Low Molecular Weight Heparin In Cancer Patients Research Articles

Efficacy and safety of DOACs versus LMWH for elderly patients with active cancer: A meta-analysis.

e13776 Background: Anticoagulant treatment in patients with cancer aims to reduce the high risk of thromboembolism. Direct oral anticoagulants (DOACs) and low-molecular-weight heparin (LMWH) are currently approved for the treatment of cancer-related thrombosis. However, there is limited data comparing the efficacy and safety of these two antithrombotic therapies among elderly patients with cancer. Methods: PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were systematically searched for studies comparing DOACs with LMWH in cancer patients with newly diagnosed venous thromboembolism (VTE) or pulmonary embolism (PE). Both solid tumors and hematologic malignancies were included. Outcomes of interest were recurrent VTE and major bleeding. Odds ratio (OR) with 95% confidence intervals (CI) were pooled with a random-effects model. Statistical analysis was performed with Review Manager 5.4.1. Heterogeneity was assessed using the I2 statistic and chi-squared test. Results: Four studies, three randomized controlled trials (RCTs) and one observational, were included. A total of 3,266 patients older than 65 years who underwent anticoagulation with DOACs (35%) or LMWH (65%) were incorporated in the analysis. There was no statistically significant difference between anticoagulation therapies for recurrent VTE (OR, 0.68; 95% CI, 0.41-1.11; p = 0.13; I² = 56%; Table) or major bleeding (OR, 1.18; 95% CI, 0.61-2.25; p = 0.08; I² = 60%; Table). Conclusions: Our findings suggest no statistically significant differences in recurrent VTE or major bleeding between DOACs and LMWH in elderly oncologic patients with newly diagnosed VTE or PE. Given the practical challenges of using LMWH, DOACs may be considered an alternative anticoagulation strategy for these patients. [Table: see text]

Non-Vitamin K Antagonist Oral Anticoagulants versus Low Molecular Weight Heparin for Cancer-Related Venous Thromboembolic Events: Individual Patient Data Meta-Analysis.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in cancer patients. Low molecular weight heparin (LMWH) has been the standard of care but new guidelines have approved the use of non-vitamin K antagonist oral anticoagulants (NOAC). By conducting an individual patient data (IPD) meta-analysis of randomised controlled trials (RCTs) comparing the outcomes of NOAC versus LMWH in cancer patients, we aim to determine an ideal strategy for the prophylaxis of VTE and prevention of VTE recurrence. Three databases were searched from inception until 19 October 2022. IPD was reconstructed from Kaplan-Meier curves. Shared frailty, stratified Cox and Royston-Parmar models were fit to compare the outcomes of venous thromboembolism recurrence and major bleeding. For studies without Kaplan-Meier curves, aggregate data meta-analysis was conducted using random-effects models. Eleven RCTs involving 4844 patients were included. Aggregate data meta-analysis showed that administering NOACs led to a significantly lower risk of recurrent VTE (RR = 0.65; 95%CI: 0.50-0.84) and deep vein thrombosis (DVT) (RR = 0.60; 95%CI: 0.40-0.90). In the IPD meta-analysis, NOAC when compared with LMWH has an HR of 0.65 (95%CI: 0.49-0.86) for VTE recurrence. Stratified Cox and Royston-Parmar models demonstrated similar results. In reducing risks of recurrent VTE and DVT among cancer patients, NOACs are superior to LMWHs without increased major bleeding.

Direct Oral Anticoagulants in Cancer Patients. Time for a Change in Paradigm

Thrombosis is a more common occurrence in cancer patients compared to the general population and is one of the main causes of death in these patients. Low molecular weight heparin (LMWH) has been the recognized standard treatment for more than a decade, both in cancer-related thrombosis and in its prevention. Direct oral anticoagulants (DOACs) are a new option for anticoagulation therapy. Recently published results of large randomized clinical trials have confirmed that DOAC may be a reasonable alternative to LMWH in cancer patients. The following review summarizes the current evidence on the safety and efficacy of DOAC in the treatment and prevention of cancer-related thrombosis. It also draws attention to the limitations of this group of drugs, knowledge of which will facilitate the selection of optimal therapy.

Prevention of venous thromboembolism in patients with cancer with direct oral anticoagulants: A systematic review and meta-analysis.

