Rivaroxaban for treatment of livedoid vasculopathy: A systematic review
Yimeng Gao | Hongzhong Jin
Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
Correspondence
Hongzhong Jin, Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.
Email: [email protected]
Funding information
National Natural Science Foundation of China, Grant/Award Number: 81773331; National Natural Science Foundation of China, Grant/ Award Number: 82073450; National Key Research and Development Program of China, Grant/Award Number: 2016YFC0901500
1 | INTRODUCTION
Livedoid vasculopathy (LV) is a thrombotic occlusive vascular dis- ease mainly affecting the ankles, the dorsal feet, and the lower extremities. The condition is exacerbated during the summer and is characterized by recurrent erythema, macules, painful ulcers, and white atrophic satellite scars. LV recurrence significantly impairs quality of life.1 Although a variety of hereditary and acquired coagu- lation abnormalities have been documented in LV patients,2 its etiol- ogy and pathogenesis remain unclear. LV is thought to be a vascular disease rather than a classical cutaneous vasculitis in which hyp- ercoagulability and impairment of fibrinolysis play major roles. This judgment is based on the pathological features of the thrombotic occlusive vascular changes in LV and the absence of inflammatory cell infiltration.
Treatment of LV is challenging and controversial, and there is currently no established first-line therapy to effectively cure ulcerations and prevent relapse. Treatment and wound care in LV patients is difficult and costly. Current treatment strategies for LV are mainly based on physicians’ clinical experiences, case series, and case reports. Anticoagulants are the most common monotherapies for LV.3 Less commonly, other treatments have been used to treat LV patients including anabolic steroids, intravenous immunoglobulin, immunosup- pressive agents, antiplatelet drugs, danazol, hyperbaric oxygen ther- apy, and off-label medications.3 However, no standard therapy for LV has been established. The efficacy of these treatments varies and treatment rarely results in long-term remission. Excessive systemic therapy occasionally leads to severe adverse events.
In recent years, rivaroxaban, a factor Xa inhibitor, has been widely used for therapy and secondary prophylaxis of venous thromboembo- lism and other embolic diseases.4 Rivaroxaban is well tolerated and convenient to administer compared with warfarin and low molecular weight heparin. In 2013, Kerk et al. successfully treated three LV patients with rivaroxaban.5 Since then, several case reports and case series as well as one clinical trial registered in the Cochrane database have described the use of rivaroxaban to treat LV patients. Because of its rarity (incidence of 1:100,0006,7), there have been no large case control studies of rivaroxaban therapy for LV. Thus, we performed a systematic review of the efficacy and safety of rivaroxaban for treat- ment of LV. Our goal was to summarize and evaluate the clinical evi- dence for LV therapy.
2 | METHODS
2.1 | Literature search
We searched the PubMed, Cochrane, and Embase databases for arti- cles on rivaroxaban treatment on LV patients. The search was con- ducted on December 17, 2020 (Figure 1). The search terms included “livedoid vasculopathy”, “livedoid vasculitis”, “livedo vasculitis”, “atrophie blanche”, “white atrophy”, “segmental hyalinizing vasculi- tis”, and “rivaroxaban”. The dates covered by the search were from inception of the databases to December 17, 2020, and language was restricted to English articles only. No other filters or restrictions were used for the search.
2.2 | Eligibility criteria
Inclusion criteria were: (a) diagnosis of LV confirmed by both clinical examination and pathological manifestations; (b) research studies, case series, or case reports of the efficacy and safety of rivaroxaban for treatment of LV; and (c) articles written in English.
Exclusion criteria were: (a) uncertain diagnosis of LV; (b) impor- tant treatment details related to dosage, duration, and efficacy missing or vaguely recorded; (c) article types other than research studies, case series, or case reports such as review articles or editorial articles; and (d) articles in languages other than English.
FIG U R E 1 PRISMA flow figure for literature reviewing.
3 | RESULTS
In total, 22 articles and one registered clinical trial were identified from the PubMed, Cochrane, and Embase databases using the search strategy described above. After a comprehensive assessment by two independent reviewers, 12 studies, case series, and case reports as well as one clinical trial were included.5,8–19 The studies were from the United States, the United Kingdom, Korea, Germany, China, and Brazil. The following data were extracted from each article: authors, year, country, number of patients, age, gender, com- orbidities, thrombophilic factors, previous treatments, combination treatments, dose of rivaroxaban, treatment duration, efficacy, recur- rence, and side effects (Tables 1 and 2).
3.1 | General results
A total of 73 LV patients received rivaroxaban. Thirteen patients (26.53%) were male and 36 patients (73.47%) were female (female to male ratio of 2.77:1); for the remainder of patients, general data and demographic characteristics were vaguely recorded. The ages of LV patients ranged from 15 to 83 years. Two patients had comorbid venous insufficiency. Other comorbidities were documented in a few LV patients including deep venous thrombosis, right carotid thrombo- sis, polycythemia vera, systemic lupus erythematosus, chickenpox, and urticaria. At least one thrombophilic factor or elevated lipoprotein a [Lp(a)] was detected in 36 LV patients. Most LV patients had been previously treated with anticoagulants and antiplatelet drugs, intrave- nous immunoglobulin, glucocorticoid, immunosuppressive agents, and danazol. However, responses were generally poor and patients often suffered relapses after withdrawal of medications.
