TITLE: Tinzaparin versus Dalteparin or Enoxaparin for the Treatment of Venous Thromboembolism in Adults: Safety and Guidelines

DATE: 12 March 2013

RESEARCH QUESTION

1. What is the clinical evidence for the safety of tinzaparin versus dalteparin or enoxaparin for the treatment of venous thromboembolism in adults with a glomerular filtration rate (eGFR) less than 30 ml/min?

2. What is the clinical evidence for the safety of tinzaparin versus dalteparin or enoxaparin for the treatment of venous thromboembolism in adults who require dialysis?

3. What are the evidence-based guidelines for the use of tinzaparin for adults with venous thromboembolism and a glomerular filtration rate less than 30 mL/min or adults who require dialysis?

KEY MESSAGE

Two meta-analyses, one randomized controlled trial, and one non-randomized study were identified regarding the safety of tinzaparin versus dalteparin or enoxaparin for the treatment of venous thromboembolism. No evidence-based guidelines were identified.

METHODS

A limited literature search was conducted on key resources including Pubmed, The Cochrane Library (2013, Issue 2), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No methodological filters were applied. Where possible, retrieval was limited to the human population. The search was also limited to documents published between January 1, 2003 and March 1, 2013. Internet links were provided, where available.

Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid 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.

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The summary of findings was prepared from the abstracts of the relevant information. Please note that data contained in abstracts may not always be an accurate reflection of the data contained within the full article.

RESULTS

Rapid Response reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports, systematic reviews, and meta-analyses are presented first. These are followed by randomized controlled trials (RCTs), non-randomized studies, and evidence-based guidelines.

Two meta-analyses, one randomized controlled trial, and one non-randomized study were identified regarding the safety of tinzaparin versus dalteparin or enoxaparin for the treatment of venous thromboembolism. No relevant health technology assessments, systematic reviews, or evidence-based guidelines were identified. Additional references of potential interest are provided in the appendix.

OVERALL SUMMARY OF FINDINGS

One meta-analysis1 examined the use of low-molecular-weight heparin (LMWH) and bleeding in patients with severe renal insufficiency. While the authors indicated that renal insufficiency was associated with an increased risk of major bleeding, it was not clear whether any of the included studies compared LMWHs to each other and the authors could not make any conclusions regarding tinzaparin. A second meta-analysis2 examined the safety and efficacy of LMWHs for patients with end-stage renal disease. Within the analysis, one study was identified that compared tinzaparin and dalteparin and found no difference in major or minor bleeding events between the two drugs.

One RCT3 compared tinzaparin and dalteparin for periprocedural thromboembolism prophylaxis for patients on dialysis. Major bleeding at the injection was observed in the tinzaparin group, upper extremity deep vein thrombosis (DVT) in the dalteparin group, and myocardial infarction occurred in both groups. The authors indicated that the generalizability of results from this study may be limited due to the small sample size.

One non-randomized study4 surveyed the use of LMWHs and estimated the incidence of adverse events related to tinzaparin and enoxaparin in hospitals in France. The incidence of drug-related adverse events was 10.5% and included preventative and curative DVT therapy. The reports included bleeding events, thrombocytosis, thrombopenia, and hepatic cystolysis but the information in the abstract did not include which events were attributed to which drug. The authors noted that the risk of bleeding was increased for patients with creatinine clearance of less than 20 mL/min.

No guidelines for the use of tinzaparin for adults with venous thromboembolism and a glomerular filtration rate less than 30 mL/min or for adults who require dialysis were identified.

Tinzaparin versus Dalteparin or Enoxaparin for Adults with Venous Thromboembolism 2

REFERENCES SUMMARIZED

Health Technology Assessments No literature identified.

Systematic Reviews and Meta-analyses

1. Lim W, Dentali F, Eikelboom J W, Crowther M A. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Int Med 2006; 144(9): 673-684. Structured abstract available from: http://www.crd.york.ac.uk/crdweb/ShowRecord.asp?AccessionNumber=12006008200&Us erID=0 [cited 22 Mar 2013].