Background:Patients with cancer are of a high level risk of venous thromboembolism (VTE). Low molecular weight heparin (LMWH) is recommended as the normal treatment for cancer-associated venous thrombosis. Recently, some studies suggest that patients with cancer-associated venous thrombosis can get a good efficacy and safety profile from treating with direct oral anticoagulants (DOACs) compared with other anticoagulants. However, when it comes to the efficacy of DAOCs in preventing VTE in patient with cancer, the data are limited. Thus, we performed such a meta-analysis to determine the efficacy and safety of DOACs in preventing VTE in patient with cancer compared with LMWHs.Methods:Medline/PubMed and CENTRAL (The Cochrane Central Register of Controlled Trials) were systematically searched for relevant studies. For each trial, data on VTE, major bleeding, or bleeding were extracted by 2 reviewers independently. Pooled risk ratios (RRs) were calculated by using Review Manager 5.3 software and the significance was determined by the Z test.Results:A total of 6 studies with 7185 patients were included in our meta-analysis. DOACs (RR = 0.55, 95% confidence interval [95%CI]: 0.34–0.90, I2 = 31%) had a similar prevention effect of VTE to LMWH (RR = 0.59, 95% CI: 0.37–0.95, I2 = 59%). DOACs (RR = 1.52, 95% CI: 0.99–2.33, I2 = 0%) yielded a similar bleeding occurrence rate compared with LMWH (RR = 1.35, 95% CI: 1.07–1.70, I2 = 35%). DOACs (RR = 1.95, 95% CI: 0.88–4.30, I2 = 0%) showed a sight higher major bleeding occurrence rate than LMWH (RR = 1.38, 95% CI: 0.88–2.14, I2 = 0%).Conclusion:DOACs show comparable efficacy to LMWH in cancer patients without VTE with a slightly higher major bleeding occurrence rate. DOACs are inclined to be an alternative thromboprophylaxis strategy in cancer patients as they have superiorities compared to traditional anticoagulation agents. Further studies are still demanded as exiting relevant researches are limited.

Quality of Life in Patients With Cancer Under Prolonged Anticoagulation for High-Risk Deep Vein Thrombosis: a Long-Term Follow-Up.

Current guidelines recommend to prolong anticoagulant treatment in patients with cancer with venous thromboembolism (VTE); only few studies evaluated other parameters than cancer itself for selecting patients at higher risk of recurrent VTE. Long-term management of VTE is thus challenged by several controversies mainly for patients compliance. We here report results of a long-term follow-up in patients with deep vein thrombosis under anticoagulant treatment with low-molecular-weight heparin (LMWH) for residual vein thrombosis (RVT) detected at compression ultrasonography (CUS), 6 months after standard anticoagulant treatment. Patients with RVT were deemed at high risk of recurrences and included in the current observational study. They continued LMWH (reduced at 75% standard dose) for further additional 2 years after enrolment or until death. Patients were followed up every 3 months or earlier, if needed. Among ancillary study end points, there was the assessment of patients’ quality of life during daily treatment with subcutaneous injections. Quality of life was determined by the EORTC-C30 questionnaire, administered by a skilled psychologist at enrolment and every 6 months follow-up visits. Overall, 128 patients were evaluated during follow-up. Mean global EORTC-C30 score at enrollment and at 6, 12 and 24 months follow-up were 52.1, 51.4, 50.8 and 50.1, respectively. There were no statistically significant differences between scores at enrolment and at the last available follow-up (P = .1). Long-term treatment with LMWH resulted, effective and safe, it was globally well tolerated and exempt of negative impact on quality of life of the enrolled patients. Reported results support long-term anticoagulant treatment with LMWH in cancer patients at risk of recurrent VTE.

LMWH in cancer patients with renal impairment – better than warfarin?

Venous thromboembolism (VTE) is one of the leading causes of death in cancer patients, which are known to have a 5- to 7-fold increased risk for VTE. The anticoagulant treatment of VTE in cancer patients is less effective with a three-fold increased risk of VTE recurrence compared to non-cancer patients, and it is less safe with more than double rates of major bleeding. Compared to vitamin-K antagonists (VKA), long-term secondary prevention with low molecular weight heparin (LMWH) has been shown to reduce the risk of recurrent VTE in cancer-associated thrombosis (CAT), and therefore, current international guidelines recommend the use of LMWH over VKA. With increasing age, cancer prevalence and VTE incidence increase while renal function decreases. Anti-cancer treatment may impair renal function additionally. Therefore, renal insufficiency is a frequent challenge in CAT patients, which is associated with a higher risk of both bleeding and recurrent VTE. Both VKA and LMWH may be associated with less efficacy and higher bleeding risk in renal insufficiency. Unfortunately, there is a lack of prospective data on renal insufficiency and CAT. A recent sub-analysis from a large randomized controlled trial shows that the bleeding risk in patients with severe renal insufficiency in CAT is not elevated with the use of LMWH compared to VKA while efficacy is maintained. In addition, LMWH treatment has several practical advantages over VKA, particularly in patients with CAT while they are receiving anti-cancer treatment.

