcer with osteomyelitis, requiring below-the-knee- amputation. On day 57 of hospitalization, the patient had hypoxemia with INR of 2.0 and on day 60, the patient developed shock and lactic acidosis. The patient's INR increased to 7.3, and he was given 1 unit of fresh frozen plasma (FFP) along with Kcentra 50 units/kg and 10 mg of intravenous (IV) phytonadione, leading to INR reduction to 1.7 in < 80 minutes. After the shock management, the patient was eventually transferred out of the ICU and discharged into a long-term care facility.
Case presentation 2	A 53-year-old male with a history of alcoholic cirrhosis, hypertension, and type II diabetes mellitus presented with worsening renal function, leading to dialysis on hospital day 6. On the day of anticipated discharge (day 15), the patient developed an intracerebral hemorrhage with INR at 2.2 and platelet at 23. The patient received IV phytonadione 10 mg, 2 units of FFP, and 2 units of platelets. After repeat testing showed INR at 2.0, 25 units/kg of Kcentra was administered with repeat INR of 1.5 reported 60 minutes after the infusion. While the hematoma did not progress, the patient developed acute respiratory distress syndrome due to repeated blood pack transfusion and perished 5 days later from septic shock and organ failure.
Case presentation 3	A 66-year-old male with a history of alcoholic liver cirrhosis, esophageal varices treated with a shunt, and gastrointestinal bleeding presented with symptomatic subdural hematoma. He had previously been admitted 3 weeks prior for an acute subdural hematoma. After the procedure, the patient's mental status returned to baseline, and the patient received 2 platelet transfusions for a platelet count of 67 (1000/mL), 5 mg IV phytonadione, and 12.5 units/kg Kcentra for INR 1.6. The INR lowered to 1.4 ten minutes after starting Kcentra and was successfully discharged on day 12 of hospitalization.
Case presentation 4	A 46-year-old male with a history of alcoholic liver cirrhosis and end-stage renal disease presented with bleeding from his dialysis catheter. On day 1 of hospitalization, the patient developed hypotension and encephalopathy which improved with broad-spectrum antibiotics and fluid resuscitation, leading to transfer to the medical floor on hospital day 3. However, he returned to the ICU 4 days later with intracranial hemorrhage, altered mental status, and an INR of 5.9. The patient was treated with 2 units of FFP and 10 mg of IV phytonadione which reduced INR to 3.6 along with improvement to platelets; however, intracranial hemorrhage worsened and the patient received 30 units/kg of Kcentra the next day which lowered INR to 1.8 2 hours after infusion. The patient somewhat improved until 3 days later when he developed brain herniation and cardiac death on day 14.
Study Author Conclusions	Kcentra may be a safe, effective, and rapid treatment option to be considered for hemorrhagic emergencies associated with CCLD, particularly when there are concerns for cardiopulmonary complications related to FFP dosing. Further research is needed to determine the ideal monitoring and dosing regimen for use in coagulopathy of chronic liver disease.

References:

Pereira D, Liotta E, Mahmoud AA. The use of Kcentra® in the reversal of coagulopathy of chronic liver disease. J Pharm Pract. 2018;31(1):120-125. doi:10.1177/0897190017696952