Continuous infusion of recombinant activated factor VII: a review of data in congenital hemophilia with inhibitors and congenital factor VII deficiency

Figures & data

Figure 1 Open-label study design

Note: ^aFor both recombinant activated factor VII-treated groups, two bolus rescue doses (90 mcg/kg) were permitted during any 24-hour period.

Abbreviations: BI, bolus injection; CI, continuous infusion.

Table 1 Open-label study – efficacy of bolus dosing vs continuous infusion in major surgery in patients with congenital hemophilia with inhibitors

	n (%)
	Bolus injection (90 mcg/kg) (n=12)		Continuous infusion (50 mcg/kg/h) (n=12)
Postoperative time point	Effective	Ineffective	Effective	Ineffective
Hour 0	12 (100.0)	0 (0.0)	12 (100.0)	0 (0.0)
Hour 8	12 (100.0)	0 (0.0)	11 (91.7)	1 (8.3)
Hour 24	12 (100.0)	0 (0.0)	10 (83.3)	2 (16.7)
Hour 48	10 (83.3)	2 (16.7)	11 (91.7)	1 (8.3)
Hour 72	9 (75.0)	3 (25.0)	11 (91.7)	1 (8.3)
Day 4	11 (91.7)	1 (8.3)	10 (83.3)	2 (16.7)
Day 5	11 (91.7)	1 (8.3)	10 (83.3)	2 (16.7)
Day 6	11 (91.7)	1 (8.3)	10 (83.3)	2 (16.7)
Day 7	9 (75.0)	3 (25.0)	10 (83.3)	2 (16.7)
Day 8	10 (83.3)	2 (16.7)	10 (83.3)	2 (16.7)
Day 9	9 (75.0)	3 (16.7)	10 (83.3)	2 (16.7)
Day 10	9 (75.0)	3 (16.7)	10 (83.3)	2 (16.7)

Notes: Data from Pruthi et al.²³ Patients who completed the study early, having achieved hemostasis, were counted as effective at subsequent time points. Patients who discontinued due to treatment failure were counted as ineffective at subsequent time points. Eight patients completed the study early because their bleeding had resolved. Four patients dropped out of the study due to ineffective therapy, and one patient left the study due to a hemarthrosis that was described as an adverse event. One of the patients randomized to the bolus injection arm had an autoimmune inhibitor to coagulation factor VIII and was included in the efficacy analysis.

Table 2 Open-label study – dosing by treatment group in patients with congenital hemophilia with inhibitors

Parameter	Bolus injection (90 mcg/kg) (n=12)	Continuous infusion (50 mcg/kg/h) (n=12)
Days of dosing, median (range)	10 (4–15)a	10 (2–116)
Number of bolus injections, median (range)	38 (36–42)	1.5 (0–7)
Number of additional bolus injections,b median (range)	0 (0–3)	0 (0–4)
Mean total dose, mg	237.5	292.2

Notes: Data from Pruthi et al.²³

a Includes dosing during the follow-up period after the 10-day study period.

b For both recombinant activated factor VII-treated groups, two bolus rescue doses (90 mcg/kg) were permitted during any 24-hour period. Five patients in the bolus group and four patients in the continuous infusion group required additional bolus doses.

Table 3 Postmarketing surveillance study – dosing and efficacy of continuous infusion of rFVIIa in patients with congenital hemophilia with inhibitors