Long-Term Use of Low-Molecular-Weight Heparin (LMWH) for Cancer-Associated Venous Thromboembolism (VTE): Adherence to Recommendations in Clinical Practice Based on Tropique, a Prospective Non-Interventional Observational Study

IntroductionFew data are available on the long-term LMWH prescription and treatment follow-up in clinical practice in patients with cancer-associated VTE.Study objectives were to document the prescription and use of treatment doses of LMWH in cancer patients and to assess adherence to established recommendations.MethodsAdult cancer patients receiving antineoplastic treatment or palliative care, age ≥18 years, with recent symptomatic VTE in whom treatment with LMWH had been initiated within 7 days prior to inclusion, were eligible to participate in this prospective observational French multicenter study. Patients with a contra-indication to LMWH were not eligible for participation. Main study outcome was the description of LMWH use and prescription in usual medical care. Adherence to recommendations was measured as the proportion of patients receiving a prescription of a LMWH at treatment doses according to the approved dosing schedule and treated for at least 3 months in the absence of severe renal insufficiency (CrCl<30 mL/min) [1, 2]. Assuming a normal patient distribution and the unfavorable hypothesis that only 50% of patients were treated according to the national recommendations, 384 patients were needed to obtain conclusive results with a precision of 5% and a risk error of 5%.ResultsA total of 409 patients aged 65±12.1 years of whom 49.9% female were consecutively included from November 2012 to August 2013. A history of previous VTE was found in 54 (13.2%), surgery or trauma in 100 (24.4%), central venous catheter (CVC) in 303 (74.1%) and immobilization >1 month in 47 (11.5%) patients, respectively. Four (1.03%) patients had severe renal insufficiency.VTE diagnosis at inclusion included lower-limb deep-vein thrombosis (DVT) in 193 (47.2%), pulmonary embolism in 145 (35.5%), CVC-associated thrombosis in 66 (16.1%), upper-limb DVT in 45 (11.0%) and visceral thrombosis in 16 (3.9%) patients, respectively.Most cancers were solid tumors gastro-intestinal (24.4%), lung (17.4%) or breast (15.9%); 81% of patients received chemotherapy and 61.4% were metastatic cancers. LMWH prescriptions included dalteparin in 42 (10.3%), enoxaparin in 61 (14.9%), nadroparin in 5 (1.2%) and tinzaparin in 301 (73.6%) patients. Only 4 (1%) patients received LMWH despite severe renal insufficiency. Table 1 –Prescription adherence to recommendations at inclusion [n (%)]Adherence criteriaTinzaparin (N=301)Other LMWH (N=108)All (N=409)Treatment duration > 3 months293 (97.3)108 (100)401 (98.0)Adequate dosing regimen*231 (76.7)14 (13.0)245 (59.9)Adequate dosing schedule296 (98.3)45 (41.7)341 (83.4)Overall adherence219 (72.8)7 (6.5)226 (55.3)*includes adequate treatment dose and dose adjustment according to recommendationsA total of 274 (67.0%) patients received the recommended treatment dose, while 87 (21.3%) patients received doses exceeding this by more than 10% and 39 (9.5%) patients received doses more than 10% below the recommended doses.Based on the pre-defined adherence criteria, 226 (55.3%) [95% CI 50.4-60.1] patients had a LMWH prescription consistent with recommendations. Tinzaparin prescriptions were associated with higher adherence scores compared to other LMWH.During follow-up, actual mean treatment duration was 5.28 ± 2.07 months and 85.7% of patients were treated for 3 months or moreTable 2 -Adherence to recommendations at inclusion according to cancer characteristics (N=409) [n (%)]Cancer characteristicsProportion of study populationProportion of adherence to recommendationsGastro-intestinal Lung Breast Hemato lymphopoietic Other Metastatic Chemotherapy (n=405)*100 (24.4) 71 (17.4) 65 (15.9) 54 (13.2) 119 (29.1) 251 (61.4) 328 (81.0)53 (53.0) 37 (52.1) 46 (70.8) 28 (51.9) 62 (52.1) 133 (53.0) 186 (56.7)*405 patients documented with chemotherapyAt inclusion, the rate of prescriptions consistent with recommendations was low (55.3%) while the highest rate of adherence (70.8%) was observed in patients with breast cancer known to be at rather lower risk of VTE recurrence.ConclusionAdherence to treatment duration was adequate whereas dosing regimen was insufficiently compliant with recommendations. Overall adherence with tinzaparin seemed higher compared to other LMWH Management of patients with cancer-associated VTE requires further education and information of health care professionals. 1.Farge D, J Thromb Haemost. 2013 Jan; 11(1):56-70. DisclosuresFarge:Pfizer: Research Funding; LEO Pharma: Research Funding. Debourdeau:Pfizer: Research Funding; LEO Pharma: Research Funding. Cajfinger:Pfizer: Research Funding; LEO Pharma: Research Funding.

