What is the clinical comparison and clinical outcome data regarding use of Thrombin-JMI vs Recothrom?

Comment by InpharmD Researcher

A limited number of trials have evaluated the therapeutic efficacy of bovine thrombin (Thrombin-JMI) vs recombinant human thrombin (Recothrom), with even fewer investigating direct, comparative efficacy. A notable comparative study (Table 3) was a non-inferiority study in adults undergoing hepatic resection, spinal surgery, peripheral arterial bypass surgery, or arteriovenous graft formation and demonstrated similar outcomes as topical adjuncts for surgical hemostasis, with a decreased rate of antigenicity associated with recombinant human thrombin. Additional comparative studies have confirmed non-inferiority or shown equivalent efficacy between agents up to 10 minutes after application, with some evidence indicating that recombinant human thrombin may be associated with a faster onset of hemostatic effect.

Please refer to Tables 1-5 for this inquiry.

Background

According to the American College of Obstetricians and Gynecologists (ACOG) committee opinion published in 2020 on topical hemostatic agents, limited data exist evaluating the use of topical hemostatic agents in gynecologic and obstetric surgery. Thus, recommendations are primarily based on findings extrapolated from studies on the use of these agents in other types of surgeries. Topical hemostatic agents have been frequently used when the use of electrocautery or sutures for hemostatic control of surgical bleeding is considered unsafe or not ideal, including bleeding in areas with nearby vulnerable structures (e.g., ureters or nerves) or in the presence of diffuse bleeding from peritoneal surfaces or cut surfaces of solid organs. On the other hand, the panel discouraged using topical hemostatic agents for routine prophylaxis of postoperative bleeding due to an increased risk of infection, adhesion formation, and other complications. [1]

To select the most appropriate and cost-effective topical agent, clinicians should be familiar with the distinct mechanisms of action, potential adverse effect profiles, and varying costs associated with an individual agent. Generally, physical agents (oxidized regenerated cellulose, microfibrillar collagen, and gelatin matrix) are more likely to be effective in patients without coagulation abnormalities and in less severe bleeding situations. However, when bleeding is more active or in the presence of coagulopathy, biologically active agents such as topical thrombin (human, bovine, recombinant, or thrombin+gelatin granules) and fibrin sealants may be considered. While limited head-to-head study (Table 1) has suggested similar efficacy between bovine thrombin (e.g., Thrombin-JMI®) vs recombinant thrombin (e.g., Recothrom®), surgeons should avoid administering bovine-derived thrombin in patients who have previously been exposed to the agent due to increased risk of severe antibody-mediated reactions upon re-exposure. On the other hand, use of recombinant thrombin products should be avoided in patients sensitive to snake or hamster proteins. [1]

All thrombin products contain a contraindication for injection into the circulatory system due to risk of thrombosis. Bovine thrombin should not be administered to patients with hypersensitivity to any component or other components of bovine origin. Human recombinant thrombin should not be used in patients with known hypersensitivity to hamster proteins, snake proteins (enzymes derived from snake venom are used in this product to activate precursors to human thrombin), or any component of human recombinant thrombin. Based on 2008 data, the average wholesale price of human recombinant thrombin was slightly more expensive than bovine plasma-derived thrombin (approximately $103-$434 vs. $88-$340, depending on formulation). Both bovine thrombin and human recombinant thrombin are supplied as sterile powders to be stored at room temperature, as opposed to human plasma-derived thrombin, which is supplied as a frozen sterile solution and must be stored under refrigeration. Reconstituted bovine thrombin can be refrigerated for up to 24 hours or stored at room temperature for up to 8 hours prior to use. Reconstituted human recombinant thrombin can be stored at room temperature for up to 24 hours prior to use. [2], [3], [4]

Background References: [1] American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice. Topical Hemostatic Agents at Time of Obstetric and Gynecologic Surgery: ACOG Committee Opinion, Number 812. Obstet Gynecol. 2020;136(4):e81-e89. doi:10.1097/AOG.0000000000004104
[2] Cheng CM, Meyer-Massetti C, Kayser SR. A review of three stand-alone topical thrombins for surgical hemostasis. Clin Ther. 2009;31(1):32-41. doi:10.1016/j.clinthera.2009.01.005
[3] Lew WK, Weaver FA. Clinical use of topical thrombin as a surgical hemostat. Biologics. 2008;2(4):593-599. doi:10.2147/btt.s2435
[4] Plesca D. A Review of Topical Thrombin. Cleveland Clinic Pharmacotherapy Update. 2009; 12(6):1-4.
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the clinical comparison and clinical outcome data regarding use of Thrombin-JMI vs Recothrom?

