item1c-350A review article by Johansen et al.(2013) describes the elimination pathways of the different LMWHs and assesses whether the relative balance between renal and non-renal (cellular) clearance may provide a mechanistic explanation for the differences in accumulation that have been observed between LMWHs in patients with impaired renal function, such as in elderly patients or in patients with cancer.

Since low-molecular-weight heparins (LMWHs) are eliminated preferentially via the kidneys, the potential for accumulation of these agents is of particular concern in populations with a high prevalence of renal impairment, such as the elderly and patients with cancer. The risk of clinically relevant accumulation of anticoagulant activity as a result of a reduction in renal elimination appears to differ between LMWHs. Clearance studies in animals, cellular binding studies and clinical studies all indicate that the balance between renal and non-renal clearance is dependant on the molecular weight (MW): the higher the MW of the LMWH, the more the balance is shifted towards non-renal clearance. Animal studies have also provided insights into the balance between renal and non-renal clearance by examining the effect of selective blocking of one of the elimination pathways, and it is most likely that cellular clearance is increased to compensate for decreased renal function. Tinzaparin (6,500 Da) has the highest average MW of the marketed LMWHs, and there is both clinical and preclinical evidence for significant non-renal elimination of tinzaparin, making it less likely that tinzaparin accumulates in patients with renal impairment compared with LMWHs with a lower MW distribution. On the basis of this these findings, LMWHs that are less dependant on renal clearance may be preferred in patient populations with a high prevalence of renal insufficiency.

The electronic version of this article is the complete one and can be found online at: http://www.ehoonline.org/content/2/1/21

Reference

Johansen KB, Balchen T. Tinzaparin and other low-molecular weight heparins: what is the evidence for differential dependance on renal clearance. Exp Hematol Oncol 2013;2(1):21. Epub ahead of print.

 


item2c-350A large observational study of unselected patients receiving cancer chemotherapy demonstrated considerably greater rates of venous thromboembolism (VTE). The risk of VTE appears to increase progressively over the year following initiation of treatment. Moreover, cancer patients developing VTE also experience a greater risk of major bleeding than patients without VTE. Patients considered at high risk for VTE should therefore be considered for thromboprophylaxis after assessing the balance of potential benefits and harms for the patient.

Malignant disease is associated with a hypercoagulable state that increases the risk for development of venous thromboembolism (VTE) by at least 4-fold. The risk for VTE varies according to other factors, including age, obesity, history of thrombosis, recent reduced mobility, major surgery and anticancer treatment. In this retrospective study, reported by Lyman et al in The Oncologist in 2013, the risk for VTE was assessed in an unselected cohort of 27,479 patients from the United States IMPACT health care insurance claims database of patients with high-risk solid tumors who were starting chemotherapy treatment.

In this large unselected cohort of patients with cancer, the overall risk for VTE 3,5 months after chemotherapy initiation was 7,3% (range 4,6%–11,6% across cancer locations; see Figure 1). This is markedly higher than the VTE risk reported in the placebo arms in randomized clinical trials (e.g. 3,9% in PROTECHT and 3,4% in the SAVE-ONCO trial). The cumulative risk for VTE continued to increase, with an estimated risk of 13,5% (range 9.8%–21.3%) at 12 months after starting chemotherapy (see Figure 1). Those receiving chemotherapy on an outpatient basis in whom VTE developed also had a higher risk for major bleeding complications than those who did not, and this risk increased during the 12 months after starting chemotherapy. Patients with cancer in whom VTE developed experienced a significant economic burden for health care expenditure. The highest VTE risk was observed in those patients receiving chemotherapy for tumors of the pancreas, stomach, and lung. The development of VTE in patients with cancer may interfere with planned active treatment, may increase patient morbidity and early death rates, and may worsen quality of life. These results highlight that VTE prevention is not only important for reducing the risk of thrombosis, but probably also for preventing the bleeding risk associated with thrombosis and its therapy. However, the decision to use thromboprophylaxis in patients undergoing chemotherapy must involve careful evaluation of the risk-benefit profile of the anticoagulant used.

Figure 1. Proportion of VTE cases at 3,5 and 12 months post-index (VTE = venous thromboembolism, PE = pulmonary embolism).

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Reference

Lyman G, Eckert L, Wang Y, et al. Venous Thromboembolism Risk in Patients With Cancer Receiving Chemotherapy: A Real-World Analysis. The Oncologist 2013;18; Epub ahead of print.