Long-Term Efficacy and Safety of Low-Molecular-Weight Heparins (LMWH) for Cancer-Associated Venous Thromboembolism (VTE) in Tropique, a Prospective Non-Interventional Observational Study

▪IntroductionLong-term treatment with LMWH is the standard therapy for patients with cancer-associated VTE. Recommended treatment regimen include the prescription of LMWH at treatment doses according to approved administration schedule for at least 3 months in the absence of severe renal insufficiency (CrCl<30 mL/min) [1, 2]. The TROPIQUE study documented the prescription and use of long-term treatment with LMWH in cancer patients. Here we report the findings on the secondary outcomes, clinical efficacy and safety.MethodsAdult patients with cancer-associated VTE receiving antineoplastic treatment or palliative care were eligible to participate. Efficacy outcomes measures were VTE recurrence including deep-vein thrombosis (DVT) and pulmonary embolism (PE), visceral thrombosis and central venous catheter (CVC)-associated thrombosis. Safety outcomes included all and major bleeding according to ISTH definition [3], thrombocytopenia and deaths. Incidences of 7% of VTE recurrence and 6% of major bleeding were expected. With a sample of 384 patients, the rate of VTE recurrence and major bleeding would be detected with a precision of ±2.6% and ±2.4%, respectively, with a 95% confidence interval. A total of 400 patients were therefore planned to be included in the study.ResultsA total of 409 patients with symptomatic cancer-associated VTE (Table 1) aged 65±12.1 years of whom 49.9% female were consecutively included from November 2012 to August 2013. A history of previous VTE was found in 54 (13.2%), surgery or trauma in 100 (24.4%), CVC in 303 (74.1%) and an immobilization over 1 month in 47 (11.5%) patients, respectively. At study inclusion, 30 (7.3%) patients had platelet count ≤ 100 x109/L, and 129 (31.5%) had reported anemia while 16 (3.9%) patients had a history of bleeding in the last month. At baseline, more than 80% of patients presented with at least a PE or a lower-limb DVT of s.Table 1VTE diagnosis at baseline (patients at least with one of the following)VTE diagnosis (at least one of the following)n (%)PE145 (35.5)DVT lower limb193 (47.2)Proximal107 (56.0)Distal72 (37.7)DVT upper limb45 (11.0)Visceral thrombosis16 (3.9)CVC-associated thrombosis66 (16.1)Mean treatment duration was 5.28 ± 2.07 months. As the majority of patients were treated with tinzaparin (73.6%), clinical outcomes are therefore presented for tinzaparin, other LMWH and all LMWH (Table 2).A total of 21 events of VTE recurrence occurred in 19 patients during the overall study period, with a Kaplan-Meir estimate of the probability of VTE recurrence at 6 months of 6.1%.Table 2Outcomes in patients with cancer-associated VTE treated with long-term LMWH [n (%)].Patients treatedTinzaparin n=301Other LMWH n=108All LMWH n=409Patients documentedn=292n=100n=392Patients with at least14 (4.8)5 (5)19 (4.8)one VTE recurrence---Events (2 patients had347more than one event)516DVT011PE617Visceral thrombosisCVC-associated thrombosisBleedingn=292n=100n=392All44 (15.1)11 (11.0)55 (14.0)Major16 (5.5)7 (7.0)23 (5.9)Thrombocytopenian=290n=100n=390(n platelets/mm3)53 (18.3)15 (15.0)68 (17.4)Alln=65n=17n=82< 50,00022527Drop > 50%15217Deathsn=301n=107n=408All102 (33.9)44 (41.1)146 (35.8)Cause of death*n=100n=44n=144LMWH treatment**1#01##Cancer8739126Sepsis415Bleeding415Antineoplastic treatment101PE011Other7310*Multiple causes of death may have been reported in the same patient; **fatal bleeding reported as LMWH-related; #n=99;## n=143Kaplan-Meier estimate of the probability of bleeding at 6 months was 15.9% while corresponding estimates were 18.1% for thrombocytopenia and 34.5% for deaths. Of the five (3.5%) patients who reported fatal bleedings one was reported as related to the LMWH treatment. No heparin-induced thrombocytopenia was reported in the study.ConclusionClinical outcomes were consistent with previous observations in this patient population except a lower incidence of VTE recurrence compared with previous studies. Study results tend to confirm the favorable efficacy and safety profile of LMWH for the long-term treatment of patients with cancer-associated VTE, when used according to recommended treatment duration and respecting contra-indications. 1.Schulman. J Throm Haemost. 2005 Apr;3(4):692-4.2.Farge J Thromb Haemost. 2013 Jan;11(1):56-70.3.Debourdeau P, J Thromb Haemost. 2013 Jan;11(1):71-80 DisclosuresFarge:Pfizer: Research Funding; LEO Pharma: Research Funding. Debourdeau:Pfizer: Research Funding; LEO Pharma: Research Funding. Cajfinger:Pfizer: Research Funding; LEO Pharma: Research Funding.

