Treatment of superficial vein thrombosis with intermediate doses of tinzaparin

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Athanasios Giannoukas and Christos Karathanos
Athanasios Giannoukas and Christos Karathanos

Superficial vein thrombosis (SVT) is a common disease affecting 3–11% of the general population, while in patients with varicose veins the incidence of SVT increases to as much as 60%. The prevalence of SVT appears to be two-fold higher compared to deep vein thrombosis (DVT) and pulmonary embolism (PE). Patients with SVT may develop extension of the thrombotic process, recurrence or even progression to the deep vein system. In addition, SVT may coexist with DVT and/or PE in 6–53% and 1.5–33% of patients presenting with SVT, respectively. Despite these interesting observations, SVT has not been studied in a systematic manner.

Indeed, the strength of current recommendations in respect to the treatment of SVT are weak and not based on level 1 evidence regarding the use of low molecular weight heparin (LMWH), while the recommendation for treatment with fondaparinux 2.5mg for 45 days is based on only one randomised controlled study; the CALISTO trial.

The CALISTO trial has demonstrated that administration of fondaparinux at a dose of 2.5mg once a day for 45 days is an effective treatment for grade 1b SVT. The primary efficacy outcome (death from any cause or symptomatic PE, symptomatic DVT, symptomatic extension to the saphenofemoral junction or symptomatic recurrence of SVT at day 47) occurred in 0.9% of patients in the fondaparinux group and 5.9% in the placebo group (p<0.001). The rate of PE or DVT was 85% lower in the fondaparinux group. Similar risk reductions were observed at day 77. No difference was observed in major bleeding between the two groups.

Despite the significant reduction of the thrombotic process, there has been a justified criticism that treatment with fondaparinux for such a long period is not cost-effective and should be advised only in patients with high thrombotic risk, in cases of severe symptoms, thrombosis close to the saphenofemoral junction, in recurrent disease or for shorter periods of treatment. It has been estimated that treatment with fondaparinux would prevent 123 venous thromboembolism (VTE) events and two deaths in every 10,000 SVT patients, and the probability that Fondaparinux would be cost-effective has been reported as 1% at a willingness to pay of US$100,000 per quality-adjusted life years.

Low molecular weight heparin (LMWH) in intermediate doses (50–70% of a therapeutic dose) for a least one month is recommended for the treatment of grade 2a SVT. This recommendation is based on a Cochrane Database review published by Di Nisio et al in 2007. The analysis included 24 studies with a total of 2,469 patients. Treatment options ranged from LMWH to non-steroidal anti-inflammatory drugs (NSAIDs), topical treatment, surgery or compression stockings. They concluded that both LMWH and NSAIDs significantly reduced the incidence of extension or recurrence of SVT by 70% compared with placebo treatment, although the optimal dose, treatment duration or whether combination therapy may be more effective than single therapy are questions that still need to be answered by future studies.

The STEFLUX study, which compared different doses and duration of Parnaparin, has reported that the incidence of symptomatic VTE was not different when intermediate or prophylactic doses were given for 30 days, although symptomatic VTE was reduced with 30-day treatment with intermediate doses compared with 10-day treatment. In addition, SVT extension at three months was significantly reduced by 30-day treatment with intermediate doses compared with 30-day treatment with prophylactic doses or 10-day treatment with intermediate doses. Unfortunately, the study was unable to determine the impact on the most clinically important end points (DVT or PE) because of low follow-up rates and premature study termination. The Vesalio group compared 30-day treatment with therapeutic doses of LMWH with 30-day treatment with a prophylactic dose. No differences in the SVT extension, recurrence or VTE events during the three-month follow-up were reported. In both studies no cases of major bleeding or heparin-induced thrombocytopenia were recorded.

In a recent, as-yet unpublished, retrospective study (which was presented at the 2016 European Venous Forum annual meeting in London in July) involving 296 patients with SVT (SeVEN study), intermediate doses of tinzaparin (0.5ml, 10,000 anti-Xa IU) once daily—for a duration that was at the treating physician’s discretion—were analysed. The primary outcome was recurrence of VTE or death within 12 weeks. Approximately two thirds (64%) of the patients received treatment for a mean period of 37 days while the remaining patients received short-duration treatment for a mean period of 16 days. During follow-up, recurrence of VTE or death occurred in 18 patients, although VTE recurrence was not related to the duration of treatment as the majority of the events occurred after the discontinuation of the treatment at four weeks. This study probably represents the real world practice and it shows, for the first time, that approximately a third of patients with SVT do not need treatment lasting as long as 45 days or even a month.

Direct oral anticoagulants (DOACs) have recently been approved for VTE therapy. The SURPISE study is a randomised trial evaluating the efficacy and safety of 10mg of rivaroxaban compared with 2.5mg of fondaparinux for SVT treatment in a subset of high-risk SVT patients over a period of 45 days. The results of the SURPRISE trial will provide evidence concerning the role of DOACs in the treatment of SVT.

The need for further studies

Several questions about the management of SVT remain under investigation. This may explain the disparity in current practice. Future studies are needed to address a number of key questions and to clarify optimal treatment of SVT, including:

  1. A cost-effectiveness analysis comparing fondaparinux 2.5mg for 45 days with LMWH in intermediate doses for 15 days.
  2. The role of DOACs in the treatment of SVT.
  3. The role of etiology and location of the SVT to the regime, dose and duration of treatment.

Christos Karathanos and Athanasios D Giannoukas are at the Department of Vascular Surgery, Faculty of Medicine, School of Health Sciences, University Hospital of Larissa, University of Thessaly, Larissa, Greece