Hull 350A recent review article published in Thrombosis and Haemostasis updated the evidence-based knowledge on long-term treatment of deep-vein thrombosis (DVT) with low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKAs) of all types of patients and also of cancer patients separately. In total, 11 trials with more than 100 participants were identified comparing DVT treatment with long-term (3 months or longer) LMWH versus VKA, in broad populations or limited to cancer patients. This review article underscores that LMWHs should be the therapy of choice for long-term treatment of cancer patients, and offer an alternative for any patient whom the clinician feels may be particularly at risk of developing post-thrombotic syndrome (PTS).

Four comparative trials were identified in patients with cancer and DVT (in whom anticoagulation treatment is more complex and bleeding complications more frequent). In the 11 trials in broad patient populations, LMWHs were shown to be as effective as VKAs in preventing recurrent venous thromboembolism (VTE), and there were no consistent differences in the incidence of bleeding complications during long-term treatment. However, in patients with cancer, VTE recurrence was significantly reduced with LMWH versus VKA in two studies, while major bleeding complications did not differ between groups in any of the trials. As a result, current evidence-based European and American guidelines recommend LMWH over VKA for the long-term treatment of DVT in patients with cancer. Moreover, LMWH and VKA are recommended over the new oral anticoagulant drugs, for which there are limited data on use in long-term treatment.

Post-thrombotic syndrome, a common complication of DVT, causes considerable morbidity. The Home-LITE trial showed that long-term use of tinzaparin reduced the risk of PTS compared with usual care and a meta-analysis demonstrated a favourable effect of LMWHs versus VKA on PTS-related outcomes. Moreover, a meta-analysis of nine studies in total demonstrated a consistently favourable effect of LMWHs versus VKA on PTS-related outcomes. Given the high morbidity and economic burden of PTS, and the limited options for treating it, this finding would, if confirmed, be an important reason to use LMWH rather than oral anticoagulation.

Treatment satisfaction and patient preference are increasingly important factors in both the formulation of treatment guidelines and in physician-prescribing decisions for the treatment of DVT. Acceptance of LMWH treatment in patients with cancer was investigated in a study in palliative care showing that patients found LMWH to be a preferable treatment to VKA. Furthermore, the Home-LITE study indicated that patients in the tinzaparin group expressed significantly greater treatment satisfaction than those in the VKA group, particularly regarding freedom from the inconvenience of blood monitoring.

 

Reference

R. Hull, G. Townshend. Long-term treatment of deep-vein thrombosis with low-molecular weight heparin: An update of the evidence. Thromb Haemost 2013;110(1):14-22.

 


Phan-350Preventive measures for outpatient chemotherapy patients are not widely advocated. To gain more insight in this matter Phan et al conducted a meta analysis of 11 clinical trials (N= 7,805) evaluating outpatient VTE prevention effectiveness and safety. This analysis revealed that the odds of VTE was lower in the prophylaxis group (OR[95%CI]: 0.56[0.45–0.71]) and improved when heparin-based prevention was analyzed (OR[95%CI]: 0.53[0.41–0.70]) (Figure). Strong prevention was found among patients with lung cancer (OR[95%CI]: 0.46[0.29–0.74]) and pancreatic cancer (OR[95%CI]: 0.33[0.16–0.67]). Thromboprophylaxis reduced VTE episodes with a reduction in VTE events of 47% in heparin-based prophylaxis trials compared to placebo. However, major bleeding events were frequent in the intervention group (OR[95%CI]: 1.65[1.12–2.44]). The patients receiving heparin-based prophylaxis had a 60% increase in bleeding events. Of note, no mortality benefit derived from VTE prophylaxis, but the analysis was limited by short follow up in the included studies.