 


Click to enlarge. Patients with unprovoked venous thromboembolism (VTE) have a high recurrence risk and are candidates for extended anticoagulation. However, many patients stay recurrence free and are unnecessarily exposed to anticoagulants. The updated Vienna Prediction Model has been developed to discriminate patients with unprovoked VTE with a low recurrence risk from those with a high recurrence risk based on the patient’s sex, the location of VTE, and D-Dimer, and allows risk assessment of recurrence not only at 3 weeks after anticoagulation but also at several time points later than 3 weeks after anticoagulation. This updated model was presented during the 2013 Congress of the International Society on Thrombosis and Haemostasis (ISTH) held last July 2013 in Amsterdam.

In order to update the model, the investigators analysed the data set of the Austrian Study on Recurrent Venous Thromboembolism, a prospective cohort study in patients of legal age with a first VTE who had received anticoagulants for 3 to 18 months. Patients with VTE provoked by surgery, trauma, pregnancy, or female hormone intake, or with a natural inhibitor deficiency, the lupus anticoagulant, or cancer, were excluded. The study end point was recurrent symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism (PE). D-Dimer levels were measured at several time points after anticoagulation and these data were linked with the patient’s sex and location of VTE. Nomograms were generated to calculate individual risk scores and cumulative recurrence rates from 3 weeks, 3, 9, 15 and 24 months on after discontinuation of anticoagulation using a dynamic landmark competing risks regression approach.

In total, 159 of 738 patients had recurrence during a mean follow-up of 6 years. The cumulative probability of recurrence was 5,5% (95% CI: 3,9%-7,2%) after 1 year and 18,4% (95% CI: 15,4%-21,4%) after 5 years. D-Dimer levels varied between patients, but did not substantially increase over time. The updated version of the Vienna prediction model has two main improvements: first of all, the model accounts for the competing risk of death or informative drop out by competing risks regression, and second, various time points of prediction are now considered rather than predicting just once after starting anticoagulation (after 3 weeks). Subdistribution hazard ratios (95% CI) dynamically changed from 3 weeks to 3, 9, 15 and 24 months from 0.29 (0.19-0.43), 0.31 (0.21-0.46), 0.37 (0.24-0.55), 0.43 (0.27-0.68) to 0.55 (0.32-0.94) in women vs. men, from 1.60 (0.84- 3.05), 1.58 (0.83-3.00), 1.54 (0.80-2.96), 1.49 (0.74-3.00) to 1.43 (0.64-3.20) in patients with proximal DVT or PE compared to distal DVT, and from 1.37 (1.23-1.66), 1.36 (1.14-1.62), 1.34 (1.14-1.58), 1.32 (1.11-1.58) to 1.29 (1.02-1.63) per doubling D-Dimer levels. Nomograms were created based on subdistribution hazard ratios from the multivariable dynamic model to predict the recurrence risk from 3 weeks, 3, 9, 15 or 24 months after anticoagulation. A web-based calculator allows risk assessment from random time points on between 3 weeks and 24 months.

In summary, the updated Vienna Prediction Model integrates patient’s sex, location of first VTE and serial D-Dimer measurements and now allows prediction of recurrent VTE at a random time point after discontinuation of oral anticoagulation. This is a major improvement on the more static model that existed before.


You can find a web-based version of the calculator at:
http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/


Reference

Eichinger S, Heinze G, Kyrle P. D-Dimer levels over time and the risk of recurrent venous thromboembolism: An update of the Vienna Prediction model. Presented during ISTH 2013, abstract #OC 12.5.

 


App2-350This app explains how the risk of developing a Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) in hospital can be reduced. It is intended as a helpful guide for VTE patients to use before, during and after their stay in the hospital. The app provides explanation on VTE and lots of practical exercises to prevent VTE while in hospital or after discharge.

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video-hermans1-350Take home message

  • A statistically significant reduction in mortality risk with LMWH at 3 months of follow-up has been noted. The reason for this survival benefit is unknown, but research exploring the antineoplastic properties of LMWH is ongoing.
  • In addition to better efficacy, LMWH provides other advantages versus UFH, including lower cost (because hospitalization and laboratory monitoring are not required) and simple dosing (because the total daily dose is based on body weight).
  • LMWH is also associated with a lower risk for heparin-induced thrombocytopenia (HIT)
  • See for Consensus guidelines on treatment of deep vein thrombosis or pulmonary embolism in patients with cancer following link: http://bloodjournal.hematologylibrary.org/content/122/14/2310/T1.expansion.html