Is there evidence to re-dose Kcentra when using fixed dose reversal for DOACs?

Comment by InpharmD Researcher

While re-dosing Kcentra (4-factor prothrombin complex concentrate [4F-PCC]) is generally not recommended, studies report a second dose is sometimes needed in patients who received an initial fixed dose for DOAC-related bleeding. The timing of redosing were not described.

Background

The safety and efficacy of redosing of Kcentra have not been adequately studied in the available literature. According to the 2016 guidelines for the reversal of antithrombotics in intracranial hemorrhage from the Neurocritical Care Society and Society of Critical Care Medicine, redosing is not recommended for patients who already received a full dose of 4-factor prothrombin complex concentrate (4F-PCC). However, fresh frozen plasma (FFP) may be considered in these patients if they do not have adequate INR correction following a full dose of 4F-PCC administration. Although the flat dosing is not discussed, Kcentra manufacturer labeling also recommends against the repeat dosing strategy. [1], [2], [3], [4]

A 2023 meta-analysis identified 25 studies (N= 1,760; fixed dosing, n = 228; variable dosing, n = 1,532) to evaluate the effectiveness and safety of fixed versus variable 4F-PCC dosing for the management of fXa inhibitor-associated bleeding. Twelve studies reported the need for administration of a second dose of 4F-PCC in case of an insufficient effect of the initial management. The percentage of patients who needed repeat dosing ranged between 3.03%-5.17% for fixed dosing and 0%-18.5% for variable dosing; however, insufficient data precluded a comparison between the dosing strategies. [5]

Relevant Prescribing Information

DOSAGE AND ADMINISTRATION
KCENTRA dosing should be individualized based on the patient's baseline International Normalized Ratio (INR) value, and body weight.
The safety and effectiveness of repeat dosing have not been established and it is not recommended.

Literature Review

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

Is there evidence to re-dose Kcentra when using fixed dose reversal for DOACs (25-35 units/kg with a max of 2000 units)?

Level of evidence

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

Please see Tables 1-3 for your response.

Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study
Design	Multicenter, prospective study N= 84
Objective	To assess the efficacy and safety of 4-factor prothrombin complex concentrates (PCCs) for the reversal of the anticoagulant effect of rivaroxaban and apixaban
Study Groups	Apixaban (n= 39) Rivaroxaban (n= 45)
Inclusion Criteria	Patients on rivaroxaban or apixaban who required a PCC to manage acute and active major bleeding (defined by the International Society of Thrombosis and Hemostasis); administration of the last dose of either rivaroxaban or apixaban was within 24 hours
Exclusion Criteria	Patients with a drop of hemoglobin without an evident source of bleeding; preoperative reversal of rivaroxaban or apixaban; acute coronary syndrome or ischemic stroke within the past 30 days; received other hemostatic agents
Methods	Patients were recruited from 25 hospitals in Sweden and referred to the Coagulation Unit at Karolinska University Hospital. According to the hospital protocol, a flat dose of 1,500 IU of 4-factor PCCs was given to patients < 65 kg and 2,000 IU to patients ≥ 65 kg. A second dose of a PCC could be administered at the treating physician's discretion if patients were still bleeding. Patients' medical interventions, laboratory results, and outcomes were retrieved from their medical records. Two coagulation specialists assessed the effectiveness of bleeding management in each case and reached an agreement by discussion.
Duration	Study enrollment: January 1, 2014, and October 1, 2016 Follow-up: 30 days post-treatment
Outcome Measures	Duration of hospital stay, discharge destinations, and effectiveness of bleeding management For non-intracranial hemorrhage (ICH): changes in the hemoglobin level, transfusion of blood products, intervention or surgery to stop the bleeding, and the administration of other hemostatic agents For ICH: follow-up computed tomography (CT) within 24 hours, change in neurological status, and surgical intervention Safety outcome: occurrence of arterial or venous thromboembolism and death
Baseline Characteristics		Apixaban (n= 39)	Rivaroxaban (n= 45)	p-value
	Median age, years (interquartile range [IQR])	77 (7 to 81)	73 (68 to 84)	0.52
	Female	17 (43.4%)	19 (42.2%)	1
	Median body weight, kg	75 (67 to 89)	75 (65 to 80)	0.97
	Indication for anticoagulation SPAF VTE Both	34 (87.2%) 2 (5.1%) 3 (7.7%)	29 (64.4%) 1 (2.2%) 15 (33.3%)	0.01 -- -- --
	History of stroke	11 (28.2%)	10 (22.2%)	0.62
	Concomitant medications Antiplatelet NSAID	7 (17.9%) 2 (5.1%)	3 (6.7%) 0	0.22 0.21
	Baseline laboratory results INR APTT Creatinine	1.2 (1.1 to 1.3) 35 (32 to 39) 77 (61 to 83)	1.3 (1.1 to 1.5) 41 (36 to 49) 79.5 (63.5-99.5)	0.04 0.01 0.39
	Bleeding location ICH GI bleeding Visceral Genitourinary Musculoskeletal	29 (74.4%) 5 (12.8%) 2 (5.1%) 2 (5.1%) 1 (2.6%)	30 (66.7%) 8 (17.8%) 3(6.7%) 2 (4.4%) 2 (4.4%)	0.95 -- -- -- -- --
	SPAF, stroke prevention in patients with atrial fibrillation; VTE, venous thromboembolism; NSAID, nonsteroidal anti-inflammatory drug; INR, international normalized ratio; APTT, activated partial thromboplastin time; GI, gastrointestinal
Results	Management given	Apixaban (n= 39)	Rivaroxaban (n= 45)	p-value
	Median PCC dose, IU factor IX Total dose Dose, IU/kg	2000 (2000 to 2000) 26.7 (22 to 29.9)	2000 (1500 to 2000) 26.7 (20.8 to 29.4)	0.26 0.62
	Transfusions given Red blood cell concentrate Plasma Platelet	9 (23.1%) 2 (5.1%) 2 (5.1%)	11 (24.4%) 8 (17.8%) 8 (17.8%)	1 0.1 0.1
	Outcome of management	Apixaban (n= 39)		Rivaroxaban (n= 45)
	Outcome of management	Effective	Ineffective	Effective	Ineffective
	Bleeding location ICH GI Visceral Genitourinary Musculoskeletal	21 (72.4%) 3 (60%) 0 1 (50%) 1 (100%)	8 (27.6%) 2 (40%) 2 (100%) 1 (50%) 0	22 (73.3%) 5 (62.5%) 1 (33.3%) 2 (100%) 2 (100.0%)	8 (26.7%) 3 (37.5%) 2 (66.7%) 0 0
	Hemoglobin drop	2 (33.3%)	4 (66.7%)	3 (37.5%)	5 (62.5%)
	Any invasive procedure None Craniotomy Gastroscopy Embolization Fasciotomy Laparotomy Thoracotomy	17 (68%) 5 (71.4%) 3 (75.1%) 0 1 (100%) 0 0	8 (32%) 2 (28.6%) 1 (25%) 2 (100%) 0 0 0	23 (74.2%) 6 (100%) 1 (33.3%) 1 (50%) 0 1 (50%) 0	1 (25%) 0 2 (66.7%) 1 (50%) 0 1 (50%) 1 (100%)
	Median length of hospital stay, days	7 (3 to 15)	4.5 (2 to 7)	9 (4 to 16)	2.5 (2 to 5)
	Discharge destination Home Rehabilitation facility Other hospital Deceased	14 (93.3%) 7 (63.6%) 2 (66.7%) 3 (33.3%)	1 (6.7%) 4 (36.4%) 1 (33.3%) 6 (66.7%)	10 (90.9%) 13 (92.9%) 1 (100%) 5 (35.7%)	1 (9.1%) 1 (7.1%) 0 9 (64.3%)
	PCCs were administered 6 hours after the estimated bleeding time (2 to 10 hours). Most patients with ineffective hemostasis with PCC had ICH (n = 16; 61.5%). A second PCC dose of 500-1500 IU was given in 3 cases due to an insufficient effect of the initial management with a PCC.
Adverse Events	Occurrence of arterial or venous thromboembolism: ischemic stroke (n= 2) and pulmonary embolism (n= 1)
Study Author Conclusions	The study found that the majority of patients treated with PCCs for the management of major bleeding events (MBEs) on rivaroxaban or apixaban achieved effective bleeding control, with few observed thromboembolic events. Based on the study results, the authors would suggest giving patients with MBEs on rivaroxaban or apixaban an initial PCC dose of 2000 IU, which may be repeated if the effect is suboptimal. Such an approach seems to be associated with an acceptable balance between efficacy and safety of PCCs.
InpharmD Researcher Critique	The use of flat dosing of PCCs in this study led to an overall effective anticoagulant reversal when administered within a couple of hours of bleeding onset with a low risk of thromboembolism. However, the applicability of the study results of using flat doses of PCCs as reversal agents for rivaroxaban or apixaban may be limited by the absence of a control group.