Patient	Age, years	Type of surgery	Total dose, mcg/kg	Dosing regimen
				Initial bolus dose(s), mcg/kg	Continuous infusion,a mcg/kg/h	Treatment duration, days	Postoperative controlb
Hemophilia A
1	1	Port placement	1,830	92	14–28	5	Effective
2	32	Shoulder arthroplasty	2,520	120 q3 hours ×8	15–30	6	Effective
3	11	Elbow arthroplasty	5,930	60–100	10–30c	38d	Effective
	16	Surgical contracture release	610	202	17	7	Effective
	18	Arthroscopic synovectomy	5,550	98	20–60	8	Effective
4	20	Arthroscopic synovectomy (knee)	5,470	q2 hours ×12	15–30e	16f	Slightly effective
5	7	Arthroscopic synovectomy (knee)	1,690	100	17–26e	13f	Effective
6	19	Pneumothorax, chest tube insertion, debridement	8,870	q2 hours ×13	10–50	14	Effective
	19	Port placement, thoracoscopic partial pneumonectomy for pneumothorax	10,320	q2 hours ×25	10–50	14	Effective
Hemophilia B
7	36	Arthroscopic synovectomy (knee)	3,680	102 q2 hours ×9	13–17e	14f	Slightly effective
	37	Arthroscopic synovectomy (knee)	6,100	96 q2 hours ×8	8–56e	13f	Effective
8	12	Arthroscopic synovectomy (knee)	3,470	102 q2 hours ×12	26–34e	5f	Effective
9	15	Femoral head replacement	3,890	95 q2 hours ×12	14–29	7	Effective
	17	Femoral head replacement	5,000	100 q2 hours ×16	13–33	15	Slightly effective
10	36	Sclerotherapy for esophageal varices	580	NR	14	7	Effective

Notes: Data from Takedani et al.²⁴

a Continuous rFVIIa infusion was administered after bolus injection.

b Postoperative bleeding control (up to 3 days after surgery) was judged as effective (bleeding stopped or considerably reduced), slightly effective (bleeding slightly reduced), or not effective (bleeding not reduced).

c Treatment regimen included concomitant immune tolerance induction with recombinant factor VIII from the operative day.

d rFVIIa use before physiotherapy and for regular prophylaxis is included.

e Treatment regimen included preoperative, concomitant, or sequential use of activated prothrombin complex concentrate.

f Other bypassing agents were used in addition to rFVIIa. All patients on continuous infusion with rFVIIa received concomitant therapy with tranexamic acid.

Abbreviations: NR, not reported; rFVIIa, recombinant activated factor VII.

Table 4 Prospective studies, retrospective studies, and case reports – dosing and safety of continuous infusion of rFVIIa in patients with congenital hemophilia with inhibitors

