TITLE: Recombinant Human Thrombin: Clinical Effectiveness And Cost-Effectiveness DATE: 08 November 2010 CONTEXT AND POLICY ISSUES: Excessive bleeding during surgical procedures can lead to increased morbidity and mortality. Thrombin has been long used in surgery as an aid for achieving operative hemostasis. 1 Until recently, most of the thrombin used as topical agent was derived from bovine plasma. 2 There are concerns about the safety of bovine thrombin (bthrombin) as some patients treated with bthrombin developed antibodies against bovine coagulation factors. 2 These patients would be at high risk of immune reaction when re-exposed to bthrombin. 2 The search for an alternative product lead to the recent development of a recombinant human thrombin (rhthrombin), and Phase II and III clinical trials have recently been completed. 3 This report reviews the evidence of clinical effectiveness and cost-effectiveness of rhthrombin used as topical agent to achieve surgical hemostasis. RESEARCH QUESTIONS: 1. What is the clinical effectiveness of using rhthrombin for hemostasis? 2. What is the safety of using rhthrombin for hemostasis? 3. What is the cost effectiveness of using rhthrombin for hemostasis? KEY MESSAGE: Limited clinical evidence suggests that the use of rhthrombin as an aid to hemostasis is effective and safe during surgery and at one-month follow-up. Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.
METHODS: A limited literature search was conducted on key health technology assessment resources, including PubMed, OVID EMBASE, the Cochrane Library (Issue 10, 2010), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI (Health Devices Gold), EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles published between January 1, 2005 and October 6, 2010. Filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials and economic studies. A non-randomized studies filter was applied to a focused search (omitting thrombin name variants) for targeted non-randomized studies. SUMMARY OF FINDINGS: The literature search identified one phase II randomized controlled trial (RCT), 4 one phase III RCT reported in two published articles, 5,6 and two observational studies. 7,8 No systematic review/meta-analysis, economic studies or studies with cost information were identified. The characteristics of the included studies and the efficacy and safety of rhthrombin are presented in Appendices 1 and 2, respectively. Randomized controlled trials A phase II, multicentre, double-blind, randomized controlled trial 4 evaluated the safety of rhthrombin as a topical hemostatic agent in 130 patients in four surgical settings (25% AV grafts placed, 22% liver resection, 21% peripheral arterial by-pass, and 32% spinal surgery). The treatment group received rhthrombin (1,000 IU/ml) while the control group received placebo only. The study was funded by ZymoGenetics. The authors reported that all the adverse events reported by the patients were not related to the study treatment. Compared to placebo, patients receiving rhthrombin had higher incidence of nausea (45% vs. 26%), constipation (27% vs. 12%), insomnia (19% vs. 5%), and vomiting (13% vs. 2%). The incidence of serious adverse events was 19% in the placebo group and 24% in the rhthrombin group. One patient in each group died while undergoing hepatic resections. Both groups had similar proportions of patients having preexisting antibodies (4.8% placebo, 5.6% rhthrombin). Each group had one patient who developed antibodies to rhthrombin while on the study. No statistical analysis was done for any of the comparisons. The authors concluded that rhthrombin appears to be safe in different surgical settings. A phase III, multicentre, double-blind, randomized controlled trial 5 evaluated the efficacy and safety of rhthrombin used as topical agent to the bleeding site in 411 adult patients undergoing various types of surgery including liver resection (30%), spinal surgery (30%), peripheral arterial by-pass (21%) and dialysis access surgery (19%). The treatment group received rhthrombin (1,000 IU/ml) while the control group received bthrombin (1,000 IU/ml). The study was funded by ZymoGenetics. Primary efficacy end-point was time to hemostasis, summarized as incidence of hemostasis within 10 minutes. The results showed that both agents had comparable efficacy, with 95% of the patients in each group achieving hemostasis within 10 minutes. The common adverse events were as expected after operation and were similar between treatment groups. They included incision site complication, nausea, procedural pain, constipation, pyrexia, vomiting, Recombinant human thrombin 2