Level of evidence

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


Please see Tables 1-5 for your response.

RECOTHROM versus THROMBIN-JMI

Prescribing Information

 RECOTHROM® (Baxter Healthcare Corporation)1 THROMBIN-JMI® (Pfizer)2

Description

RECOTHROM Thrombin topical (Recombinant), is a human coagulation protein produced via recombinant DNA technology from a genetically modified Chinese Hamster Ovary (CHO) cell line. RECOTHROM is identical in amino acid sequence and structurally similar to naturally occurring human thrombin. 

RECOTHROM is provided as a sterile, white to off-white, preservative-free, lyophilized powder in vials for reconstitution with diluent (sterile 0.9% sodium chloride, USP). Reconstitution with the provided diluent, as described, yields a solution with a pH of 6.0 containing 1,000 units/mL of recombinant thrombin for topical use. The formulated product is a clear, colorless solution upon reconstitution and contains the following excipients: histidine, mannitol, sucrose, polyethylene glycol 3350, sodium chloride, and calcium chloride dihydrate, USP.

THROMBIN-JMI, Thrombin, Topical (Bovine), is a protein substance produced through a conversion reaction in which prothrombin of bovine origin is activated by tissue thromboplastin of bovine origin in the presence of calcium chloride.

It is supplied as a sterile powder that has been freeze-dried in the final container. Also contained in the preparation are mannitol and sodium chloride. Mannitol is included to make the dried product friable and more readily soluble. The product contains no preservative.

Dosage Forms and Strengths

RECOTHROM Thrombin topical (Recombinant) is available as a sterile lyophilized powder in 5,000- and 20,000-unit single-use vials. When reconstituted with the sterile 0.9% sodium chloride, USP provided, the powder yields a solution containing 1,000 units/mL of Thrombin topical (Recombinant).

It is supplied as a sterile powder that has been freeze-dried in the final container. Also contained in the preparation are mannitol and sodium chloride. Mannitol is included to make the dried product friable and more readily soluble. The product contains no preservative.

Solution for topical use: 5,000 or 20,000 IU vial

Pump spray kit: 20,000 IU vial

Syringe spray kit: 5,000 or 20,000 IU vial

Epistaxis kit: 5,000 IU vial

Gelfoam-JMI kits: 5,000 IU

Indications and Usage

To aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical in adults and pediatric populations greater than or equal to one month of age

May be used in conjunction with an Absorbable Gelatin Sponge, USP

To aid hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical

May be used in conjunction with an Absorbable Gelatin Sponge, USP

Pediatric Use

The safety of RECOTHROM in pediatric patients greater than or equal to one month of age is supported by clinical trial data and by extrapolation of efficacy from adequate and well-controlled studies of RECOTHROM in adults.

Safety and effectiveness in children have not been established.

Immunogenicity

In a clinical trial comparing RECOTHROM to bovine thrombin (N=411; n=398 antibody evaluable) for the development of specific anti-product antibodies, blood samples were collected at baseline and at Day 29 in both treatment groups and were analyzed by ELISA.1 At baseline, 1.5% of RECOTHROM patients (n=3/198) had positive anti-product antibody titers compared with 5% of bovine thrombin patients (n=10/200). Of these patients, none of the RECOTHROM group and eight in the bovine thrombin group exhibited ≥1.0 titer unit (≥10-fold) increases in anti-product antibody levels after study treatment.3

At Day 29, three of 198 (1.5%; 95% CI, 0%-4%) patients in the RECOTHROM group developed specific anti-product antibodies (one patient also developed anti-CHO host cell protein antibodies); 43 of 200 patients in the bovine thrombin group (22%; 95% CI, 16%-28%) developed specific antibodies to bovine thrombin product. Treatment with RECOTHROM resulted in a statistically significant lower incidence of specific anti-product antibody development. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study. None of the antibodies in the RECOTHROM group neutralized native human thrombin. Antibodies against bovine thrombin product were not tested for neutralization of native human thrombin.3

