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48th Annual Meeting and Exposition of the American Society of Hematology

Orlando, Florida / December 9-12, 2006

There are now several studies on prophylaxis against recurrent or primary venous thromboembolism (VTE) that have individually and collectively suggested that low molecular-weight heparin (LMWH) therapy can improve outcome of patients with cancer. Some of the most rigorously placebo-controlled studies, such as one conducted with the LMWH dalteparin in patients with small-cell lung cancer (SCLC), have demonstrated an improvement in overall survival (Altinbas et al. J Thromb Haemost 2004;2(8):1266-71). In the latest of a series of meta-analyses that evaluated eight trials with a total of 9914 patients, researchers reported a significant overall reduction in VTE with LMWHs over either placebo or unfractionated heparin (UFH). The protection in both cancer patients and patients with acute illnesses is reassuring, but the mechanisms of benefit appear to be different. In cancer patients, rather than just preventing VTE secondary to immobility, LMWHs also counter the pro-thrombotic effects of the malignancy and its treatments.

Take-home Message: Survival Benefit with LMWH

As reported by Prof. Ajay Kakkar, Centre Lead for Surgical Science, Institute of Cancer, Barts and The London, Queen Mary’s School of Medicine and Dentistry, UK, the results of the meta-analysis contribute to the deep pool of data demonstrating the important role of LMWH agents in preventing VTE. He called the use of LMWHs for the prevention and treatment of thromboembolic disease in patients with acute illnesses or cancer “well validated in terms of both efficacy and safety.” Although much of the evidence has been obtained in acutely ill populations that included but were not limited to cancer patients, he noted that studies conducted specifically in cancer patients with tumours of different histological types and stage have also favoured prophylaxis. “Broadly, all the studies suggested a survival benefit which appeared to be greatest for patients exposed to LMWHs who had a better prognosis.”

In the new meta-analysis, all trials of LMWHs for VTE prophylaxis in medically ill patients that were conducted between 1981 and 2006 were considered for inclusion if they were randomized and had the incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE) as a primary end point. Of the eight trials included, four compared a LMWH to placebo and four compared a LMWH to UFH. The odds ratio for a DVT was 0.58 (95% CI, 0.45-0.75; P=0.001) for the LMWH vs. placebo or UFH. The odds ratio for a PE or DVT was 0.64 (95% CI, 0.49-0.82; P=0.01) for the LMWH vs. placebo or UFH.

Meta-Analysis Trial Components

The authors of the meta-analysis suggested that the protection from PE or DVT vs. UFH was largely driven by results of PREVENT (Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial), which randomized 3706 medically ill patients to the LMWH dalteparin or placebo, and PRIME (Prophylaxis in Internal Medicine with Enoxaparin), which randomized 959 medically-ill patients to the LMWH enoxaparin or placebo.

Overall, the compounds were found to be safe without any major bleeding with the LMWH compared to placebo (P=0.18) or UFH (P=0.42), according to senior author Dr. Abir O. Kanaan, Massachusetts College of Pharmacy and Health Sciences, Worcester. Presenting these results at ASH, Dr. Kanaan reported that there was an increased risk of any bleeding events that was primarily “driven by an increase in minor bleeding from enoxaparin use” in the MEDNOX (Medical Patients with Enoxaparin) trial.

Although this meta-analysis did not associate LMWHs with an improvement in overall survival, several individual studies have. This is significant because specific LMWH agents are not likely to be interchangeable due to differences in molecular weight and pharmacokinetics. Dr. Kakkar cited four such studies, including FAMOUS (Fragmin Advanced Malignancy Outcome Study), for which he served as the lead author (Kakkar et al. J Clin Oncol 2004;22(10):1944-8). FAMOUS was the first double-blind, placebo-controlled study to evaluate an LMWH in advanced cancer patients without evidence of an underlying thrombosis. Although the survival advantage for the LMWH at one year was modest and non-significant (46% vs. 43%), it reached a more substantial trend at three years (21% vs. 12%). Moreover, a post hoc analysis revealed that the median survival was almost doubled (43.5 months vs. 24.3 months). The relative survival advantages were even more pronounced in those patients with a good prognosis. “The difference in median survival was quite striking, although this was a post hoc analysis, but this did raise interest in identifying those subgroups that might benefit most,” Dr. Kakkar remarked.