peripheral edema, anemia, hypokalemia and insomnia. Development of antibodies detected at end of study (one month) was significantly higher in the bthrombin group than in the rhthrombin group (21.5% vs. 1.5%, p<0.0001). The authors concluded that rhthrombin has similar efficacy and safety profile, but is less immunogenic than bthrombin when used as an aid for surgical hemostasis. A sub-group study 6 of the above trial reported the efficacy and safety of rhthrombin used in 164 patients undergoing vascular surgery. In this sub-population, both rhthrombin and bthrombin also showed similar efficacy (91% vs. 94%, p=0.28) and safety profile. More patients in the bthrombin group developed antibodies compared to the rhthrombin group (27% vs. 0%, p<0.0001). It was concluded that both agents were similarly well-tolerated, and rhthrombin was less immunogenic than bthrombin. Observational studies Two multicentre, single arm, open-label studies were identified. One study 7 evaluated the safety and immunogenicity of rhthrombin on patients (N=72) undergoing burn wound excision and grafting, and the other study 8 on patients (N=209) undergoing vascular and spinal surgery. A significant proportion of patients (15.5%) in the second study 8 had anti-bthrombin antibodies at baseline. Both studies were funded by ZymoGenetics. Development of anti-rhthrombin antibodies was found in 1.6% of patients (1/62) in first study 7 and in 0% of patients (0/200) in the second study. 8 Most patients in both studies had adverse events as expected after surgery. Common adverse events included incision site pain, procedural pain, nausea, constipation, anemia, muscle spasms and hypotension. Both studies concluded that the rhthrombin was well tolerated when used as an aid to hemostasis in respective surgical procedure. Limitations The evidence was limited in that only one phase II RCT, one phase III RCT and two observational studies were identified. Safety profile beyond day 30 after operation was unknown. All of the identified studies were funded by pharmaceutical industry, ZymoGenetics. CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: rhthrombin was found to be as effective as bthrombin. The complications were those as expected after a surgical procedure. Development of immunogenicity at study end (day 29) was significantly lower with rhthrombin than with bthrombin. However, giving the limitation of the clinical evidence and the lack of cost data, the advantage of rhthrombin over bthrombin is uncertain. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca Recombinant human thrombin 3
REFERENCES: 1. Anderson CD, Bowman LJ, Chapman WC. Topical use of recombinant human thrombin for operative hemostasis. Expert Opin Biol Ther. 2009 Jan;9(1):133-7. 2. Kessler CM, Ortel TL. Recent developments in topical thrombins. Thromb Haemost. 2009 Jul;102(1):15-24. 3. Ballard JL, Weaver FA, Singla NK, Chapman WC, Alexander WA. Safety and immunogenicity observations pooled from eight clinical trials of recombinant human thrombin. J Am Coll Surg. 2010 Feb;210(2):199-204. 4. Chapman WC, Lockstadt H, Singla N, Kafie FE, Lawson JH. Phase 2, randomized, double-blind, placebo-controlled, multicenter clinical evaluation of recombinant human thrombin in multiple surgical indications. J Thromb Haemost [Internet]. 2006 [cited 2010 Oct 7];4(9):2083-5. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2006.02067.x/pdf 5. Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL, Reynolds TC, 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 Aug;205(2):256-65. 6. Weaver FA, Lew W, Granke K, Yonehiro L, Delange B, Alexander WA, 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 Jun;47(6):1266-73. 7. Greenhalgh DG, Gamelli RL, Collins J, Sood R, Mozingo DW, Gray TE, et al. Recombinant thrombin: safety and immunogenicity in burn wound excision and grafting. J Burn Care Res. 2009 May;30(3):371-9. 8. Singla NK, Ballard JL, Moneta G, Randleman CD, Renkens KL, Alexander WA. A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis. J Am Coll Surg. 2009 Jul;209(1):68-74. Recombinant human thrombin 4
