0
Communications to the Editor |

Low-Molecular-Weight Heparin and Outcomes FREE TO VIEW

Ed Arbit, MD
Author and Funding Information

Affiliations: Emisphere Technologies, Tarrytown, NY,  Ospedale Maggiore,  Maggiore-Bellaria Hospital, Bologna, Italy

Correspondence to: Ed Arbit, MD, Emisphere Technologies-Research,765 Old Saw Mill River Rd, Tarrytown, NY 10591; e-mail: earbit@emisphere.com



Chest. 2005;128(1):471-472. doi:10.1378/chest.128.1.471
Text Size: A A A
Published online

To the Editor:

Conceptually, the suggestion by Alifano et al1(August 2004) is especially compelling from both the scientific and clinical observational standpoints. However, one needs to carefully consider if low-molecular-weight heparins (LMWHs) are the best choice of drugs to conduct such an important study. First, not all LMWHs are the same, and hence should not be lumped together as one group.2Second, and more importantly, there is strong scientific evidence that the biological activities of heparins, beyond anticoagulation, including activities such as antineoplastic, antiangiogenetic, and antiinflamatory, are related to the molecular weight of heparin or more precisely to the high sulfate to carboxylate ratio of heparin (unfractionated heparin [UFH] is more heavily sulfated than LMWHs and has thus the highest ratio). This has been observed in relation to the cellular release of tissue factor pathway inhibitor, the down-regulation of vascular endothelial growth factor and endothelial growth factor, and the inhibition of the c-fos gene, reverse transcriptase, telomerase, and topoisomerase, as examples.6 The clear advantages of LMWHs relate to their predictable pharmacokinetics and the convenience of being able to administer the drug subcutaneously in an outpatient setting without the need for routine monitoring. In terms of efficacy and safety LMWHs and UFH are equivalent. While LMWH will provide for equivalent anticoagulation to UFH, we may lose an opportunity to grasp the real usefulness of the parent drug (UFH) from which the LMWHs have been sliced.

Alifano, M, Benedetti, G, Trisolini, R (2004) Can low-molecular-weight heparin improve the outcome of patients with operable non-small cell lung cancer? An urgent call for research,Chest126,601-607. [CrossRef] [PubMed]
 
Mousa, SA Are low molecular weight heparins the same?Methods Mol Med2004;93,49-59. [PubMed]
 
Mousa, SA, Mohamed, S Anti-angiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: anti-cancer efficacy.Oncol Rep2004;12,683-688. [PubMed]
 
Amirkhosravi, A, Mouse, SA, Amaya, M, et al Antimetastatic effect of tinzaparin, a low-molecular-weight heparin.J Thromb Haemost2003;1,1972-1976. [CrossRef] [PubMed]
 
Engelberg, H Actions of heparin that may affect the malignant process.Cancer1999;85,257-272. [CrossRef] [PubMed]
 
Drake, SL, Klein, DJ, Mickelson, DJ, et al Cell surface phosphatidylinositol-anchored heparin sulfate proteoglycan initiates mouse melanoma cell adhesion to a fibronectin-derived, heparin-binding synthetic peptide.J Cell Biol1992;117,1331-1341. [CrossRef] [PubMed]
 
To the Editor:

We thank Dr. Arbit for his thorough comments on our article, which basically support the idea on the possible importance of a prospective study on heparin treatment in patients undergoing lung resection for non-small cell lung cancer (NSCLC). In Dr. Arbit’s opinion, unfractioned heparin (UFH) should be probably preferred to low-molecular-weight heparins (LMWHs) because of better in vitro antineoplastic and antioangiogenetic properties. We took carefully into account the possibility of such a criticism to our proposal, and we even hypothesized in the published article that the “nonspecific protein binding” of UFH might be necessary for its putative anticancer activity. However, we commented on the efficacy of LMWHs in inhibiting selectins, although to a lesser extent than UFH. We hypothesized that this disadvantage should be compensated by the better bioavailability and more consistent serum levels of LMWHs.

It has been reported that tinzaparin, a LMWH, is particularly effective at releasing tissue factor pathway inhibitor, thus providing further experimental evidence on the potential role of this LMWH as an antimetastatic agent.1Even more recently, Mousa and Mohamed2 confirmed this data and demonstrated that tinzaparin is a potent inhibitor of angiogenesis.

