A systematic review on the efficacy and safety of low molecular weight heparin as an anticancer therapeutic in preclinical animal models

David Ripsman; Dean A Fergusson; Joshua Montroy; Rebecca C Auer; Johnny W Huang; Aditi Dobriyal; Neil Wesch; Marc Carrier; Manoj M Lalu

doi:10.1016/j.thromres.2020.07.008

A systematic review on the efficacy and safety of low molecular weight heparin as an anticancer therapeutic in preclinical animal models

Thromb Res. 2020 Nov:195:103-113. doi: 10.1016/j.thromres.2020.07.008. Epub 2020 Jul 8.

Authors

David Ripsman¹, Dean A Fergusson², Joshua Montroy³, Rebecca C Auer⁴, Johnny W Huang⁵, Aditi Dobriyal⁶, Neil Wesch⁷, Marc Carrier⁸, Manoj M Lalu⁹

Affiliations

¹ Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, ON K1H 8L6, Canada; Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON K1H 8M5, Canada. Electronic address: drips036@uottawa.ca.
² Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, ON K1H 8L6, Canada; Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON K1H 8M5, Canada. Electronic address: dafergusson@ohri.ca.
³ Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, ON K1H 8L6, Canada. Electronic address: jmontroy@ohri.ca.
⁴ Department of Surgery, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada; Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, ON K1H 8L6, Canada. Electronic address: rauer@toh.ca.
⁵ Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON K1H 8M5, Canada. Electronic address: jhuan146@uottawa.ca.
⁶ Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, ON K1H 8L6, Canada; Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON K1H 8M5, Canada. Electronic address: adobr075@uottawa.ca.
⁷ Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, ON K1H 8L6, Canada.
⁸ Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, ON K1H 8L6, Canada; Faculty of Medicine, University of Ottawa, 451 Smyth Rd #2044, Ottawa, ON K1H 8M5, Canada. Electronic address: mcarrier@toh.ca.
⁹ Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, ON K1H 8L6, Canada; Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Room B307, 1053 Carling Avenue, Mail Stop 249, Ottawa, ON K1Y 4E9, Canada; Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Box 511, Ottawa, ON K1H 8L6, Canada. Electronic address: mlalu@toh.ca.

PMID: 32683148
DOI: 10.1016/j.thromres.2020.07.008

Abstract

Objective: The therapeutic effects of low molecular weight heparins (LMWH) may extend past thrombosis prevention, with preclinical evidence demonstrating anti-metastatic properties. Clinical evidence on the topic, however, remains controversial. A systematic review of preclinical evidence may help elucidate reasons for this contradictory evidence. The objective of our systematic review is to assess the anti-metastatic properties of LMWHs in solid tumour animal models.

Methods: MEDLINE, Embase, Web of Science and PubMed were searched from inception to May 12th, 2020. All articles were screened independently and in duplicate. Studies that compared LMWH to a placebo or no treatment arm in solid tumour animal models were included. The primary outcome was the burden of metastasis. Secondary outcomes included primary tumour growth and mortality. The risk of bias was assessed in duplicate using a modified Cochrane Risk of Bias tool.

Results: Forty-two studies were included in the review. Administration of a LMWH was associated with a significant decrease in the burden of metastasis (SMD -2.18; 95% CI -2.66 to -1.70). Additionally, the administration of a LMWH was also associated with a significant reduction in primary tumour growth (SMD -1.95; 95% CI -2.56 to -1.34) and risk of death (RR 0.39; 95% CI 0.16-0.97). All included studies were deemed to be at an unclear risk of bias for at least one methodological criterion.

Conclusions: Our results demonstrate that LMWH can effectively reduce metastatic burden and reduce tumour growth in preclinical animal models of solid tumour malignancies. Reasons for the contradiction with clinical evidence require further exploration.

Keywords: Animal models; Heparin; Meta-analysis; Neoplasms; Systematic review; Thrombosis.

Publication types

Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Animals
Anticoagulants
Heparin
Heparin, Low-Molecular-Weight* / therapeutic use
Models, Animal
Neoplasms* / drug therapy

Substances

Anticoagulants
Heparin, Low-Molecular-Weight
Heparin