Meta‐analysis of the efficacy and safety of new oral anticoagulants in patients with cancer‐associated acute venous thromboembolism

Treatment of acute venous thromboembolism (VTE) in cancer patients is challenging, owing to a high risk of recurrent VTE and bleeding complications. The anticoagulants of choice are low molecular weight heparins (LMWHs), because of a proven higher efficacy than vitaminK antagonists (VKAs) and a similar bleeding profile. The recently introduced new oral anticoagulants (NOACs) have the potential to be alternative options for these patients, as these drugs share practical advantages with LMWH, are administered orally, and had similar efficacy to VKAs but a lower bleeding risk in phase3 studies in the general VTE population. A systematic literature search was performed to identify phase3 trials investigating NOACs for the treatment of VTE. The efficacy outcome was recurrent VTE, and the safety outcome was major and clinically relevant non-major bleeding. Pooled incidence rates and risk ratios (RRs) were calculated for cancer patients and non-cancer patients separately. Five studies were included, with 19060 patients, of whom 973 (5.1%) had active cancer. The pooled incidence rates of recurrent VTE were 4.1% (95% confidence interval [CI]2.6-6.0) in cancer patients treated with NOACs, and 6.1% (95%CI4.1-8.5) in patients treated with VKAs (RR0.66, 95%CI0.38-1.2). The pooled incidence rates of major or non-major clinically relevant bleeding were 15% (95%CI12-18) in cancer patients treated with NOACs, and 16% (95%CI9.9-22) in patients treated with VKAs (RR0.94, 95%CI0.70-1.3). These results form a solid basis for the initiation of a head-to-head comparison of NOACs with LMWH in cancer patients.

1616P - Low Molecular Weight Heparin (LMWH) Resistance in Cancer Patients

ABSTRACT Introduction Cancer patients have an increased risk of developing venous thrombo-embolism (VTE). Treatment of VTE involves the administration of heparin, low molecular weight heparin (LMWH) or coumarin derivatives. Heparin resistance is a situation in which the administration of heparin does not result in an increase of the activated partial thromboplastin time (APTT) and blood anticoagulation. While heparin resistance is a known entity, LMWH resistance is not well documented, and anti factor Xa activity is not tested routinely in cancer patients treated with LMWH. Here, we report the pharmacokinetics of LMWH in cancer patients suffering from VTE and receiving treatment with enoxaparin at standard doses of 1 mg/kg twice daily. Patients/methods Patients suffering from malignancy and VTE, and treated with the LMWH, enoxaparin at standard dose of 1mg/kg q12 hr were enrolled. Ambulatory patients were admitted to the oncology day care unit for 8 hours in order to facilitate repeated blood testing. Blood samples were obtained before the injection of LMWH and 1, 2, 3, 4, 6 and 8 hours after LMWH subcutaneous administration, and tested for anti Xa activity as a surrogate marker of bioavailable LMWH levels. The trial was approved by the ethics committee of Shaare Zedek Medical Center. ClinicalTrials.gov Identifier: NCT00716898. Study funding: Israel Cancer Association. Results Eleven patients were enrolled; one was excluded from analysis due to complete remission at time of VTE diagnosis. Peak anti Xa activity was achieved after 2, 3, 4, 6, and 8 hours in 2, 3, 2, 2, and 1 patient respectively. 60% of the patients (n = 6) did not reach the therapeutic anti Xa activity target (0.6 -1.0 IU/ml) at 4 hours after subcutaneous administration of LMWH. Average anti Xa activity at 4 hours was 0.62 ± 0.29 IU/ml as opposed to 1.1 IU/ml in historical controls of non-oncology patients. Conclusions Our results show that a substantial number of cancer patients suffering from VTE and treated with standard dose enoxoparin do not reach therapeutic target anti Xa activity. If confirmed in a larger study, our results suggests that cancer patients suffering from VTE should be tested for anti Xa activity and LMWH dose should be titrated accordingly in order to achieve effective anticoagulation. Disclosure All authors have declared no conflicts of interest.

The treatment of venous thromboembolism with low-molecular-weight heparins

The currently recommended method of venous thromboembolism (VTE) treatment is the application of vitamin K antagonists (VKA) in most patients, and low-molecular-weight heparins (LMWH) in selected groups. The VKA dose adjustment is difficult which might well render the treatment ineffective. The study aimed to compare LMWH with VKA in treating VTE in terms of efficacy and safety. A systematic review of literature and the meta-analysis of the treatment results were performed. The main differences between LMWH and VKA in terms of their respective effectiveness in treating VTE consist in appreciably more advantageous effects of LMWH in preventing deep venous thrombosis (DVT). The key difference in terms of respective safety is the greater effectiveness of LMWH inpreventing minor bleedings. The advantage of LMWH in cancer patients consists predominantly in a significantly better protection against DVT episodes, whereas the advantage of LMWH in non-cancer patients is mainly owed to better protection against minor bleedings. In none of the analysed outcomes of VTE treatment, the application of VKA proved to hold any advantage over LMWH. Although, arguably, there might well be sufficient medical grounds to propose more widespread use of LMWH, it still remains a debatable issue whether the currently used therapeutic standard should also be modified accordingly. Apart from the actual findings of the present meta-analysis, pertinent economic considerations must also be addressed.