In a trial of patients with a high likelihood of prior exposure to bovine thrombin, 15.6% of patients (n=32/205) had anti-bovine thrombin product antibodies and 2% of patients (n=4/200) had anti-RECOTHROM product antibodies at baseline. Following treatment, none of the 200 evaluable patients (patients for whom post-treatment specimens were available) developed antibodies to RECOTHROM.4

In a trial of patients previously exposed to RECOTHROM, 31 patients were re-exposed to RECOTHROM during a subsequent surgery. None of the evaluable patients (n=30) had anti-RECOTHROM product antibodies at baseline and none developed antibodies at Day 29.5

In a trial of RECOTHROM, including 26 pediatric patients (aged one month to 16 years) and four patients 17 years of age, one patient without prior thrombin exposure had pre-existing anti-RECOTHROM product antibodies at baseline. None of the 27 evaluable patients developed anti-RECOTHROM product antibodies at Day 29.6

Inhibitory antibodies may develop in patients and interfere with hemostasis. Do not re-expose patients to THROMBIN-JMI if there are known or suspected antibodies to bovine thrombin and/or factor V, due to the potential for these antibodies to interfere with hemostasis. Monitor patients for abnormal coagulation laboratory values, bleeding, or thrombosis.

Bleeding may result from the development of antibodies against factor V. These antibodies may cross-react with human factor V and lead to human factor V deficiency.

Thrombosis may result from the development of antibodies against bovine thrombin.
Table 1 References:
[5] RECOTHROM (thrombin topical recombinant kit). Prescribing information. Baxter Healthcare Corporation; 2025
[6] THROMBIN-JMI (thrombin, topical, bovine origin). Prescribing information. Pfizer; 2025
[7] Chapman WC, Singla N, Genyk Y, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. 2007;205(2):256-65.
[8] Singla NK, Ballard JL, Moneta G, et al. A phase 3b open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis. J Am Coll Surg. 2009;209(1):68-74.
[9] Singla NK, Gasparis AP, Ballard JL, et al. Immunogenicity and safety of re-exposure to recombinant human thrombin in surgical hemostasis. J Am Coll Surg. 2011;213(6):722-727.
[10] Foster KN, Mullins RF, Greenhalgh DG, et al. Recombinant human thrombin: safety and immunogenicity in pediatric burn wound excision. J Ped Surg. 2011;46(10):1992-1999.

 

A Phase 3, Randomized, Double-Blind Comparative Study of the Efficacy and Safety of Topical Recombinant Human Thrombin and Bovine Thrombin in Surgical Hemostasis

Design

Randomized, double-blind, multicenter, comparative, phase III clinical trial

N= 411

Objective

To compare the efficacy, safety, and antigenicity of recombinant human thrombin (rhThrombin) and bovine thrombin (bThrombin) as adjuncts to hemostasis in liver resection, spine, peripheral arterial bypass, and dialysis access surgery

Study Groups

bThrombin (n= 206)

rhThrombin (n= 205)

Inclusion Criteria

Aged ≥ 18 years, no history of heparin-induced thrombocytopenia, no known sensitivity to Thrombin-JMI components, bovine materials, or porcine collagen

Exclusion Criteria

 Treated in a clinical study of rhThrombin, undergone a therapeutic surgical procedure or been treated with any experimental agent within 30 days, or had received blood products within 24 hours prior to operation

Methods

Patients were randomized 1:1 to receive either bThrombin 1,000 U/mL or rhThrombin 1,000 U/mL. The designated thrombin medication was applied topically to bleeding sites in combination with an absorbable gelatin sponge for spinal surgery and Surgifoam for other types of surgery. Gauze pad was utilized, held in place with gentle pressure and changed at least every 30 seconds until hemostasis. 

Enrollment was monitored during the study to ensure that patients undergoing vascular procedures comprised approximately 40% and patients undergoing spinal or hepatic surgery each comprised approximately 30% of the total population. 

