Regular articleLong-term treatment of venous thromboembolism with tinzaparin compared to vitamin K antagonists: A meta-analysis of 5 randomized trials in non-cancer and cancer patients☆
Introduction
Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep-vein thrombosis (DVT) is a major cause of morbidity and mortality, affecting over 2 million people in the United States [1], [2], [3]. Patients with cancer face a significant increase in the incidence of VTE compared to non-cancer patients, of at least 7-fold in certain malignancies [4].
Patients with proximal DVT or PE require anticoagulant treatment for at least 3 months to prevent symptomatic extension and/or recurrent VTE [5], [6]. Standard therapy includes initial unfractionated heparin (UHF), low-molecular-weight heparin (LMWH) or pentasaccharides followed by vitamin K antagonists (VKA) which have been considered for decades as the reference long-term anticoagulant therapy in patients with symptomatic VTE as oral administration is effective and more convenient for long-term treatment [7], [8]. VKA reduce the risk of VTE recurrence as long as they are used [9]. However, the high variability in the response to VKA requires regular INR monitoring and dose adaptation. Although VKA achieves a low rate of recurrent VTE in the general population of patients with VTE (10), its use is associated with a high recurrence rate in patients with cancer (11).
LMWH has been considered as an effective and safe alternative for the long-term anticoagulant treatment in patients with side effects or other complications on VKA [10] or in patients in whom the use of VKA would be contraindicated or problematic [11]. The issue of the benefit-risk ratio of long-term curative doses of LMWH and their potential advantage compared to VKA is not fully addressed [12]. Based on a meta-analysis of randomized trials, early comparisons of LMWH to VKA for the long-term treatment of symptomatic VTE showed a statistically non-significant reduction in the risk of VTE at 3 months (OR 0.66 [95%CI 0.41; 1.07]) and in the risk of bleeding (OR 0.45 [95%CI 0.18; 1.11]) in favor of LMWH treatment [11]. Previous reviews or meta-analyses in adult patients with cancer have shown that the long-term use of LMWH after the acute first week of treatment is superior to VKA for secondary prevention of venous thromboembolism [13], [14], [15]. Overall, meta-analyses on LMWH show a reduction of VTE recurrence and bleeding risk compared to VKA but statistical significance is not reached. This may be due to: i) old studies with sub-optimal methodology, ii) the mix in clinical studies of cancer and non-cancer patients who are at different levels of risk, iii) the inclusion of different LMWHs in the same analyses.
Only one of the available LMWH, dalteparin, has received formal approval for the long term treatment of patients with cancer at curative doses, based on the CLOT study [16]. However, enoxaparin and tinzaparin (Innohep®, LEO Pharma) curative doses are also recommended by academic and regulatory guidelines for the long-term treatment of symptomatic VTE in patients with cancer [7], [8], [17], [18], [19]. Tinzaparin has the highest molecular weight compared to other LMWH. It is not exclusively eliminated by the kidney as the reticulo-endothelial system and the liver contribute to tinzaparin metabolism (21). Therefor unlike other LMWHs such as enoxaparin, tinzaparin does not seem to cause an accumulation of anti-factor Xa activity in patients with renal insufficiency [20], [21] which is of particular interest in patients with cancer with a high prevalence of renal impairment (24) in whom tinzaparin could be associated with a lower risk of bleeding.
The purpose of this meta-analysis is to assess the benefit-risk ratio of the LMWH, tinzaparin, when used at curative doses for the long-term treatment of patients with symptomatic VTE, in comparison to VKA.
Section snippets
Literature search and study identification
Our aim was to identify all the relevant published and unpublished randomized controlled trials (RCTs) comparing long-term tinzaparin (3–6 months), at the curative dosage of 175 IU/kg once daily for the treatment of VTE to a vitamin K antagonist adjusted to maintain an INR of 2 to 3. An exhaustive literature search, both manual and computer assisted, was performed without any restriction on language or dates. The computer-assisted search was carried out on electronic databases (MEDLINE, the
Search strategy and studies description
Out of 266 citations found after electronic search, 256 were discarded for various reasons (Fig. 1). One was added after a manual search. A total of 11 were carefully reviewed, 5 studies were found eligible to the meta-analysis (Fig. 1) and are described in Table 1 (6, 30–33). There was no discordance in the selection of the study. A total of 1668 patients with symptomatic VTE of whom 406 had cancer were enrolled in the studies, all treated with curative doses of tinzaparin (n = 835) or VKA (n =
Discussion
The 5 eligible randomized clinical trials included in this meta-analysis compared long-term (3 to 6 months) curative treatment with tinzaparin to VKA (warfarin or acenocoumarol) for the prevention of thromboembolic recurrence in 1668 patients with symptomatic VTE, of whom 406 (24%) had cancer. When combining these trials, long-term treatment with tinzaparin was associated with a 15% non-significant relative risk reduction of VTE-recurrence compared to VKA after 3–6 month treatment period. This
Conflict of interest statement
No conflict for this manuscript.
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Disclosure of funding received for this work: None.