Cancer-associated thrombosis: updates and controversies

Abstract Emerging data have enhanced our understanding of cancer-associated thrombosis, a major cause of morbidity and mortality in patients with cancer. This update will focus on recent findings, including the phenomenon of incidental venous thromboembolism (VTE), novel approaches to risk assessment, and the results of randomized clinical trials focusing on prophylaxis of cancer outpatients. Incidental VTE is an important contributor to rates of cancer-associated VTE and, in terms of outcomes, appears to be as consequential for patients as symptomatic VTE. Multiple biomarkers have been studied, with the highest level of evidence for prechemotherapy elevated platelet counts, elevated leukocyte counts, and low hemoglobin. Other candidate biomarkers, including D-dimer and tissue factor, are currently being evaluated. A recently validated risk score for chemotherapy-associated VTE has now been evaluated in more than 10 000 cancer patients in a variety of clinical settings and trials and is ready for clinical use (Level 1 clinical decision rule). Several randomized clinical trials in solid-tumor patients with low-molecular-weight heparins and semuloparin, an ultra-low-molecular-weight heparin, demonstrate clearly that outpatient thromboprophylaxis is feasible, safe, and effective. Selecting the appropriate patients for prophylaxis, however, continues to be a matter of controversy.

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The efficacy and safety of low-molecular-weight heparins (LMWHs) compared with vitamin K antagonists (VKAs) in the treatment of recurrent venous thromboembolism (VTE) in patients with cancer: An analysis of randomized clinical trials

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.9609 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 9609-9609

Author(s):

C. P. Escalante

Keyword(s):

Molecular Weight ◽

Clinical Trials ◽

Venous Thromboembolism ◽

Randomized Clinical Trials ◽

Vitamin K Antagonists ◽

Low Molecular Weight ◽

Efficacy And Safety ◽

Low Molecular Weight Heparins ◽

Patients With Cancer ◽

Recurrent Venous Thromboembolism

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Treatment of cancer-related thrombosis: from recommendations to real clinical practice

Modern Oncology ◽

10.26442/18151434.2019.1.190247 ◽

2019 ◽

Vol 21 (1) ◽

pp. 60-65

Author(s):

Oksana V Somonova ◽

Anna L Elizarova ◽

Valentina N Blindar ◽

Marina B Dobrovolskaya ◽

Yulia A Nesterova ◽

...

Keyword(s):

Molecular Weight ◽

Secondary Prevention ◽

Cancer Patients ◽

Oral Anticoagulants ◽

Comparable Efficacy ◽

Low Molecular Weight ◽

Patients With Cancer ◽

First Choice ◽

Thrombotic Complications ◽

Cancer Associated Thrombosis

Aim. To highlight the modern treatment and secondary prevention of recurrent thrombotic complications in patients with cancer. Materials and methods. We studied 40 scientific sources published in the Russian and foreign press in the period of 1997 to 2018. Results. Oncology patients are at higher risk of thrombotic complications which can worse outcomes of antitumor treatment and occupy one of the leading places among causes of death. Low molecular weight heparins (LMWHs) are the drugs of first choice for the treatment of cancer-associated thrombosis. Taking into account the complexity of LMWH application, many patients stop receiving the recommended therapy and are switching to oral anticoagulants. For instance, according to the GARFIELD-AF prospective registry direct oral anticoagulants (DOACs) are used in 25% of cancer patients. The most promising drug in this group is rivaroxaban (Xarelto). Multiple studies are currently undergoing in the framework of CALLISTO Program, designed to study various issues of managing patients with cancer-associated thrombosis: primary and secondary prevention of thrombosis using rivaroxaban, to study quality of life and the treatment adherence. In the Mayo Clinic Thrombophilia database retrospective study was demonstrated comparable efficacy of rivaroxaban and LMWH and in the studies US claims analysis and US Humana database were noted the reduction of recurrences of thromboembolic complications on using rivaroxaban treatment in comparison with LMWH on the same frequency of severe bleeding. In subanalysis of the prospective XALIA study was showed a favorable profile of efficacy and safety of rivaroxaban therapy in cancer patients, so the results proved the results of real practice. Conclusion. In 2018 the results of submitted studies helped several international societies, such as International Society on Thrombosis and Hemostasis and The National Comprehensive Cancer Network, to recommend rivaroxaban as one of the treatment options for patients with cancer-associated thrombosis with low risk of bleeding and no drug-drug interactions with current systemic therapy. Rivaroxaban can be considered as an alternative to low molecular weight

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Are All Low Molecular Weight Heparins Equivalent in the Management of Venous Thromboembolism?

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029608319881 ◽

2007 ◽

Vol 14 (4) ◽

pp. 385-392 ◽

Cited By ~ 8

Author(s):

Jawed Fareed ◽

Walter Jeske ◽

Daniel Fareed ◽

Melaine Clark ◽

Rakesh Wahi ◽

...