The potential for a survival advantage was reinforced by the CLOT (Comparison of Low Molecular-weight Heparin and Oral Anticoagulant Therapy) trial, which randomized cancer patients to dalteparin or an active control in the form of the oral anticoagulant coumarin derivative (Lee et al. N Engl J Med 2003;349(2):146-53). In this study, which was conducted to prevent recurrent VTE in patients with a symptomatic proximal DVT or PE, the overall mortality rates at one year did not differ significantly except in the subgroup without metastases. In these patients, survival at one year was 80% on dalteparin vs. 65% on the oral anticoagulant (P=0.03).

While CLOT was a secondary prevention study, the one undertaken in patients receiving chemotherapy for SCLC was for primary prevention. In this study, 84 patients with SCLC were randomized to receive chemotherapy alone or chemotherapy and dalteparin. Median progression-free survival was 10.0 months among those receiving the LMWH vs. six months in those who did not (P=0.01). In addition, median overall survival was 13 months among those receiving the LMWH vs. eight months in those who did not (P=0.01). Similar relative improvement was observed in those with limited and extensive disease.

In the MALT (Malignancy and Low Molecular-weight Heparin Therapy) trial, 302 patients with solid tumour malignancies were randomized to receive six weeks of the LMWH nadroparin or placebo (Klerk et al. J Clin Oncol 2005;23(10):2130-5). The risk of death was reduced by 25% (P<0.05) among those who were randomized to the LMWH. In the subgroup of patients with a life expectancy of greater than six months at the time of entry, the risk of death was reduced by 36% and the median survival on the LMWH was 15.9 months vs. 9.4 months on placebo (P<0.01).

Cancer Prophylaxis

Initially, the protection from VTE in cancer patients was considered to stem from the same mechanisms as that observed in patients with acute illness, which is primarily reducing the coagulability of the blood in patients who are immobile for extended periods. However, substantial evidence has emerged to suggest that LMWH therapies have both direct and indirect effects on the pro-thrombotic state produced by many cancers and commonly used therapies, such as alkylating agents that can generate thrombin and venous access catheters that can produce endothelial damage that is pro-thrombotic. The most recent data suggest that LMWHs may even inhibit cancer progression promoted by the hypercoaguable state. Citing published studies, Dr. Kakkar observed that coagulation proteases inhibited by LMWHs have been implicated in promotion of growth and invasion of malignant cells, angiogenesis and metastatic spread. In addition, there have been several experimental studies associating LMWHs with increased apoptosis of malignant cells.

There are numerous studies planned or ongoing to further explore the association between LMWH therapy and opportunities to improve outcome, particularly in patients with cancer. While LMWH agents already have an important treatment role in cancer patients with symptomatic VTE, there is a strong potential to extend the indications for prophylaxis. Rather than focusing only on inhibiting the VTE generated by immobility, new studies are planned to evaluate the effect of LMWHs on the mechanisms of cancer progression. From a practical point of view, the studies are expected to not only better identify appropriate candidates for LMWH treatment but determine how long to keep cancer patients on this therapy for optimal benefits.

Summary

LMWHs protect both acutely ill and cancer patients from VTE, but the mechanisms of protection appear to differ. While both groups can be protected from thrombus formation secondary to immobility, cancer patients may also derive protection from the hypercoaguable state induced by their disease and its treatments. In addition, there are new data suggesting mechanisms of benefit independent of preventing life-threatening clots. Improved survival with dalteparin in patients with SCLC and in other cancer patient subgroups, particularly those with a good prognosis, has generated studies to look for benefits beyond VTE prophylaxis. Although LMWH agents should be employed routinely to treat VTE and in secondary prophylaxis, ongoing studies of primary prophylaxis in cancer have the potential to substantially increase the indications for these agents.