Low molecular weight heparins in cancer patients: to treat thromboembolic events, the tumor, or both?

The interrelationship between cancer and thrombosis is well known. Recent data help physicians to optimize the management of thrombotic complications occurring in cancer patients. However, many issues are still uncertain. First, although the development of venous thromboembolism (VTE) in a patient with known cancer is the most common presentation, concerns remain about the optimal duration and dosages of anticoagulants. Questions also arise concerning the need to implement heparin prophylaxis in the course of chemotherapy. Secondly, in some patients, thrombosis precedes the diagnosis of malignancy. In this case, the question is whether or not to screen patients for an occult cancer. Thirdly, very recent studies have shown the hemostatic system plays a key role at different stages of tumor growth. Anticoagulants, especially low molecular weight heparin (LMWH), appear therefore to be an attractive strategy not only for managing the risk for thrombosis but, possibly, to improve patient outcome and survival. However, the use of these compounds in settings other than VTE is questionable. Finally, most of the data come from studies evaluating patients with different types of cancer at different stages, thus making results difficult to evaluate. Additional research is required to clarify the biological mechanisms involved and to answer still unresolved clinical questions. In this review, the evidence for the use of LMWHs in cancer patients will be presented and remaining doubts discussed.

The use of extended perioperative low molecular weight heparin (tinzaparin) to improve disease-free survival following surgical resection of colon cancer

Auer, Rebeccaa; Scheer, Adenaa; Wells, Philip S.b,c; Boushey, Robina; Asmis, Timd; Jonker, Derekd; Carrier, Marcb,c Author Information

Bemiparin in Oncology

An association between cancer and thrombosis has been recognized since 1865. It is considered to be a two-way association; cancer is associated with an increased risk of venous thromboembolism (VTE), whereas activation of the coagulation cascade enhances the proliferation, angiogenesis potential and metastasis of tumour cells. A sizeable proportion of VTE events in cancer patients undergoing major surgery occur after discharge from hospital, suggesting that extended thromboprophylaxis beyond the normal 7-10 days is warranted in these patients. Studies have demonstrated reduced incidences of VTE with extended thromboprophylaxis using low molecular weight heparins (LMWH) and guidelines recommend continuing thromboprophylaxis after discharge in patients who have undergone major cancer surgery, but the evidence is still considered limited and of low quality, and the recommendations have not been widely implemented in clinical practice. Extended prophylaxis with bemiparin was shown to reduce significantly the incidence of major VTE in patients undergoing major cancer surgery in the Cancer, Bemiparin and Surgery Evaluation study, providing further support for the routine use of extended thromboprophylaxis with LMWH in cancer patients. Heparins, particularly LMWH, in addition to preventing VTE in cancer patients, can block tumour cell growth, invasion, metastasis and angiogenesis. As with other LMWH, bemiparin and its ultra-low molecular weight derivative, RO-14, appear to be effective in preventing angiogenesis in in-vitro models. Recent clinical studies have demonstrated significant survival advantages when LMWH have been added to chemotherapy in cancer patients. This could be partly due, not only to the prevention of thromboembolic diseases in these patients, but also to 'direct' antineoplastic properties of LMWH. The survival benefits appeared greater in patients with limited cancer, especially limited small cell lung cancer. The Adjuvant Bemiparin in Small Cell Lung Cancer study is assessing the effect of bemiparin on survival in patients with limited small cell lung cancer, and although results are not yet available, preliminary data appear very promising.