Keyword(s):

Molecular Weight ◽

Clinical Trials ◽

Venous Thromboembolism ◽

Unfractionated Heparin ◽

Low Molecular Weight Heparin ◽

Randomized Clinical Trials ◽

Safety Data ◽

Low Molecular Weight ◽

Efficacy And Safety ◽

Low Molecular Weight Heparins

Low molecular weight heparins are replacing unfractionated heparin in a number of clinical indications because of their improved subcutaneous bioavailability and more predictable antithrombotic response. Clinical trials have demonstrated that low molecular weight heparins are at least as safe and effective as unfractionated heparin for the initial treatment of venous thromboembolism, and unfractionated heparin and warfarin for primary and secondary thromboprophylaxis. The mechanism behind the antithrombotic action of low molecular weight heparins is not fully understood but is likely to involve inhibition of coagulation factors Xa and IIa (thrombin), release of tissue-factor-pathway inhibitor, and inhibition of thrombin activatable fibrinolytic inhibitor. Different low molecular weight heparins have been shown to have various effects on coagulation parameters. Seven low molecular weight heparins are currently marketed worldwide, each demonstrated distinct chemical entities with unique pharmacokinetic and pharmacodynamic profiles. Each low molecular weight heparin is approved for specific indications based on the available efficacy and safety data for that product. The relative efficacy and safety of the low molecular weight heparins are unclear because there have been very few direct comparisons in randomized clinical trials. While recommending low molecular weight heparins for the prevention and treatment of venous thromboembolism, clinical guidelines have not specified individual agents. National and international organizations recognize that low molecular weight heparins are distinct entities and that they should not be used interchangeably in clinical practice. Each low molecular weight heparin should be used at the recommended dose when efficacy and safety data exist for the condition being treated. When these data are not available, the dosing and administration of low molecular weight heparins must be adapted from existing data and recommendations.

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PO-43 Low molecular weight heparin (LMWH) in central venous catheter antithrombotic prophylaxis: meta-analysis of randomized clinical trials

Thrombosis Research ◽

10.1016/s0049-3848(07)70196-2 ◽

2007 ◽

Vol 120 ◽

pp. S158

Author(s):

D. Tassinari ◽

E. Scarpi ◽

S. Rupoli

Keyword(s):

Molecular Weight ◽

Clinical Trials ◽

Central Venous Catheter ◽

Low Molecular Weight Heparin ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Venous Catheter ◽

Low Molecular Weight ◽

Central Venous ◽

Antithrombotic Prophylaxis

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Do Heparins Do More than Just Treat Thrombosis? The Influence of Heparins on Cancer Spread

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615937 ◽

1999 ◽

Vol 82 (08) ◽

pp. 947-952 ◽

Cited By ~ 151

Author(s):

Rohan Hettiarachchi ◽

Susanne Smorenburg ◽

Jeffrey Ginsberg ◽

Mark Levine ◽

Martin Prins ◽

...

Keyword(s):

Molecular Weight ◽

Clinical Trials ◽

Venous Thromboembolism ◽

Beneficial Effect ◽

Cancer Patients ◽

Treatment Effect ◽

Initial Treatment ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Low Molecular Weight

IntroductionThe influence of unfractionated heparin (UFH) and other anticoagulants on the spread of cancer has been reported since the early 1960s.1 However, clinical studies investigating the use of heparins in cancer patients have not produced consistent results.2 Intravenous, adjusted-dose UFH for 5 to 10 days has been the standard initial treatment for venous thrombosis. More recently, subcutaneous, fixed-dose, low molecular weight heparins (LMWHs), which are fractions of the parent compound, have been shown to be safe and effective alternatives to UFH in the initial treatment for venous thromboembolism.3-5 In one of our randomized clinical trials comparing LMWH and UFH in the initial treatment of deep vein thrombosis (DVT), we observed an unexpected difference in 6-month mortality among cancer patients in favor of LMWH, which could not be attributed to a difference in the incidence of thrombotic or bleeding complications.6 A similar observation in favor of LMWH was reported in a subsequent study and in a meta-analysis of trials.7,8 The number of cancer patients included in these studies was small, and adjustment of the observed effect for the baseline characteristics of the cancer patients was not possible. However, these findings suggested an inhibitory effect of LMWH on tumor growth or metastasis, which is less apparent or absent for UFH, resulting in a beneficial effect on the survival of cancer patients. This hypothesis is supported by the observations, in experimental studies, that LMWH and low molecular weight heparan sulfate, in comparison to UFH, effectively suppressed angiogenesis, a process necessary for tumor growth and metastasis.9,10 On the other hand, animal studies that investigated the effect of chemically-modified heparins on the spread of cancer did not detect a superior anti-tumor effect of LMWH compared to UFH; both were found to inhibit metastasis.11,12 To date, the effect of LMWH on cancer survival in humans has not been investigated as a primary objective. If a consistent and beneficial effect of LMWH on mortality is indeed present, such a study would be warranted.We performed a meta-analysis of all available randomized clinical trials where LMWH was compared with UFH in the treatment of venous thromboembolism (VTE) to estimate the crude treatment effect of LMWH on mortality in cancer patients compared to UFH. Subsequently, we adjusted this treatment effect for age, gender, and primary malignancy site by reanalyzing data from three of those trials.3-5 This effect was further adjusted for other prognostic factors, including cancer histology, tumor stage, presence of metastases, duration of cancer, and concomitant use of cancer treatment, by analyzing individual patient data from the largest randomized trial.5