In our article, we also pointed out that a few randomized studies evaluated the impact of LMWHs on survival of cancer patients. We quoted the study by Von Tempelhoff et al,3who provided evidence that certoparin, a LMWH, more favorably affected the survival of operated patients with pelvic or breast cancer as compared to UFH. Since the submission of our article, two studies have been published on the impact of dalteparin, another LMWH, on survival of cancer patients. A randomized clinical trial4of combination chemotherapy with and without dalteparin in small-cell lung cancer showed that the association resulted in significantly improved progression-free survival and overall survival. In the Fragmin Advanced Malignancy Outcome Study,5 which included patients with different kinds of malignancy and adopted no restriction on concomitant use of chemotherapy or radiotherapy, a trend toward improvement in survival (not reaching significance) was observed in patients receiving dalteparin as compared to patients receiving placebo. In this study, analysis of a group of patients with a better prognosis and who survived > 17 months showed that dalteparin treatment was associated with a significant survival advantage.

These last studies should further prompt us to undertake a trial in patients with resectable NSCLC, the subset of NSCLC patients with better prognosis. Which LMWH should be preferred for such a trial is difficult to say. The few available clinical studies might support the use of certoparin or dalteparin, although experimental data tend to suggest that most LMWHs share anticancer activity.

References
Amirkhosravi, A, Mousa, SA, Amaya, M, et al Antimetastatic effect of tinzaparin, a low-molecular-weight heparin.J Thromb Haemost2003;1,1972-1976. [CrossRef] [PubMed]
 
Mousa, SA, Mohamed, S Antiangiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: anti-cancer efficacy.Oncol Rep2004;12,683-688. [PubMed]
 
Von, Tempelhoff GF, Harenberg, J, Nieman, F, et al Effect of low-molecular weight heparin (certoparin) versus unfractionated heparin on cancer following breast and pelvic cancer surgery: a prospective randomized double-blind trial.Int J Oncol2000;16,815-824. [PubMed]
 
Altinbas, M, Coskun, HS, Er, O, et al A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer.J Thromb Haemost2004;2,1266-1271. [CrossRef] [PubMed]
 
Kakkar, AK, Levine, MN, Kadziola, Z, et al Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS).J Clin Oncol2004;22,1944-1948. [CrossRef] [PubMed]
 

Figures

Tables

References

Alifano, M, Benedetti, G, Trisolini, R (2004) Can low-molecular-weight heparin improve the outcome of patients with operable non-small cell lung cancer? An urgent call for research,Chest126,601-607. [CrossRef] [PubMed]
 
Mousa, SA Are low molecular weight heparins the same?Methods Mol Med2004;93,49-59. [PubMed]
 
Mousa, SA, Mohamed, S Anti-angiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: anti-cancer efficacy.Oncol Rep2004;12,683-688. [PubMed]
 
Amirkhosravi, A, Mouse, SA, Amaya, M, et al Antimetastatic effect of tinzaparin, a low-molecular-weight heparin.J Thromb Haemost2003;1,1972-1976. [CrossRef] [PubMed]
 
Engelberg, H Actions of heparin that may affect the malignant process.Cancer1999;85,257-272. [CrossRef] [PubMed]
 
Drake, SL, Klein, DJ, Mickelson, DJ, et al Cell surface phosphatidylinositol-anchored heparin sulfate proteoglycan initiates mouse melanoma cell adhesion to a fibronectin-derived, heparin-binding synthetic peptide.J Cell Biol1992;117,1331-1341. [CrossRef] [PubMed]
 
Amirkhosravi, A, Mousa, SA, Amaya, M, et al Antimetastatic effect of tinzaparin, a low-molecular-weight heparin.J Thromb Haemost2003;1,1972-1976. [CrossRef] [PubMed]
 
Mousa, SA, Mohamed, S Antiangiogenic mechanisms and efficacy of the low molecular weight heparin, tinzaparin: anti-cancer efficacy.Oncol Rep2004;12,683-688. [PubMed]
 
Von, Tempelhoff GF, Harenberg, J, Nieman, F, et al Effect of low-molecular weight heparin (certoparin) versus unfractionated heparin on cancer following breast and pelvic cancer surgery: a prospective randomized double-blind trial.Int J Oncol2000;16,815-824. [PubMed]
 
Altinbas, M, Coskun, HS, Er, O, et al A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer.J Thromb Haemost2004;2,1266-1271. [CrossRef] [PubMed]
 
Kakkar, AK, Levine, MN, Kadziola, Z, et al Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS).J Clin Oncol2004;22,1944-1948. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
PubMed Articles
Thrombosis in the setting of cancer. Hematology Am Soc Hematol Educ Program 2016;2016(1):196-205.
Anti-Xa monitoring of low-molecular-weight heparin in adult patients with cancer. Hematology Am Soc Hematol Educ Program 2016;2016(1):206-207.
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543