APPENDICES: Appendix 1: Characteristics of included studies Author Design Population Treatment arm(s) Control arm Co-intervention Follow-up 42 patients receiving NR NR (2006) 4 Multicentre, doubleblind, randomized, two parallel groups placebo (2007) 5 Weaver et al. (2008) 6 [Sub-group study of (2007) 5 ] Multicentre, doubleblind, randomized, two parallel groups Multicentre, doubleblind, randomized, two parallel groups 130 patients (age, NR) undergoing surgery (dialysis access surgery (20%), liver resection (22%), spine (32%), peripheral arterial bypass (21%)) 411 patients (age 21-89 years) undergoing surgery (liver resection (30%), spine (30%), peripheral arterial bypass (21%), dialysis access surgery (19%)) 164 patients (age 28-88 years) undergoing vascular surgery 88 patients receiving rht (1,000 IU/ml) as topical agent to bleeding site 205 patients receiving rht (1,000 IU/ml) as topical agent to bleeding site 82 patients receiving rht (1,000 IU/ml) as topical agent to bleeding site 206 patients receiving bt (1,000 IU/ml) as topical agent to bleeding site 82 patients receiving bt (1,000 U/ml) as topical agent to bleeding site Absorbable gelatin sponge; gauze pad Hold pad in place with gentle pressure and change at least every 30 seconds until hemostasis achieved Absorbable gelatin sponge; gauze pad Hold pad in place with gentle pressure and change at least every 30 seconds until hemostasis achieved 1 month after operation 1 month after operation Greenhalgh et al. (2009) 7 Singla et al. (2009) 8 Multicentre, single arm, open-label Multicentre, single arm, open-label 72 patients (age 12 to 70 years) with acute burns, who were receiving partial- or fullthickness autologous skin grafts 209 patients (mean age 61.5 years) 72 patients receiving rht (1,000 IU/ml) through a spray applicator 209 patients receiving rht (1,000 N/A Graft type: mesh grafts (25%); sheet graft (75%) 29 days after operation N/A Not mentioned 16 to 48 hours after surgery; and day 29 Recombinant Human Thrombin 5
Author Design Population Treatment arm(s) Control arm Co-intervention Follow-up undergoing vascular and spinal surgery, and 15.5% being at high risk for preexisting antibthrombin antibodies IU/ml) during surgical procedure as an aid to hemoatasis after surgery bt : bovine Thrombin; IU: international unit; N/A: not applicable; NR: not reported; rht : recombinant human thrombin Appendix 2: Efficacy and safety of recombinant human thrombin Author Patients completed / Efficacy (Incidence of hemostasis within 10 min) discontinued Absolute Difference Adverse events NR NR All patients (2006) 4 rht: 83 / 88 Pla: 41 / 42 reported at least one AE. None of the AE was considered to be related to (2007) 5 Weaver et al. (2008) 6 [Sub-group study of (2007) 5 ] rht: 201 / 4 bt: 200 / 6 rht: 80 / 2 bt: 81 / 1 rht: 95.4% bt: 95.1% rht: 91% bt: 94% Range from -0.7% (95% CI: -16.0, 14.6) in peripheral arterial bypass surgery to 1.6% (95% CI: -3.78, 6.91) in hepatic surgery No significant difference (data not shown) study treatment All patients reported at least one AE. None of the AE was considered to be related to study treatment Severity and specific AE: similar between treatment groups Similar between rht and bt groups for hemorrhagic (20% vs. 21%), cardiac (15% vs. 13%), Safety Immunogenicity at study end rht: 1.2% Pla: 2.4% rht: 1.5% bt: 21.5%, p<0.0001 rht: 0% bt: 27%, p<0.0001 Conclusion rhthrombin appears tp be safe in multiple surgical settings and did not provoke a clinically significant immune response rhthrombin has comparable efficacy, a similar safety profile, and is considerably less immunogenic than bthrombin when used for surgical hemostasis In patients undergoing vascular surgery, both treatments were similarly well tolerated, although rhthrombin demonstrated a superior immunogenicity profile Recombinant Human Thrombin 6
Author Greenhalgh et al. (2009) 7 Singla et al. (2009) 8 Patients completed / discontinued 71 patients evaluated for efficacy; 72 for safety 206 patients completed study; 200 patients were available for immunogenicity; 197 patients experienced AE Efficacy (Incidence of Safety hemostasis within 10 min) Absolute Difference Adverse Immunogenicity events at study end hypersensitivity (11% vs. 11%), thromboembolic (9% vs. 9%) Hemostasis at N/A Any AE: 88% 20 minutes Procedural pain: 1/62 (1.6%) rht: 91.5% 35% Skin graft failure: 6% N/A N/A Any AE: 94% Procedural pain: 39% Nausea: 27% Two deaths related to comorbidities 0/200 (0%) AE: adverse event; Ab: antibody; bt: bovine thrombin; IU: international unit; N/A: not applicable; NR: not reported; Pla: placebo; rht : recombinant human thrombin Conclusion rhthrombin was well tolerated when administered with a pump spray in patients undergoing skin grafting for burns rhthrombin can be used safely as an aid to hemostasis in patients with or without preexisting anti-bovine thrombin antibodies Recombinant Human Thrombin 7