This meta-analysis is larger than previously published and focuses on two key aspects; it only included solid tumor malignancies and data were pooled on outcomes specific to heparin-based prevention. The results of this analysis are in agreement with results found by Di Nisio et al. where nine randomized controlled trials showed a reduction of 40% in the incidence of symptomatic VTE. In a combined analysis on 811 patients with lung cancer using data from PROTECHT and TOPIC-2, published by Verso et al. the authors reported a value of LMWH for primary VTE primary thromboprophylaxis (OR[95%CI]: 0.54[0.31–0.95]). These results were replicated in this meta-analysis after adding patients with lung cancer form the SAVE-ONCO trial and a reduction by half of the VTE events in patients with lung cancer who used primary prophylaxis was found. Moreover, among the 430 patients with pancreatic cancer the VTE incidence in the treatment arm was a third of the expected rate. Given the strong preventive effect in these 2 patient groups, the cost and bleeding risks of primary thromboprophylaxis is most likely to be justified in patients with lung or pancreatic malignancies.

Although there is a clearly measurable VTE rate reduction when primary thromboprophylaxis is given to patients with cancer, more information on the value of risk stratification tools to personalize prevention strategies is needed before anticoagulants are added to the conventional treatment of patients with cancer.

Figure. VTE prevention in patients with solid tumors (only trials with heparin-based prevention)

tabel 

Reference

M. Phan, S. John, A. Casanegra et al. Primary venous thromboembolism prophylaxis in patients with solid tumors: a meta-analysis. J Thromb Thrombolysis 2013. Epub ahead of print. http://link.springer.com/article/10.1007%2Fs11239-013-1014-9

 


tinzaparinResults of a recent retrospective study indicate that the safety profile of tinzaparin in pregnancy is equivalent to that of other low molecular weight heparins with the advantage of single daily dosing. As such, the investigators conclude that tinzaparin is a safe and effective anticoagulant for pregnant women.

Pregnancy and the puerperium are hypercoagulable states increasing the risk of venous thromboembolism (VTE) by sixfold. Although maternal death from VTE is decreasing, risk factors for VTE are increasing in the general population. Recent RCOG guidelines recommend much increased use of prophylactic heparin both antenatally and in the puerperium. These recommendations have significant implications for the maternity services in terms of cost and it becomes even more important to examine the safety and efficacy of the low molecular weight heparins in this setting. Previous studies have yielded reassuring data with low molecular weight heparins in pregnancy, namely enoxaparin, dalteparin and nadroparin, but there has been little information about the safety and efficacy of tinzaparin. To address this issue, Khalifeh et al retrospectively reviewed the medical records of 149 women who were prescribed tinzaparin during pregnancy and the puerperium. Tinzaparin was given as a single daily prophylactic dose to women with a history of venous thromboembolism (VTE) or recurrent miscarriage and as a single daily therapeutic dose to women diagnosed with VTE.

The dose administered was therapeutic in 21 (14%) cases and prophylactic in all other. VTE recurred in three women who had a history of VTE (3.6%). Among the 149 cases analysed in our study, three women experienced recurrent VTE (2%) despite daily administration of a prophylactic dose of tinzaparin. Antepartum and postpartum haemorrhage occurred in 9.7% and 5% of cases, respectively and two women developed thrombocytopenia but their platelets remained above 100,000/ml. Fifty-seven women (38%) had regional anaesthesia without complication. Caesarean section rates were not different from the general population. This study demonstrates that once daily tinzaparin is an effective LMWH in pregnancy and has a favourable safety profile which is equivalent to other low molecular weight heparins with the advantage of single daily dosing. However, in view of the retrospective nature of the study at hand, prospective randomized studies comparing tinzaparin and other LMWH, are still required to better determine the anticoagulation treatment of choice in pregnancy.

Tinzaparin figuur2a

Reference

A. Khalifeh, J. Grantham, J. Byrne et al. Tinzaparin safety and efficacy in pregnancy. Ir J Med Sci 2013. Epub ahead of print.

 


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video-peeters-350Take home messages

  • Clinicians should be aware of the high VTE risk associated with cancer.
  • Based on all international guidelines, the initial therapy for acute VTE should consist of subcutaneous LMWHs.
  • The lack of bioaccumulation of tinzaparin in patients with renal impairment is a major advantage in an oncological setting.