Reference	Select content	Continuous infusion dosinga			Adverse drug reactionsb
		Dose, mcg/kg/h	Duration	Previously failed/concurrent treatment
Prospective studies
Chuansumrit et al, 2000^Citation25	Two of five patients with CHwI (four HA, one HB) received rFVIIa for three acute bleeding episodes	16.5 (individual dosing)	64–202 hours	Tranexamic acid, packed red blood cells, fibrin glue, intravenous immunoglobulin	None
Kenet et al, 2000^Citation26	Six patients with CHwI (HA) received rFVIIa for 101 bleeding episodes with either regular dose protocol (R) or augmented dose protocol (A)	R: 15–16 ×12 hours A: 30 ×6 hours	R: 29–100 hours A: 9–18 hours	NR	None
Santagostino et al, 2001^Citation19	28 patients with CHwI (25 HA) received rFVIIa for 31 episodes and 3 patients with AH received rFVIIa for 4 episodes. Overall, there were 10 spontaneous bleeding episodes, 11 major surgeries, and 14 minor surgeriesc	10–50	1–34 days	Tranexamic acid, porcine FVIII, other FVIII, packed red blood cells	None
Smith et al, 2001^Citation22	Eight patients with CHwI (six HA) received rFVIIa for six major surgeries and two patients with AH received rFVIIa for two minor surgeries	16.5	1–26 days	Platelets, cryoprecipitate	Device failure (1), hemarthrosis (1), therapeutic response decreased (1), extravasation (1), device-related sepsis (1), injection site thrombosis (2), postprocedural hemorrhage (3), postoperative wound infection (4), procedural hemorrhage (4)
Mauser-Bunschoten et al, 2002^Citation27	Ten patients with CHwI (eight HA, two HB) received rFVIIa for 28 bleeds and seven surgeries, and four patients with AH received rFVIIa for six bleeds and two surgeries	2.5–35	44 hours–12 days	Tranexamic acid	None
Ludlam et al, 2003^Citation28	Nine patients with CHwI (HA) received rFVIIa prior to nine elective major orthopedic surgeries	50	7–20 days	Tranexamic acid	Incision site hemorrhage (1), thrombocytopenia (1), thrombophlebitis (1), anemia (1), wound infection (1), cellulitis (2), hemarthrosis (6)
Kenet et al, 2003^Citation29	Three patients with CHwI received rFVIIa under two continuous infusion treatment regimens (CIa, CIb) for 244 bleeding episodes	CIa: 15–16 CIb: 30	4–100 hours	NR	None
Takedani et al, 2010^Citation30	Three of seven patients with CHwI received rFVIIa for four orthopedic surgeries with bolus injection + continuous infusion	16.5	3–7 days	Tranexamic acid	None
Ogura et al, 2011^Citation31	Six patients with CHwI received rFVIIa for 46 unspecified episodes (bleeds/surgeries)	15–50	3–8 days	Tranexamic acid	None
Retrospective studies
Schulman et al, 1998^Citation20	28 patients with CHwI (25 HA, 3 HB), 2 patients with AH, and 2 patients with GT received rFVIIa for 29 bleeding episodes or 26 surgeriesc	NR	1–16 days	Fresh frozen plasma, antithrombin, packed red blood cells, platelets, tranexamic acid, epsilon-aminocaproic acid	Thrombophlebitis (4)
Mauser-Bunschoten et al, 1998^Citation63	Seven patients with CHwI received rFVIIa for four bleeding episodes and five surgeries	6–30	1–14 days	Tranexamic acid	None
Ettingshausen et al, 1999^Citation32	Six patients with CHwI (HA) received rFVIIa for five surgeries and five bleeding episodes	10–35	4–18 days	Tranexamic acid, packed red blood cells	None
Habermann et al, 2004^Citation33	Four patients with CHwI (HA) received rFVIIa for six major elective orthopedic surgeries	35–50	≥8 days	FVIII, tranexamic acid	None
Solimeno et al, 2006^Citation34	Two of six patients with CHwI received rFVIIa for total knee replacement surgeries	16.5	NR	Porcine FVIII, PCC	Insufficient response (1)
Jenkins et al, 2013^Citation35	One of eight patients with CHwI received rFVIIa for total knee replacement surgery	50	NR	NR	None
Batorova et al, 2014^Citation36	One of seven patients with HA (six severe, one moderate, two with inhibitors) received rFVIIa for iliopsoas bleed	3	5 days	PCC	None
Mancuso et al, 2014^Citation37	Patients with CHwI (HA) received rFVIIa for four major orthopedic procedures	31	NR	Tranexamic acid, packed red blood cells	None
Linari et al, 2015^Citation38	Eleven patients with CHwI received rFVIIa for 15 total knee replacement surgeries	15–50	14 days	Packed red blood cells, PCC	Pulmonary embolism (1)
Case reports/series
Gringeri et al, 1991^Citation39	One patient with CHwI (HA) received rFVIIa for inguinal hernioplasty surgery	38	12 hours	Porcine FVIII, tranexamic acid, packed red blood cells	None