Anticoagulation in cancer patients in hospice

e20509 Background: Low-molecular weight heparin (LMWH) is preferred over warfarin in patients with thromboembolic disease and active cancer, but no guidelines exist in hospice. Although warfarin may be less safe in hospice patients, hospices may prefer to provide warfarin due to lower cost and less invasiveness compared to LMWHs. We sought to identify disparities in the use of warfarin vs. LMWHs in cancer patients enrolled in hospice. Methods: We analyzed a dataset from a national pharmacy provider for more than 800 hospices. We identified patients with a terminal diagnosis of cancer who were enrolled and died in hospice in 2006 and who were prescribed warfarin or LMWH. Patient characteristics included age, gender, race, cancer diagnosis, length of hospice service, and number of comorbidities. For descriptive comparisons, the Kruskal-Wallis test was used for continuous variables, and the Chi-square test was used for categorical variables. Results: Of 54,764 patients with cancer admitted and deceased in 2006, 3874 (7.1%) were prescribed warfarin, and 1137 (2.1%) were prescribed LMWH. Patients prescribed warfarin (n=576) or enoxaparin (n=5) for treatment of atrial arrhythmias were excluded. The mean age was 70.6 years for warfarin and 64.8 years for LMWH (p&lt;0.0001). The mean and median lengths of service, respectively, were 43.6 days and 23.0 days for warfarin and 35.0 and 18.0 days for LMWH, (p&lt;0.0001). There were no differences for gender, and a higher proportion of white patients were prescribed warfarin. Patients prescribed warfarin had an average of 2.1 comorbid conditions, versus 1.6 conditions for LMWH (p&lt;0.0001). Cancer diagnoses were significantly different between the two groups, with a higher proportion of patients with lung and prostate cancer taking warfarin. Conclusions: Patients prescribed warfarin were older, had more comorbidities, and a longer length of service than patients prescribed LMWHs. Further research is needed to determine the impact of anticoagulation on outcomes, especially cost and quality of life, for cancer patients in hospice. This study raises the need to establish guidelines for the appropriateness of anticoagulation in hospice patients with cancer. No significant financial relationships to disclose.

Long-term use of daily subcutaneous low molecular weight heparin in cancer patients with venous thromboembolism: why hesitate any longer?

Cancer disease inducing an acquired hypercoagulable state is a well-established feature. Venous thromboembolism (VTE) occurs in 4% to 20% of the patients and is the second cause of mortality in cancer; VTE incidence is four to six times higher in cancer patients compared to other patients. In the last 10 years, important randomised clinical trials have clearly demonstrated that long-term use of daily subcutaneous low molecular weight heparin (LMWH) is more efficient than Vitamin K antagonists to treat VTE in cancer patients. First Italian, then American and more recently French national guidelines recommend the use of LMWH for 3 to 6 months for curative treatment of VTE in cancer patients with a clearly high level (A) of evidence. Despite convincing data, many physicians have not yet modified their clinical practice, doubting the tolerability of such a long period of subcutaneous injections. In fact, LMWH long-term use appears well tolerated and may also increase cancer patient survival. The aim of this review is to present the scientific rationale for long-term daily subcutaneous LMWH in cancer patients, and to reinforce the favourable benefit/tolerance tolerability ratio with this specific antithrombotic strategy.

Daily low-dose aspirin in cancer patients with central venous catheter: new role for an old drug

Central venous catheters (CVC) placement increases the risk of blood clots in cancer patients [1–2]. Several randomized trials have evaluated antithrombotic prophylaxis in cancer patients with CVCs with oral anticoagulant or low-molecular-weight heparins (LMWHs) [3–13]. We agree with concerns and questions raised by Dr. Tassinari et al. We can argue that, based on interpretation of the results of contemporary trials, we could not recommend for all patients routine prophylaxis with anticoagulants or LMWH. Cancer patients are receiving increasingly complex chemotherapy regimens in combination with biologic therapies, such as bevacizumab, that can also increase incidence of deep venous thrombosis (DVT) [14]. We believe in the potential efficacy of LMWH but trials with much larger power, with a longer duration of treatment or higher dose would be required. Aspirin can be considered an attractive and safe drug for primary prevention of thrombosis in cancer patients with CVCs. Several trials assessed its efficacy in primary prevention of DVT in normal subjects. A comparison trial designed for high-risk subject (>10 h flight) evaluated impact of prevention with one dose of LMWH (equivalent to 0.1 mL per 10 kg of body weight) versus aspirin (400 mg one dose daily for 3 days, starting 12 h before the beginning of the flight) versus control [15]. Investigators reported 4.8% of subjects with DVT in the control arm, 3.6% in the aspirin arm and no DVT in the LMWH group [15]. Another recent trial investigated the efficacy of long-term aspirin therapy for preventing venous thromboembolism (VTE) in female health care professionals in the Women's Health Study. In this large study, subjects were randomized to aspirin, 100 mg, or placebo on alternate days. The incidence of VTE (per 1,000 person-years) was 1.18 among women randomly assigned to active aspirin, compared with 1.25 among women randomly assigned to placebo. Subgroup analysis for subjects with factor V Leiden, G20210A prothrombin, and MTHFR 677C>T polymorphisms showed a trend versus a beneficial effect from aspirin treatment in this subpopulation [16]. Translating these data into a cancer population, no current studies are so robust to support use of aspirin in the primary prevention of DVT in cancer patients with CVCs. A recent non randomized study in elderly patients with myeloma treated with melphalan, prednisone and lenalidomide demonstrated the efficacy of aspirin in preventing DVT [17]. Another recent meta-analysis evaluated the efficacy and safety of anticoagulation in reducing VTE events in cancer patients with CVCs [18]. Nine randomized controlled trials (RCTs) were included in the meta-analysis. The use of LMWHs in cancer patients with CVC was associated with a trend towards a reduction in symptomatic DVT, but the data did not show any statistically significant effect on mortality, major bleeding or thrombocytopenia. When studies assessing different types of anticoagulants were pooled, symptomatic DVT rates were significantly Support Care Cancer (2008) 16:313–314 DOI 10.1007/s00520-007-0387-8