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PO-59 Low molecular weight heparin (LMWH) versus best supportive care in cancer patients. A meta-analysis of randomized clinical trials

Thrombosis Research ◽

10.1016/s0049-3848(07)70212-8 ◽

2007 ◽

Vol 120 ◽

pp. S164

Author(s):

S. Laporte ◽

G. Meyer ◽

H.R. B¨uller ◽

H. Decousus ◽

N. Moulin ◽

...

Keyword(s):

Molecular Weight ◽

Clinical Trials ◽

Supportive Care ◽

Cancer Patients ◽

Low Molecular Weight Heparin ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Best Supportive Care ◽

Low Molecular Weight

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L-arginine effect on inflammatory mediators: A systematic review of randomized controlled clinical trials

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000619 ◽

2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Seyed Reza Mirhafez ◽

Mitra Hariri

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Inflammatory Mediators ◽

Randomized Clinical Trials ◽

Randomized Controlled Clinical Trials ◽

Patients With Cancer ◽

Reactive Protein ◽

Randomized Controlled ◽

Human Adults ◽

Factor Α

Abstract. L-arginine is an important factor in several physiological and biochemical processes. Recently, scientists studied L-arginine effect on inflammatory mediators such as C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We conducted a systematic review on randomized controlled trials assessing L-arginine effect on inflammatory mediators. We searched data bases including Google scholar, ISI web of science, SCOPUS, and PubMed/Medline up to April 2019. Randomized clinical trials assessing the effect of L-arginine on inflammatory mediators in human adults were included. Our search retrieved eleven articles with 387 participants. Five articles were on patients with cancer and 6 articles were on adults without cancer. L-arginine was applied in enteral form in 5 articles and in oral form in 6 articles. Eight articles were on both genders, two articles were on women, and one article was on men. L-arginine could not reduce inflammatory mediators among patients with and without cancer except one article which indicated that taking L-arginine for 6 months decreased IL-6 among cardiopathic nondiabetic patients. Our results indicated that L-arginine might not be able to reduce selected inflammatory mediators, but for making a firm decision more studies are needed to be conducted with longer intervention duration, separately on male and female and with different doses of L-arginine.

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Low Molecular Weight Heparin Therapy: Is Monitoring Needed?

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648866 ◽

1994 ◽

Vol 72 (03) ◽

pp. 330-334 ◽

Cited By ~ 72

Author(s):

B Boneu

Keyword(s):

Molecular Weight ◽

Clinical Trials ◽

Plasma Proteins ◽

Bleeding Risk ◽

Heparin Therapy ◽

Low Molecular Weight ◽

Vein Thrombosis ◽

Meta Analyses ◽

Deep Vein ◽

Initial Check

SummaryRecent meta-analyses indicate that low molecular weight heparins (LMWH) are more effective than unfractionated heparin (UH) in preventing and treating deep vein thrombosis. This article presents the arguments for and against the need for laboratory monitoring. At the present time, the only tests currently available for monitoring LMWH therapy are those which measure the anti Xa activity in the plasma. Due to lower binding to plasma proteins and to cell surfaces,the plasma anti Xa activity generated by a given dose of LMWH is more predictable than for UH.Some clinical trials suggest that LMWH delivered at the recommended dose expose the patient to less bleeding risk than UH. Several . meta-analyses indicate comparable risk while any overdose unaccept-ably increases the haemorrhagic risk. The lowest dose of LMWH still effective in treating established DVT is presently unknown; some reports indicate that inadequate doses of LMWH are associated with a lack of efficacy for prevention. An overview of the published clinical trials indicates that the LMWH dose has never been monitored for prevention of DVT. In the treatment of established DVT, several trials have been performed without any monitoring, while in others the dose was adapted to target a given anti Xa activity. These considerations suggest that in prevention of DVT, monitoring the dose is not required. In the treatment of established DVT, considering the haemorrhagic risk of LMWH, the risk of undertreating the patient and the absence of large clinical trials comparing the advantages of monitoring the dose or not, it might be useful to check anti Xa activity at least once at the beginning of the treatment but the need for this initial check remains to be established. Because a large proportion of patients will be in the desired range, dose adjustments will be far less frequent than for UH.

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