Hedner, 1991^Citation15	One patient with CHwI received rFVIIa for extensive herniotomy surgery	38	NR	Porcine FVIII, tranexamic acid	None
Schulman et al, 1996^Citation40	Two patients with CHwI (HA) received rFVIIa for four treatment episodes prior to elective surgery or traumatic procedure	15.5–31	3.5–14 days	Tranexamic acid, fibrin glue	None
Stieltjes et al, 1997^Citation41	One patient with CHwI (HA) received rFVIIa for removal of osteosynthesis surgery	20	NR	Porcine FVIII, anti-inhibitor coagulant complex	None
Vermylen and Peerlinck, 1998^Citation42	Two patients with CHwI (HA) received rFVIIa for three surgeries	6–29	13–14 days	Tranexamic acid	None
Ménart et al, 1998^Citation43	One patient with CHwI (HA) received rFVIIa postoperatively after a total knee replacement surgery	20	10 days	pd-FVIII, other FVIII, cryoprecipitate	None
Montoro et al, 1998^Citation44	One patient with CHwI (HA) received rFVIIa via minipump as prophylaxis during insertion of central venous catheter	4.3–7.6	5 days	Tranexamic acid	None
Scaraggi et al, 1999^Citation45	One patient with CHwI (HA) received rFVIIa for severe iliopsoas hematoma	4.7–16.7	17 days	NR	None
Lorenzo et al, 1999^Citation46	One patient with CHwI (HA) received rFVIIa for open knee evacuation surgery	20	7 days	NR	None
Peerlinck and Vermylen, 1999^Citation47	One patient with CHwI (HA), aged 72 years, received rFVIIa for dental extraction surgery	30	NR	Tranexamic acid, packed red blood cells	Acute myocardial infarction (1)
Baudo et al, 2000^Citation48	Four patients with CHwI (HA) received rFVIIa through a central vein catheter for two surgeries in one patient and three bleeding episodes in three patients	11.5–20	4–18 days	Porcine FVIII	None
Tagariello et al, 2000^Citation49	Two patients with CHwI (HA) received rFVIIa for two total hip replacement surgeries	11–42	12–29 days	Tranexamic acid, packed red blood cells	None
McPherson et al, 2000^Citation50	Six Australian patients with CHwI or AH (three HA, one HB, two AH) received rFVIIa for seven bleeding episodes (includes patients with CHwI with one intracranial hemorrhage, one iliopsoas hemorrhage, two wrist hemarthrosis, one sublingual hematoma, and one patient with AH with compartment syndrome and hemorrhage) and three surgeries (two Australian patients with AH for one retroperitoneal bleed and one surgical debridement and skin grafting; one Thai patient with CHwI for one surgery)	10–49	3–11 days	Epsilon-aminocaproic acid, tranexamic acid, pd-FVIII	None
Faradji et al, 2001^Citation51	One patient with CHwI (HA) received rFVIIa for knee joint arthroplasty surgery	14–28	14 days	Packed red blood cells	None
Nakamura et al, 2002^Citation52	One patient with CHwI (HA) received rFVIIa for left elbow arthroplasty surgery	10–30	6 days	Tranexamic acid	None
Perez et al, 2002^Citation53	One patient with CHwI (HA) received rFVIIa for hip arthroplasty surgery	7–15	12 days	Tranexamic acid	None
Tagariello et al, 2002^Citation54	Six patients with CHwI received rFVIIa for seven major hemorrhages and two surgeries	100–120	7–8 days	NR	None
Divanon et al, 2002^Citation55	Two of five patients with CHwI received rFVIIa for gastrointestinal bleeding or cholecystectomy	10–30	9–10 days	PCC, packed red blood cells, tranexamic acid, FVIII	None
Tagariello et al, 2003^Citation56	One patient with CHwI (HA) received rFVIIa during concurrent total hip replacement and total knee replacement surgery	21–40	13 days	Tranexamic acid	None
Hayashi et al, 2004^Citation57	One patient with CHwI (HA) received rFVIIa for serious retroperitoneal hematoma	30–40	7–10 days	PCC, packed red blood cells	None
Slaoui et al, 2004^Citation58	One of five patients with CHwI (HA) received rFVIIa before intestinal surgery	NR	9 days	Tranexamic acid	None
Margit et al, 2004^Citation59	One patient with CHwI (HA) received rFVIIa for major surgery	18–29	24 hours	Tranexamic acid	None
Horvathova et al, 2004^Citation60	One patient with CHwI received rFVIIa for hematuria and kidney hematoma	9–15	7 days	NR	None
Sartori et al, 2008^Citation61	One patient with CHwI (HA) received rFVIIa for bleeding episode	14–30	13 days	Packed red blood cells, tranexamic acid	None
Candiotto et al, 2015^Citation62	One patient with CHwI (HA) received rFVIIa for replacement of infected knee prosthesis surgery	25–40	12 days	pd-FVIII	None