Low-molecular-weight heparin in cancer-associated thrombosis: treatment, secondary prevention, and survival

Venous thromboembolism (VTE) occurs more frequently in cancer patients than in non-cancer patients and outcomes are poor in patients with both cancer and thrombosis. Patients with cancer who develop thrombosis are more likely to experience a recurrence of VTE and have increased bleeding complications while receiving oral anticoagulant treatment. The purpose of this paper is to discuss the causes and outcomes of thrombosis in cancer patients, the limitations of warfarin therapy, the guidelines and data for the use of low-molecular-weight heparins (LMWHs) in the treatment and secondary prevention of thrombosis in cancer patients, and emerging data regarding survival with the use of LMWH in cancer patients. Literature for this paper has been collected using multiple sources, including primary, secondary, and tertiary references. Online searches have been conducted utilizing the PubMed and OVID databases, and abstracts from the Proceedings of the American Society of Clinical Oncology and the American Society of Hematology Annual Meeting and Exhibition. The following key terms were used in the search: cancer, deep vein thrombosis, pulmonary embolism, anticoagulation, LMWHs, guidelines, survival, cost. The long-term use of LMWHs in the settings of cancer and thrombosis are supported by recent clinical trial evidence that demonstrate their equivalent safety and improved efficacy when compared to oral anticoagulants resulting in their inclusion in current guidelines. Finally, newer studies offer further evidence of improved outcomes with dalteparin and nadroparin, including possible survival benefits. Treatment with LMWHs has been shown to be more effective than warfarin in the extended treatment of VTE in patients with cancer and is safe in this setting. Use of a LMWH for at least the first 3-6 months of long-term treatment is now considered the standard of care for patients with cancer and is recommended in numerous guidelines. Additionally, further evaluation of the survival benefits of LMWH in cancer patients is warranted.

Low molecular weight heparins in cancer patients: to treat thromboembolic events, the tumor, or both?

The interrelationship between cancer and thrombosis is well known. Recent data help physicians to optimize the management of thrombotic complications occurring in cancer patients. However, many issues are still uncertain. First, although the development of venous thromboembolism (VTE) in a patient with known cancer is the most common presentation, concerns remain about the optimal duration and dosages of anticoagulants. Questions also arise concerning the need to implement heparin prophylaxis in the course of chemotherapy. Secondly, in some patients, thrombosis precedes the diagnosis of malignancy. In this case, the question is whether or not to screen patients for an occult cancer. Thirdly, very recent studies have shown the hemostatic system plays a key role at different stages of tumor growth. Anticoagulants, especially low molecular weight heparin (LMWH), appear therefore to be an attractive strategy not only for managing the risk for thrombosis but, possibly, to improve patient outcome and survival. However, the use of these compounds in settings other than VTE is questionable. Finally, most of the data come from studies evaluating patients with different types of cancer at different stages, thus making results difficult to evaluate. Additional research is required to clarify the biological mechanisms involved and to answer still unresolved clinical questions. In this review, the evidence for the use of LMWHs in cancer patients will be presented and remaining doubts discussed.

From Trousseau to targeted therapy: new insights and innovations in thrombosis and cancer

Venous thromboembolism (VTE) commonly occurs in patients with malignant disease. At the 1997 ISTH meeting, cancer and thrombosis was discussed in a state-of-the-art symposium. Since then, there have been many new developments on this topic. Tumors, through expression of tissue factor can activate coagulation. Furthermore, local peritumor activation of coagulation may have important effects on the biology of cancer. A randomized trial has been conducted which evaluated extensive screening to detect underlying malignancy vs. no screening in patients presenting with idiopathic VTE. No statistically significant difference was detected in cancer-related mortality between the two groups. A trial has evaluated extended prophylaxis in patients undergoing surgery for abdominal malignancy. There was a statistically significant reduction in venographically detected deep vein thrombosis in favor of 4 weeks of treatment. In contrast, there is clearly a need for more information on the use of thromboprophylaxis in medical cancer patients. Low molecular weight heparin (LMWH) has replaced unfractionated heparin as the first line treatment in the majority of patients with acute VTE. Many cancer patients with acute VTE can be treated safely at home with subcutaneous LMWH without admission to hospital. The results of a recent trial demonstrated that long-term low molecular weight heparin administered over a 6-month period substantially reduced the rate of recurrent VTE compared with oral anticoagulant therapy with no increase in bleeding. Finally, the first trial specifically designed to evaluate the anticancer effect of long-term LMWH in cancer patients has been conducted and will no doubt stimulate future research.