References:

Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017;130(15):1706-1712. doi:10.1182/blood-2017-05-782060

Comparison of Hemostatic Outcomes in Patients Receiving Fixed-Dose vs. Weight-Based 4-Factor Prothrombin Complex Concentrate
Design	Single-center, retrospective, cohort study N=72
Objective	To evaluate the efficacy and safety of 4F-PCC administration using a fixed dose of approximately 2000 factor IX units to achieve hemostasis in anticoagulated patients, compared with weight-based therapy
Study Groups	Weight-based dosing (n=38) Fixed-dosing (n=34)
Inclusion Criteria	Age > 18 years, on warfarin or direct factor Xa inhibitor (apixaban, edoxaban, or rivaroxaban), in need of emergent hemostasis or anticoagulation reversal, administered 4F-PCC
Exclusion Criteria	On direct thrombin inhibitor (e.g. dabigatran), history of heparin-induced thrombocytopenia, history of disseminated intravascular coagulation, death within 24 hours of hospitalization, included in a vulnerable population
Methods	Before January 1, 2018, patients received weight-based dosing of 4F-PCC which ranged from 35 to 50 factor IX units/kg. The amount administered depended on bleed severity at the time. After January 1, 2018, the fixed-dosing of 2000 factor IX units of 4F-PCC was adopted. An additional 2000 units was available if deemed appropriate.
Duration	January 1, 2014 to December 31, 2018
Outcome Measures	Primary outcome: clinically effective hemostasis after administration of 4F-PCC Effective hemostasis is defined as: no further reports of significant bleeding, stabilization of bleeding noted on serial computed tomography scans, no further significant drop in repeat hemoglobin measurements defined as a drop of > 2 g/dL within 2 to 6 hours post PCC administration. Secondary outcomes: Inpatient all-cause mortality, hospital length of stay, need for repeat dose, need for fresh frozen plasma (FFP) or packed red blood cells, safety, acquisition cost savings
Baseline Characteristics		Weight-based (n=38)	Fixed-dose (n=34)	p-value
	Age, years	76.9 ± 10.8	71.1 ± 12.5	0.100
	Male	52.6%	52.9%	0.979
	White	92.1%	91.2%	0.887
	Total dose given, units	3452 ± 1265	2336 ± 605	<0.001
	Total dose given, units/kg	43.6 ± 11.9	29.8 ± 11.1	<0.001
	Comorbidities Diabetes mellitus Hypertension Myocardial infarction Congestive heart failure Cerebrovascular accident Peripheral vascular disease	42.1% 97.4% 36.8% 44.7% 42.1% 47.4%	44.1% 91.2% 23.5% 52.9% 41.2% 38.2%	0.863 0.338 0.221 0.487 0.936 0.435
	Charlson Comorbidity Index score	10.7 ± 3.7	9.5 ± 3.8	0.192
Results	Endpoint	Weight-based (n=38)	Fixed-dose (n=34)	p-value
	Effective hemostasis after administration Subgroup analysis of warfarin patients Subgroup analysis of factor Xa-inhibitor patients	78.9% 83.3% 76.9%	91.2% 84.6% 95.0%	0.150 0.930 0.091
	Mortality	4 (10.5%)	5 (14.7%)	0.592
	Hospital length of stay, days	7.8 ± 5.9	8.7 ± 7.8	0.901
	Repeat dose given	3 (7.9%)	3 (8.8%)	0.887
	Need for fresh frozen plasma	7 (18.4%)	8 (23.5%)	0.594
	Need for packed red blood cells	17 (44.7%)	6 (17.6%)	0.014
	Total acquisition cost savings were calculated to be $91,029 or approximately $2,677 per patient when switching to a fixed-dose regimen based on cost of one factor IX unit of $1.58
Adverse Events	Fixed-dose group: n=0 Weight-based group: n=2 (5.3%)
Study Author Conclusions	A fixed-dose regimen of approximately 2000 factor IX units of 4F-PCC may be a reasonable approach to achieve hemostasis in patients receiving warfarin or factor Xa inhibitors. Additionally, utilization of a fixed-dose regimen may lead to significant acquisition cost savings for facilities.
InpharmD Researcher Critique	This is a retrospective review of a small group of patients. Data is exploratory at best. The goal of 4F-PCC therapy was not to reverse factor Xa inhibitor but to achieve hemostasis. There is a newer reversal agent (andexanet alfa) specific for Xa inhibitors which may override the results.

References:

Kim C, Cottingham L, Eberwein K, Komyathy K, Ratliff PD. Comparison of Hemostatic Outcomes in Patients Receiving Fixed-Dose vs. Weight-Based 4-Factor Prothrombin Complex Concentrate. J Emerg Med. 2020;59(1):25-32. doi:10.1016/j.jemermed.2020.04.049

Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study
Design	Prospective observational multicenter cohort study N= 66
Objective	To evaluate the use of prothrombin complex concentrate (PCC) at a dose of 2,000 units for the management of factor Xa-inhibitor–associated major bleeds
Inclusion Criteria	Received infusion of PCC (2,000 units) for major bleeding while on treatment with rivaroxaban or apixaban and not received other hemostatic agents, including plasma, platelets, activated PCC, or recombinant factor VIIa (antifibrinolytic drugs and local hemostatic agents were permitted) prior to administration of PCC
Exclusion Criteria	Established 'do not resuscitate' (DNR) orders, drop of hemoglobin without evidence of a source of bleeding, acute coronary syndrome, or ischaemic stroke in past 30 days
Methods	Patients were given 2,000 units PCC for reversal of rivaroxaban or apixaban and were followed up after PCC treatment, with information acquired using medical records and from patients directly. Treating physicians assessed the effectiveness of PCC treatment at 24 hours using all lab/testing results and imaging. Rating categories included 'good,' 'moderate,' or 'poor,' with each category having preset criteria. Good: bleeding stopped ≤ 1-hour post-infusion without an additional coagulation intervention Moderate: bleeding stopped 1 to 4 hours post-infusion without an additional coagulation intervention Poor: bleeding stopped > 4 hours post-infusion with an additional coagulation intervention (plasma, whole blood, or coagulation factors)
Duration	Enrollment: July 2014 to July 2017 Follow-up: 30 ± 2 days
Outcome Measures	Primary: proportion of patients with effective PCC (as assessed by physicians) Secondary: use of other blood products, decrease in hemoglobin from admission, length of stay in intensive care unit/hospital Safety: thromboembolic events (including symptomatic DVT or pulmonary embolism, ischaemic stroke, heart valve or cardiac chamber thrombosis, symptomatic peripheral arterial thrombosis or myocardial infarction) within 7 days after PCC, 30-day event rate of thromboembolic events, deaths
Baseline Characteristics		All patients (N= 66)
	Age, years	76.9 ± 10.4
	Male	42 (67%)
	Weight, kg (interquartile range [IQR])	81 (68 to 90)
	Anticoagulant treatment:
	Patients on rivaroxaban Daily dose, mg (IQR) Time from last dose to PCC, hours	37 (56%) 20 (15 to 20) 18.1 ± 10.3
	Patients on apixaban Daily dose, mg (IQR) Time from last dose to PCC, hours	29 (44%) 10 (5 to 10) 17.8 (9.3)
	Treatment with PCC:
	Time from onset of bleed to PCC, hours (IQR) Time from arrival to PCC, hours (IQR) First dose of PCC, IU First dose of PCC, IU/kg	8.6 (4.8 to 18.1) 5.4 (3.3 to 7.8) 2,072 ± 464 26.4 ± 7.7
Results	Endpoint	All patients (N= 66)
	Effectiveness rating: Good Moderate Poor	43 (65%) 13 (20%) 10 (15%)
	Use of other blood products: Second dose of PCC (1,000 U and 2,000 U) Red cells (1-8 U) Platelets (1-3 apheresis or pooled U) Cryoprecipitate	2 (3%) 13 (20%) 8 (12%) 1 (2%)
	Decrease in hemoglobin from admission after PCC, g/L (IQR)	18 (3 to 34)
	Length of stay, days (IQR): Hospital Intensive care unit	16 (5.3 to 30) 0 (0 to 6)
	Thromboembolic events: Days 0-7 Days 8-30	2 (3%) 3 (5%)
	Deaths	9 (14%)
	Two patients required a second dose of PCC. An additional dose of PCC, 1,000 U, was given 1 day after the first dose to the patient who took warfarin together with rivaroxaban, as the INR was 2.7 (baseline INR: 7.2). A second dose of 2,000 U was given as a last effort to a patient with large intracerebral, subdural and subarachnoid hemorrhage after the second CT scan showed further expansion.
Adverse Events	In addition to adverse events listed in results section above, eight serious adverse events were reported: gastrointestinal bleeding (n= 3), gross hematuria (n= 2), cellulitis (n= 1), infection/hypernatremia/delirium (n= 1), neurological deterioration due to expansion of previously evacuated subdural hematoma (n= 1)
Study Author Conclusions	Management of oral factor Xa-inhibitor–associated major bleeding using PCC to achieve initial hemostasis was assessed by the treating physician as good in 65% of the cases, with 67% for intracranial and 69% for gastrointestinal bleeding. For another 20% of the cases, it was assessed as moderate. Despite these ratings, patients still had significant morbidity and mortality, mainly after intracranial bleeding on anticoagulation. The risk of thromboembolism after reversal must be remembered and anticoagulation with at least a prophylactic dose should be started when bleeding has been controlled.
InpharmD Researcher Critique	This was a Canadian study done without a control group, making it difficult to assess if the results were clinically significant. Additionally, patients were recruited after PCC treatment had already been administered; selection bias in deciding whether to treat with PCC may have excluded certain groups of patients.

References:

Schulman S, Gross PL, Ritchie B, et al. Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study [published correction appears in Thromb Haemost. 2018 Dec;118(12):2188]. Thromb Haemost. 2018;118(5):842-851. doi:10.1055/s-0038-1636541