Notes:

a Single bolus doses (18.5–180 mcg/kg) may have been given to patients before and after continuous infusion with rFVIIa at the discretion of investigator or treating physician.

b Only adverse reactions possibly or probably related to rFVIIa treatment are provided.

c Bleeding episodes and surgeries are not separated by diagnosis.

Abbreviations: AH, acquired hemophilia; CHwI, congenital hemophilia with inhibitors; FVIII, coagulation factor VIII; GT, Glanzmann’s thrombasthenia; HA, hemophilia A; HB, hemophilia B; NR, not reported; PCC, prothrombin complex concentrate; pd, plasma derived; rFVIIa, recombinant activated factor VII.

Table 5 Prospective studies, retrospective studies, and case reports – dosing and safety of continuous infusion of rFVIIa in patients with congenital factor VII deficiency

Reference	Select content	Continuous infusion dosinga			Adverse drug reactionsb
		Dose, mcg/kg/h	Duration	Previously failed/concurrent treatment
Prospective studies
Tran et al, 2011^Citation64	Ten patients with severe C7D received rFVIIa for 13 major and 12 minor surgeries	0.41–4	4–10 days	PCC, tranexamic acid	Major perioperative bleeding (1), transient rFVIIa inhibitors (1)
Mariani et al, 2011^Citation65	3 of 34 patients with C7D received rFVIIa for two major surgeries and one minor surgery	0.2–3.2	NR	NR	None
Retrospective studies
Schulman et al, 2005^Citation66	Seven patients with C7D received rFVIIa for 12 elective surgeries	0.325–6.25	2–7 days	Tranexamic acid	None
Case reports/series
Jiménez-Yuste et al, 2000^Citation67	One pregnant patient with moderate C7D received rFVIIa during cesarean section delivery	1.66–3.33	4 days	NR	None
Katori et al, 2008^Citation68	Two pediatric patients with C7D received rFVIIa for cardiac surgery after cardiopulmonary bypass termination	30	8 hours	NR	None
Nagao et al, 2014^Citation69	One patient with severe C7D received rFVIIa for left total hip replacement surgery	1–2	7 days	NR	None
Rajpurkar et al, 2014^Citation70	One patient with severe C7D received rFVIIa for intracranial surgery	4.5–9	9 days	None	None
Miyata et al, 2016^Citation71	One patient with asymptomatic C7D received rFVIIa for a right middle and lower lobectomy	2.5–3.75	3 days	None	None

Notes:

a Single bolus doses (5–66 mcg/kg) may have been given to patients before and after continuous infusion with rFVIIa at the discretion of the investigator or treating physician.

b Only adverse reactions possibly or probably related to rFVIIa treatment are provided.

Abbreviations: C7D, congenital factor VII deficiency; NR, not reported; PCC, prothrombin complex concentrate; rFVIIa, recombinant activated factor VII.

Table 6 Summary of continuous infusion-treated events in patients with congenital hemophilia with inhibitors and congenital factor VII deficiency

	Congenital hemophilia with inhibitors		Congenital factor VII deficiency		Total
	No. of patients	No. of episodes or procedures	No. of patients	No. of episodes or procedures	No. of patients	No. of episodes or procedures
Clinical trial	12	12 surgeries	NR	NR	12	12 surgeries
Post-approval study	10	15 surgeries	NR	NR	10	15 surgeries
Prospective reports	84 (includes 9 AH)	392 bleeds 55 surgeries 46 other (bleeds/surgeries)	13	28 surgeries	97	392 bleeds 83 surgeries 46 other (bleeds/surgery)
Retrospective reports	64 (includes 2 AH, 2 GT)	39 bleeds 64 surgeries	7	12 surgeries	71	39 bleeds 76 surgeries
Case reports and series	45	22 bleeds 31 surgeries	6	6 surgeries	51	22 bleeds 37 surgeries
Total	215 (includes 11 AH, 2 GT)	453 bleeds 177 surgeries 46 other (bleeds/surgery)	26	46 surgeries	241	453 bleeds 223 surgeries 46 other (bleeds/surgery)

Abbreviations: AH, acquired hemophilia; GT, Glanzmann’s thrombasthenia; NR, not reported.

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