3.2 | Efficacy of rivaroxaban
Among the 73 LV patients treated with rivaroxaban, five patients discontinued treatment, 60 patients had effective responses with few adverse events, and eight patients showed insufficient efficacy; among the lattermost group, eight patients received backup therapy with enoxaparin.8,14 Thus, rivaroxaban was effective in 82.2% (60/73) of LV patients. Treatment was effective in both LV patients with and without thrombophilic factors or elevated Lp(a). In most LV patients, rivaroxaban therapy rapidly produced pain relief, which was followed by improvement of ulcerations. Pain was relieved within 1 week at the earliest following rivaroxaban therapy in LV patients.5,10 Remission of skin ulcerations lasted from 4 weeks to 5 months. A multicenter, single-arm, open label, phase 2a, proof-of- concept trial registered in the Cochrane database showed that the visual analogue scale for evaluation of median pain improved from 65 at baseline to 6 following rivaroxaban therapy.14 However, there were some examples of poor responses, and two LV patients even reported increased frequency of ulceration following rivaroxaban treatment.
3.3 | Dosage and duration
The most common dose of rivaroxaban was 10–20 mg per day. In some cases, a dose of 20 mg per day was used for initial treatment, then tapered to 10 mg per day for maintenance. The duration of rivaroxaban therapy for LV varied from 2 to 14 months. Drerup et al. demonstrated that prolonged administration of rivaroxaban for up to 14 months was effective in preventing LV recurrence.15 Among the 73 LV patients treated with rivaroxaban, 65 received monotherapy. Seven LV patients received rivaroxaban and enoxaparin (1 mg/kg)14,15 and one patient received rivaroxaban with 8 mg methylprednisolone and pentoxyfilline.12 Patients who required salvage therapy preferred oral rivaroxaban compared with enoxaparin subcutaneous injection.14 The frequency of enoxaparin salvage therapy was gradually reduced during rivaroxaban therapy.
3.4 | Recurrence
Recurrences were reported in 13 LV patients. Ten LV patients had relapses of skin lesions at a median of 24.9 weeks after discontinuing treatment; there was a tendency for recurrence to occur during the summer.17 One patient suffered from recurrent pain and ulcerations within 1 week of withdrawal of rivaroxaban for potential adverse events or drug interactions (sleepiness).10 Another patient experi- enced relapse in the summer about 8 months after stopping rivaroxaban.16 Relapse and exacerbation occurred in most LV patients after suspending treatment. However, one LV patient developed recurrence related to overwork and occupational stress during rivaroxaban therapy.12 However, this patient recovered soon after and his skin lesions were stable for another 11 months.12 During follow-up, the longest interval without recurrence was 23 months.
3.5 | Adverse events
Approximately 24% of patients (6/25) had side effects related to rivaroxaban treatment in the multicenter, single-arm, open label, phase 2a, proof-of-concept trial.14 The most common side effects of rivaroxaban among LV patients, menorrhagia, and excessive menstru- ation, were identified in three studies.8,14,17 A serious adverse reac- tion requiring pause of rivaroxaban therapy occurred in one LV patient with endometriosis and menorrhagia.14 The main side effects were symptoms related to increased risks of bleeding, including hemarthrosis, nose bleeding, gingival bleeding, bleeding during dental procedures, and bleeding from minor wounds.8,14,17 Other rare adverse events of rivaroxaban therapy such as dysmenorrhea and dys- pnea have been identified.
Other reported events were potentially related to rivaroxaban dose or drug interactions. One LV patient suffered from malaise, sweating, and headache when administered a dose of 10 mg rivaroxaban twice a day.16 These symptoms relieved spontaneously after tapering the rivaroxaban dose to 10 mg per day. Another LV patient initiated rivaroxaban therapy at 20 mg per day in combination with long-term oral administration of pregabalin. This regimen led to sleepiness, which was considered to be associated with drug interac- tions and was resolved by reducing the rivaroxaban dose to 10 mg per day and then escalating it to 20 mg per day 2 months later.
