Elsevier

The Lancet Haematology

Volume 3, Issue 2, February 2016, Pages e72-e79
The Lancet Haematology

Articles
Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial

https://doi.org/10.1016/S2352-3026(15)00251-3Get rights and content

Summary

Background

Livedoid vasculopathy is a thrombotic skin disease characterised by recurrent occlusion of the cutaneous microcirculation in lower extremities, which results in skin infarctions with painful ulcerations and irreversible scar formation. Rivaroxaban is a direct factor Xa inhibitor that prevents thrombus formation. We investigated whether rivaroxaban is effective for the treatment of livedoid vasculopathy.

Methods

We did this single-arm, open-label, multicenter, phase 2a, proof-of concept trial at three university hospitals in Germany. Patients with livedoid vasculopathy and a minimum pain score of 40 on the visual analogue scale were eligible to participate. Patients received oral rivaroxaban tablets for 12 weeks at an initial dose of 10 mg twice per day, which was reduced to once per day if a reduction of pain by 50% on the visual analogue scale was achieved. Subcutaneous enoxaparin at 1 mg per kg bodyweight once or twice per day was allowed as a backup treatment in case of insufficient efficacy and increased pain. The primary endpoint was change in pain on the visual analogue scale from baseline to 12 weeks. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EudraCT number 2012-000108-13-DE, and is closed to new participants.

Findings

Between Dec 28, 2012, and April 24, 2014, 36 patients were screened, 28 patients were recruited for the study, and 25 patients received treatment. During treatment, five patients dropped out of the study because of withdrawal of consent (one patient), lack of compliance (one patient), violation of inclusion criteria (two patients), and a serious adverse event (one patient). Median pain on the visual analogue scale decreased from 65·0 (IQR 52·0–78·0) at baseline to 6·0 (1·0–14·0) after 12 weeks of treatment (p<0·0001). Six of the 20 patients required additional treatment with enoxaparin. Eight treatment-related adverse events were recorded in six (24%) of the 25 patients: five cases of menorrhagia including one classified as both menorrhagia and dysmenorrhoea, one case of dyspnoea, and one case of gingival bleeding. The only serious adverse reaction to rivaroxaban during the study was one case of menorrhagia in a patient with concomitant endometriosis, which resulted in study discontinuation.

Interpretation

Rivaroxaban seems to effectively reduce pain in livedoid vasculopathy. Therefore we suggest that rivaroxaban with enoxaparin as a backup treatment is a suitable treatment option for patients with livedoid vasculopathy.

Funding

Deutsche Forschungsgemeinschaft and Bayer Vital.

Introduction

Livedoid vasculopathy is a thrombotic skin disease characterised by recurrent occlusion of the cutaneous microcirculation.1, 2, 3, 4 Typical clinical symptoms of livedoid vasculopathy are rapidly occurring skin ulcerations, white scars (atrophie blanche), and irregular broken circles of skin discolouration (livedo racemosa). The disease mainly affects the ankle, foot, and lower calf. Because of the vascular occlusion, patients suffer from intense local ischaemic pain. Furthermore, the ulcerations and subsequent scarring lead to irreversible disfigurement of the skin and have a severe effect on quality of life. Patients with livedoid vasculopathy have been recorded as having poorer quality of life than patients with psoriasis, diabetes, or cancer.5, 6 Thus, this orphan disease with an estimated incidence of 1:100 000 and a female-to-male ratio of 3:1 creates a substantial disease burden7 and still needs an efficient treatment to be developed.

Livedoid vasculopathy is thought to be of either idiopathic origin or, in 36–42% of cases, secondary to defined states of thrombophilia1, 8, 9 that cause thromboses in the cutaneous microcirculation. Prothrombotic states associated with livedoid vasculopathy have been reported previously.1, 7, 8, 9, 10 Existing treatment regimens make use of either anticoagulants (eg, low-molecular-weight heparins, coumarins, or fibrinolytics), immune modulators (prednisolone or immunoglobulins), or a combination of both approaches.11 So far, there are no data from trials that would allow the development of an evidence-based standard of care.

We postulated that rivaroxaban, a direct factor Xa antagonist licensed for the treatment and prevention of major thromboembolic diseases,12, 13, 14, 15 would be effective for the treatment and prevention of thromboses in the cutaneous microcirculation and the resulting sequelae. We and others16, 17 have reported the effects of rivaroxaban use in single patients with livedoid vasculopathy. Rivaroxaban has been reported to have a favourable safety profile and a superior degree of patient satisfaction compared with treatment with enoxaparin and vitamin K antagonists in the treatment of pulmonary embolism.18 These characteristics led us to investigate the therapeutic efficacy of rivaroxaban for livedoid vasculopathy. Because there is no standard of care for livedoid vasculopathy, we aimed to assess whether rivaroxaban is able to effectively reduce pain and clinical symptoms and improve quality of life for patients with livedoid vasculopathy, in order to establish a validated treatment regimen.

Research in context

Evidence before this study

So far, treatment of livedoid vasculopathy has been based on findings from case reports, retrospective studies, and two prospective trials. We searched PubMed, ClinicalTrials.gov, and clinicaltrials.eu up to Nov 5, 2015, using the search terms “Livedoid vasculopathy” or “Livedo vasculitis” with no language restrictions. Our search showed that all previous studies about treatment for livedoid vasculopathy have been both single-centred and unregistered.

Added value of this study

To our knowledge, this trial is the first registered trial that assesses a treatment option for livedoid vasculopathy in a prospective manner. The trial was designed as a single-arm, open-label, multicentre, phase 2a, proof-of concept trial of the factor Xa antagonist rivaroxaban. Our results provide robust evidence to support the use of anticoagulants as a treatment for livedoid vasculopathy.

Implications of all the available evidence

The findings of our trial will have a direct effect on the treatment of livedoid vasculopathy. Our results provide further evidence for the use of anticoagulant treatment for livedoid vasculopathy and set the basis for future head-to-head studies.

Section snippets

Study design and participants

We designed a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial to find an effective treatment regimen for livedoid vasculopathy that reduces pain, ulcer formation, and skin disfigurement and thus improves patients' quality of life. A two-armed study could not be done because, so far, no evidence-based standard of care exists for livedoid vasculopathy. A placebo-controlled design was not used because the ethics committee deemed such a design unethical on the basis of the

Results

36 patients were screened from Dec 28, 2012, to April 24, 2014. Of these patients, eight were excluded and 28 were allocated treatment with rivaroxaban (figure 1). Two patients dropped out because of violation of inclusion criteria and one dropped out because of lack of compliance, resulting in an ITT population of 25 patients. The patients who dropped out did so because of retraction of consent (one patient), violation of inclusion criteria (intake of drugs excluded by protocol [two

Discussion

In this trial, treatment with rivaroxaban for livedoid vasculopathy resulted in a significant reduction of clinical symptoms such as pain, erythema, and ulceration. These clinical improvements were accompanied by increases in patient-reported quality of life. However, the major challenge in livedoid vasculopathy is acute pain due to cutaneous infarction, and rapid pain relief is essential. Our results showed that pain was reduced by 50% within 11 days; whether this is significantly faster than

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