2. Lim W, Cook DJ, Crowther MA. Safety and efficacy of low molecular weight heparins for hemodialysis with end-stage renal failure: a meta-analysis of randomized trials. J Am Soc Nephr 2004; 15(12): 3192-3206. Structured abstract available from: http://www.crd.york.ac.uk/crdweb/ShowRecord.asp?AccessionNumber=12004007060&Us erID=0 Full-text: http://jasn.asnjournals.org/content/15/12/3192.full.pdf+html

Randomized Controlled Trials

3. Rodger MA, Ramsay T, MacKinnon M, Westphal M, Wells PS, McCormick B, et al. Tinzaparin versus dalteparin for periprocedure prophylaxis of thromboembolic events in hemodialysis patients: a randomized trial. Am J Kidney Dis. 2012 Sep;60(3):427-34. PubMed: PM22480794

Non-Randomized Studies

4. Cestac P, Bagheri H, Lapeyre-Mestre M, Sie P, Fouladi A, Maupas E, et al. Utilisation and safety of low molecular weight heparins: prospective observational study in medical inpatients. Drug Saf. 2003;26(3):197-207. PubMed: PM12580648

Guidelines and Recommendations No literature identified.

PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca

Tinzaparin versus Dalteparin or Enoxaparin for Adults with Venous Thromboembolism 3

APPENDIX – FURTHER INFORMATION:

Safety Advisories

5. LEO Pharma. Health Canada important safety information in the use of INNOHEP® (tinzaparin sodium). Ottawa: Health Canada; 2010. Available from: http://www.hc- sc.gc.ca/dhp-mps/alt_formats/pdf/medeff/advisories-avis/prof/2010/innohep_hpc-cps- eng.pdf

6. Celgene Corporation. Important INNOHEP® (tinzaparin sodium injection) safety information. Summit (NJ): Celgene; 2008. Available from: http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHuman MedicalProducts/ucm128135.pdf

Review Articles

7. Scotte F, Rey JB, Launay-Vacher V. Thrombosis, cancer and renal insufficiency: low molecular weight heparin at the crossroads. Support Care Cancer. 2012 Dec;20(12):3033- 42. PubMed: PM22960941

8. Canadian Agency for Drugs and Technologies in Health. Low molecular weight heparins: review of the comparative effectiveness for various indications. Ottawa: The Agency; 2009 Jan 19 (Rapid response report). [cited 11 Mar 2013]. Structured abstract available: http://www.crd.york.ac.uk/crdweb/ShowRecord.asp?AccessionNumber=32011001221&Us erID=0 Full-text: http://www.cadth.ca/media/pdf/htis/L0059%20Low%20Molecular%20Weight%20Heparins %20final.pdf

9. Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother. 2009 Jun;43(6):1064-83. PubMed: PM19458109

10. Schmid P, Fischer AG, Wuillemin WA. Low-molecular-weight heparin in patients with renal insufficiency. Swiss Med Wkly 2009;139 (31-32): 438-452. Available from: http://www.anestesia- dolor.org/repositorio/Farmacologia/Heparina%20de%20bajo%20peso%20molecular%20e n%20falla%20renal.pdf

11. Clark NP. Low-molecular-weight heparin use in the obese, elderly, and in renal insufficiency. Thromb Res. 2008;123 Suppl 1:S58-S61. PubMed: PM18809206

12. Crowther M, Lim W. Low molecular weight heparin and bleeding in patients with chronic renal failure. Curr Opin Pulm Med. 2007 Sep;13(5):409-13. PubMed: PM17940486

Tinzaparin versus Dalteparin or Enoxaparin for Adults with Venous Thromboembolism 4

13. Tincani E, Crowther MA, Turrini F, Prisco D. Prevention and treatment of venous thromboembolism in the elderly patient. Clin Int Aging 2007;2(2): 237-246. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684509/pdf/cia-2-237.pdf

14. George-Phillips KL, Bungard TJ. Use of low-molecular-weight heparin to bridge therapy in obese patients and in patients with renal dysfunction. Pharmacotherapy. 2006 Oct;26(10):1479-90. PubMed: PM16999658

15. Cheer SM, Dunn CJ, Foster R. Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease. Drugs. 2004;64(13):1479-502. PubMed: PM15212562

16. Nutescu EA, Shapiro NL, Feinstein H, Rivers CW. Tinzaparin: considerations for use in clinical practice. Ann Pharmacother. 2003 Dec;37(12):1831-40. PubMed: PM14632588

Additional References

17. Harenberg J, Bauersachs R, Diehm C, Lawall H, Burkhardt H, Gerlach H, et al. [Anticoagulation in the elderly]. Internist (Berl). 2010 Nov;51(11):1446-55. Full-text in German. PubMed: PM20802990

18. Hainer JW, Sprogel P, Lindenstroem E. Extending the role of antithrombotic agents: an example based on the low-molecular-weight heparin, tinzaparin. Semin Thromb Hemost. 2004 Feb;30 Suppl 1:3-9. PubMed: PM15085461

19. Pineo GF, Hull RD. Tinzaparin in the treatment of venous thromboembolism. Expert Opin Pharmacother. 2003 Dec;4(12):2355-62. PubMed: PM14640933

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