Duration

Trial: patients treated between October 2005 to July 2006

Intervention: up to 10 minutes

Follow-up: 1 month after operation

Outcome Measures

 Hemostasis within 10 minutes, antibody production, adverse events

Baseline Characteristics

  

bThrombin (n= 206)

rhThrombin (n= 205)

 

Age, years

 59.5 60.0  

Male

 112 (54%) 104 (51%)  

Surgical operation

     Spine

     Liver

     Peripheral artery bypass

     Arteriovenous graft

 

61 (30%)

63 (31%)

44 (21%)

38 (18%)

 

61 (30%)

62 (30%)

44 (21%)

38 (19%)

      

Results

Endpoint

bThrombin

rhThrombin

p-Value

Hemostasis within 10 minutes†

 95.1% (n= 203) 95.4% (n= 198) Not significant

Antibody detection

 43/200 (21.5%) 3/198 (1.5%) < 0.0001

Patients with a serious adverse event‡

 46 (22%) 36 (18%) – 

†Both treatments had similar efficacy in the various surgical settings.

‡Serious adverse events include those that necessitate hospitalization, are life-threatening or result in significant disability or death

Adverse Events

 The most common adverse events reported were: injection site complications (63% bThrombin vs. 63% rhThrombin), nausea (35% vs. 28%), and procedural pain (34% vs. 29%). Also reported was anemia (11% vs. 14%).

Study Author Conclusions

This study demonstrated that bThrombin and rhThrombin have comparable efficacy when used with a gelatin sponge as a topical adjunct for surgical hemostasis. Although the safety profiles were similar between the bThrombin and rhThrombin treatment groups, there was a notably decreased rate of antigenicity associated with rhThrombin.

InpharmD Researcher Critique

No placebo group was incorporated, however use of placebo in this scenario may present ethical complications. 

 

Table 2 References:
[11] Chapman WC, Singla N, Genyk Y, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. 2007;205(2):256-65.

 

A Comparison of Recombinant Thrombin to Bovine Thrombin as a Hemostatic Ancillary in Patients Undergoing Peripheral Arterial Bypass and Arteriovenous Graft Procedures

Design

Double-blind, randomized, multicenter trial

N= 164

Objective

To evaluate the comparative safety and efficacy of recombinant thrombin (rThrombin) and bovine plasma-derived thrombin (bThrombin) when used as adjuncts to surgical hemostasis

Study Groups

bThrombin (n= 82)

rThrombin (n= 82) 

Inclusion Criteria

Undergoing peripheral artery bypass (PAB) or arteriovenous (AV) graft procedures with a polytetrafluoroethylene (PTFE) graft or revision procedures with PTFE graft-graft anastomoses

Exclusion Criteria

 Not specified 

Methods

Eligible patients were randomized (1:1) prior to surgery to receive either bThrombin (1,000 U/mL) or rThrombin (1,000 U/mL), applied topically to anastomotic bleeding site(s) in combination with an absorbable gelatin sponge. Surgeons were blinded to the treatment assignments. 

Duration

Enrollment: between October 2005 and July 2006

Follow-up: up to day 29 ± 5 days

Outcome Measures

Time to hemostasis (TTH) as the incidence of hemostasis within 10 minutes at anastomotic sites, adverse events 

Baseline Characteristics

  

bThrombin (n= 82)

rThrombin (n= 82) 

  

Age, years, median (range)

 63.5 (30-85) 65 (28-88)  

Female

41%  43%  

Surgery

PAB

Proximal and distal

Proximal only

Distal only

AV graft 

Arterial and venous

Arterial only

Venous only

 

44 (54%)

39 (89%)

3 (7%)

2 (5%)

38 (46%)

35 (92%)

2 (5%)

1 (3%) 

 

44 (54%)

38 (86%)

2 (5%)

4 (9%)

38 (46%)

32 (84%)

3 (8%)

3 (8%)

  

Preoperative coagulation impeding medications

 54 (66%) 51 (62%)  

Comorbidity

Hypertension

Diabetes

Renal insufficiency

Coronary artery disease

Heart failure

COPD/pulmonary

 

73 (89%)

42 (51%)

41 (50%)

28 (34%)

16 (20%)

17 (21%)

 

70 (85%)

42 (51%)

42 (51%)

33 (40%)

15 (18%)

17 (21%)

  
PAB, peripheral artery bypass; AV, arteriovenous; COPD, chronic obstructive pulmonary disease