4 | DISCUSSION
LV is an entity with complex mechanisms. Hypercoagulability plays a major role in its pathogenesis. Hereditary and acquired thrombophilic factors such as single nucleotide polymorphisms in coagulation- related genes, abnormalities in protein C, protein S, and antithrombin III, and elevated Lp(a) have been observed in LV patients.20 In general, there is strong evidence that treatment with anticoagulants and anti- platelet drugs can improve circulation within dermal vessels in LV patients.3
In this systematic review, almost 50% of LV patients (36/73) had at least one thrombophilic factor or elevated Lp(a). In the remaining patients, LV might have been idiopathic or thrombophilic factors may have been missed during screening. Notably, rivaroxaban therapy was effective in 82.2% of LV patients. Treatment was effective in both LV patients with thrombophilic factors or elevated Lp(a) as well as in those with idiopathic disease. Pain in LV patients is believed to be caused by ischemia of dermal blood vessels. This explains the efficacy of rivaroxaban in producing rapid pain relief, followed by later ulcera- tion improvements. LV is a chronic and recurrent vascular disease with a tendency to become exacerbated during the summer. Long- term rivaroxaban therapy for maintenance was effective in preventing recurrence. The longest interval without recurrence was 23 months.
Rivaroxaban competitively inhibits factor Xa by reversibly and directly binding to factor Xa without the requirement for any other cofactors. Rivaroxaban shows over 10,000 fold selectivity for factor Xa compared with other serine proteases.21 Rivaroxaban was approved for treatment of thrombotic diseases and secondary pro- phylaxis after total knee or hip replacement surgery.4 Rivaroxaban also induced promising responses in LV patients both with and with- out thrombophilic factors. Compared with other anticoagulants used for treatment of LV, such as low molecular weight heparin and war- farin, rivaroxaban has two advantages in addition to its favorable efficacy. One is the possibility for oral administration rather than subcutaneous injection. Another is convenience for both patients and physicians, as there is no need to monitor the international nor- malized ratio.
One of the most common adverse events of rivaroxaban is increased risk of bleeding. In this systematic review, bleeding risk was mainly reflected in menorrhagia and excessive menstruation. The one case of a severe adverse event was menorrhagia with concomitant endometriosis. No evidence of visceral organ hemorrhage has been observed in LV patients treated with rivaroxaban. Comparison of the bleeding risks of rivaroxaban and warfarin showed that rivaroxaban had reduced risks of overall, gastrointestinal, and intracranial major bleeding in patients with unprovoked venous thromboembolism.22 A few cases of rivaroxaban-induced hepatotoxicity have been docu- mented. Liver damage was classified as hepatocellular, cholestatic, or mixed; hepatocellular was the major type.23 Although rarely empha- sized, hair loss caused by rivaroxaban has been reported, although alo- pecia often occurred during therapy with other anticoagulants such as heparin and vitamin K antagonists. A 26-year-old woman experienced severe hair loss after 3 months of rivaroxaban treatment for pulmo- nary embolism. Her hair loss resolved spontaneously after pausing medication.
Compared with vitamin K antagonists, rivaroxaban has a relatively low number of drug interactions. Cytochrome P450 (CYP) 3A4, CYP2J2, and P-gp are the major pathways that influence exposure to rivaroxaban. Azole antimycotics and antiviral drugs may interact with rivaroxaban and interfere with its metabolism.4 However, there are no reports of interactions with pregabalin except for the one case report mentioned above.
In reviewing articles on rivaroxaban treatment of LV patients, sev- eral hypotheses and assumptions became apparent. First, LV has a tendency to become aggravated during summer. Previous studies showed that prolonged administration of rivaroxaban could reduce recurrence of LV. Therefore, whether intermittent rivaroxaban ther- apy can be used in LV patients in the long term remains unclear. One possibility might be to start rivaroxaban administration in the summer or increase dosage in the summer to prevent recurrence. Second, LV mainly affected young and middle-aged women. Menorrhagia and excessive menstruation were the most common adverse events reported in LV patients treated with rivaroxaban. The single severe adverse effect reported was menorrhagia with concomitant endome- triosis. Thus, depending on the severity and activity of LV, rivaroxaban therapy may be paused or the dosage reduced during menstrual periods to prevent adverse events.
There were some limitations to this systematic review. Case reports and case series were the main sources of data contributing to the analysis. Some LV cases with poor responses to rivaroxaban might not have been reported. The absence of a control group in the one clinical trial included also complicates interpretation of the relatively high effectiveness of rivaroxaban in LV patients.
5 | CONCLUSION
In this systematic review, we found that rivaroxaban dosed at 10– 20 mg per day was effective in 82.2% of LV patients both with and without thrombophilic factors. Prolonged therapy was effective in preventing recurrence. Although a phase 2a clinical trial has been car- ried out, experiences and perspectives on rivaroxaban therapy for LV patients are still limited. This review provides support and clinical evi- dence for use of rivaroxaban for treatment of LV patients. However, our results should be confirmed by large prospective and/or case con- trol studies.
ACKNOWLEDGMENT
This study was funded by National Natural Science Foundation of China (81773331), National Natural Science Foundation of China (82073450) and National Key Research and Development Program of China (2016YFC0901500).
CONFLICT OF INTEREST
The authors declare no conflict of interest.
DATA AVAILABILITY STATEMENT
Data sharing not applicable.
ORCID
Yimeng Gao https://orcid.org/0000-0002-3717-224X
Hongzhong Jin https://orcid.org/0000-0001-6234-1554
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