Results

Endpoint

bThrombin (n= 82)

rThrombin (n= 82)

p-value

Cumulative incidence of hemostasis (PAB + AV graft)

Number of bleeding sites

Time to hemostasis, n (%) within,

1.5 min

3 min

6 min

10 min

 

156

-

56 (36%)

90 (58%)

124 (79%)

147 (94%)

 

152

-

62 (41%)

103 (68%)

128 (84%)

138 (91%)

 

 

 

0.44

0.11

0.33

0.28

Cumulative incidence of hemostasis (AV graft)

Number of bleeding sites

Time to hemostasis, n (%) within

1.5 min

3 min

6 min

10 min

n= 38

73

-

39 (53%)

58 (79%)

68 (93%)

72 (99%)

n= 38

70

-

42 (60%)

58 (83%)

66 (94%)

67 (96%)

 

 

 

0.49

0.66

0.77

0.29

Cumulative incidence of hemostasis (PAB graft)

Number of bleeding sites

Time to hemostasis, n (%) within

1.5 min

3 min

6 min

10 min

n= 44 

83

-

17 (20%)

32 (39%)

56 (67%)

75 (90%)

n= 44

82

-

20 (24%)

45 (55%)

62 (76%)

71 (87%)

 

 

 

0.58

0.046

0.28

0.47
PAB, peripheral artery bypass; AV, arteriovenous

Adverse Events

Common Adverse Events (bThrombin vs. rThrombin): Hemorrhagic (21% vs. 20%), cardiac (13% vs. 15%), hypersensitivity (11% vs. 11%), thromboembolic (9% vs. 9%)

Serious Adverse Events: 22% vs. 17%; antibody positive (27% vs. 0; p< 0.0001)

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

rThrombin or bThrombin used as a hemostatic ancillary for anastomotic bleeding was equally effective at 10 minutes; however, rThrombin compared with bThrombin may provide a more rapid onset of hemostasis at 3 minutes in PAB procedures. Adverse events were similar between the two thrombins. In patients undergoing vascular surgery, both treatments were similarly well tolerated, although rThrombin demonstrated a superior immunogenicity profile.

InpharmD Researcher Critique

While the accumulative incidences of hemostasis were reported based on prespecified anastomotic sites, the study is not powered to detect statistically significant differences between the two groups in regard to subgroup analyses. Results may not be readily applicable to other surgical interventions. 



Table 3 References:
[12] Weaver FA, Lew W, Granke K, et al. A comparison of recombinant thrombin to bovine thrombin as a hemostatic ancillary in patients undergoing peripheral arterial bypass and arteriovenous graft procedures. J Vasc Surg. 2008;47(6):1266-1273. doi:10.1016/j.jvs.2008.01.034

Phase 3, randomized, double-blind study of plasma-derived human thrombin versus bovine thrombin in achieving hemostasis in patients undergoing surgery
Design

Phase 3, multicenter, prospective, randomized, active-controlled, double-blind study in the US

N= 305
Objective To compare the effectiveness of plasma-derived human thrombin and bovine thrombin for achieving hemostasis during surgery
Study Groups

Human thrombin (n= 153)

Bovine thrombin (n= 152)
Inclusion Criteria Adults (age ≥18 years) scheduled for cardiovascular, neurologic (spine), or general or post-traumatic (hemodynamically stable and non-coagulopathic) elective surgical procedures with ≥1 mild to moderate bleeding site requiring a topical hemostat
Exclusion Criteria Disorders interfering with hemostasis, clinically significant preoperative complete blood count (CBC), prothrombin time (PT), or activated partial thromboplastin time (aPTT) findings, recent anticoagulant or non-steroidal anti-inflammatory drug (NSAID) therapy, known antibodies to bovine thrombin, organ transplant, morbid obesity, liver failure, severe bleeding sites, alcohol/drug abuse, pregnancy, uncontrolled diabetes, recent investigational drug/device research, sensitivities to porcine/bovine components
Methods Baseline information for each patient was collected as a screenining visit 2 weeks prior to surgery. Patients were randomized 1:1 based on surgical specialty to receive either human or bovine thrombin (Thrombin-JMI, control) applied topically with an absorbable gelatin sponge. Bleeding was assessed at 3, 6, and 10 minutes post-application. Other evaluations included laboratory assessments, vital signs, blood loss, blood transfusions, time in specialty-care units, procedure duration, and length of hospital stay. Antibody assessments were conducted at baseline and postoperative week 5 (+/- 7 days).
Duration Not explicitly stated, but includes preoperative assessments within 2 weeks prior to surgery and follow-up at 5 weeks post-surgery
Outcome Measures

Primary: Effective hemostasis within 10 minutes of hemostatic product application (defined as complete arrest of accumulation of blood at the treated bleeding site)

Secondary: Success in achieving hemostasis within 6 and 3 minutes, intraoperative blood loss, blood transfusions, procedure duration, length of hospital stay
Baseline Characteristics  

Human thrombin

(n = 153)

Bovine thrombin

(n = 152)

Total

(N = 305)

 p-value
Mean (SD) age, years 60.2 (14.5) 60.0 (14.1) 60.1 (14.3) 0.90
Sex, % male 64.0 58.6 61.3 0.32
Ethnicity, % - White 90.2 85.5 87.9 0.21
Mean (SD) BMI, kg/m2 27.8 (4.4) 27.8 (5.1) 27.8 (4.8) 0.92
Results   Human thrombin Bovine thrombin Ratio of human/bovine thrombin 95% CI for ratio of human/bovine thrombin
Percentage of patients achieving hemostasis within 10 min 97.4 (149/153) 97.4 (148/152) 1.00 0.96–1.05
Percentage of patients achieving hemostasis within 6 min 94.8 (145/153) 92.8 (141/152) 1.02 0.96–1.09
Percentage of patients achieving hemostasis within 3 min 73.2 (112/153) 72.4 (110/152) 1.01 0.88–1.16
Median intraoperative blood loss, mL (range) 200 (0-5000) 200 (0-2000) - -
Proportion of patients requiring blood transfusion, % 22 26 - -
Median duration of surgery, minutes (range) 126 (41-534) 142 (37-478) - -
Median hospital length of stay, days (range) 3 (0-60) 4 (0-24) - -
Overall, 282 patients (92%) completed the study (human thrombin n=141, bovine thrombin n=141); 248 patients (81%) had samples available for antibody testing from both screening and follow-up periods. 
Adverse Events Nearly all patients experienced one or more adverse events (99.7%). The most frequently occurring adverse events were laboratory abnormalities, nausea, and serious adverse events such as respiratory arrest and post-procedural hematoma. A significantly greater proportion of patients who received bovine thrombin demonstrated seroconversion for at least one of the four antibodies assayed than did patients who received human thrombin (12.70% vs. 3.28%).
Study Author Conclusions Plasma-derived human thrombin and bovine thrombin were equivalent in achieving hemostasis within 10, 6, and 3 minutes and had comparable safety profiles. None of the patients receiving human thrombin developed seroconversion for antibodies to any of the human antigens.
Critique The study's strengths include its randomized, double-blind design and the large sample size. However, limitations include the lack of a placebo-control group, potential inter-surgeon variability, and incomplete antibody assessment in all patients. The study's findings may not be generalizable to all surgical settings due to these limitations.
Table 4 References:
[13] Doria C, Fischer CP, Wood CG, Li PM, Marra S, Hart J. Phase 3, randomized, double-blind study of plasma-derived human thrombin versus bovine thrombin in achieving hemostasis in patients undergoing surgery. Curr Med Res Opin. 2008;24(3):785-794. doi:10.1185/030079908X273426

Prospective, Randomized, Phase II, Non-Inferiority Study to Evaluate the Safety and Efficacy of Topical Thrombin (Human) Grifols as Adjunct to Hemostasis During Vascular, Hepatic, Soft Tissue, and Spinal Open Surgery
Design

Randomized, double-blind, multicenter, non-inferiority phase II study in the US

N= 205
Objective To demonstrate that topical thrombin (human) [TTH-Grifols] is both effective and safe as an adjunct to hemostasis during vascular, hepatic, soft tissue, and spinal surgical procedures, and to compare it with bovine thrombin [BT-JMI]
Study Groups

TTH-Grifols (n= 137)

BT-JMI (n= 68)
Inclusion Criteria Adult and pediatric patients requiring elective, open surgical procedures in vascular, hepatic, soft tissue, and spinal categories; preoperative hemoglobin ≥9.0 g/dL and fibrinogen level ≥150 mg/dL within 24 hours before the procedure
Exclusion Criteria Traumatic injury or infective process in the surgical area, history of severe reactions to blood-derived products, pregnancy
Methods

Patients were randomized 2:1 to receive TTH-Grifols or BT-JMI. Hemostasis was evaluated at target bleeding sites within 5 minutes of treatment application. Safety was assessed through adverse events, vital signs, and immunogenicity studies.

Non-inferiority was defined in terms of the lower limit of a 2-sided 95% CI for the ratio of percentage of patients achieving hemostasis success by 5 minutes in the TTH-Grifols group divided by the corresponding percentage in the BT-JMI group (response ratio). If the lower limit for the 95% CI anal ysis was >0.8, then non-inferiority was deemed to have been demonstrated.
Duration January 2014 to November 2015
Outcome Measures

Primary: Percentage of patients achieving hemostasis at target bleeding sites (TBS) by 5 minutes

Secondary: Cumulative response by 3 and 4 minutes, number of treatment failures
Baseline Characteristics  

TTH-Grifols

(n= 120)

BT-JMI

(n= 61)
Male sex, n (%) 50 (41.7%) 19 (31.1%)
Age, years, mean (SD) 55.5 (16.0) 56.4 (16.5)
White race, n (%) 97 (80.8%) 50 (82.0%)
TBS bleeding intensity - Mild, n (%) 66 (55.0%) 29 (47.5%)
TBS bleeding intensity - Moderate, n (%) 54 (45.0%) 32 (52.5%)
Type of operation - Spinal, n (%) 57 (47.5%) 28 (45.9%)
Type of operation - Soft tissue, n (%) 23 (19.2%) 12 (19.7%)
Type of operation - Hepatic, n (%) 20 (16.7%) 10 (16.4%)
Type of operation - Vascular, n (%) 20 (16.7%) 11 (18.0%)
Results  

TTH-Grifols

(n= 120)

BT-JMI

(n= 61)

 Response ratio (95% CI)
Patient achieving hemostasis by 5 min, n (%) 94 (78.3%) 49 (80.3%) 0.973 (0.833-1.135)
Patient achieving hemostasis by 4 min, n (%) 85 (70.8% 45 (73.8%) 0.955 (0.796-1.146)
Patient achieving hemostasis by 3 min, n (%) 74/120 (61.7%) 39/61 (63.9%) 0.959 (0.765-1.202)
Vascular, n (%) 15/20 (75%) 6/11 (54.5%) -
Hepatic, n (%) 15/20 (75%) 8/10 (80%) -
Soft tissue, n (%) 17/23 (73.9%) 11/12 (91.7%) -
Spinal, n (%) 47/57 (82.5%) 24/28 (85.7%) -
Treatment failures, n (%) 26 (21.7%) 12 (19.7%) -
Adverse Events The percentages of patients for whom treatment-emergent adverse events (TEAEs) were reported were similar between treatment groups at approximately 85% to 88%. No patients experienced a confirmed adverse reaction. Severe adverse events were reported in 8.3% of patients in the TTH-Grifols treatment group and in 9.8% of patients in the BT-JMI treatment group.
Study Author Conclusions The TTH-Grifols was safe and well tolerated as a local hemostatic agent and was non-inferior to BT-JMI. No antibodies to thrombin developed in TTH-Grifols-treated patients.
Critique The study was well-designed with a randomized, double-blind approach, providing robust evidence for the non-inferiority of TTH-Grifols. However, the subjectivity in evaluating bleeding intensity and the focus on mild to moderate bleeding cases may limit the generalizability of the findings. Additionally, the study did not use an ITT approach, which could affect the interpretation of efficacy outcomes.
Table 5 References:
[14] Minkowitz H, Navarro-Puerto J, Lakshman S, et al. Prospective, Randomized, Phase II, Non-Inferiority Study to Evaluate the Safety and Efficacy of Topical Thrombin (Human) Grifols as Adjunct to Hemostasis During Vascular, Hepatic, Soft Tissue, and Spinal Open Surgery. J Am Coll Surg. 2019;229(5):497-507.e1. doi:10.1016/j.jamcollsurg.2019.07.008