For decades, deep vein thrombosis (DVT), as well as superficial vein thrombosis and pulmonary embolism (PE) combined into venous thromboembolism (VTE) group, has been considered a significant medical problem with a substantial social and economic burden [1]. According to the official statistics, the incidence of DVT in Russia remained stable in 2012—2016, accounting for 1.5—1.6 cases per 1000 population per year [2—4], which is consistent with the worldwide epidemiological data estimating DVT incidence from 0.05 (Asia) to 1.6 (Western Europe) cases per 1000 population per year [1]. The economic burden of DVT is not limited to the cost of initial treatment but also includes charges for therapy of recurrent VTE events, bleeding complications, repeated hospitalizations and disability [5]. It was accounted that VTE associated with inpatient treatment appears to be the leading cause of disability, getting ahead of nosocomial pneumonia, catheter-related bloodstream infections, and adverse drug events [6]. So, adequate prevention, safe and effective treatment for DVT is an important medical and social issue.

Anticoagulation is a primary method of treatment for VTE. Using parenteral heparins switched to vitamin K antagonists (VKA) was considered as a conventional approach for decades. It required several days of hospitalization for the initial dose adjustment of unfractionated heparin (UFH) and VKA. Confinement to bed during this period of treatment led to the thrombus propagation in 12—38% [7]. Early ambulation in comparison with bed rest did not increase the risk of PE but demonstrated a trend to reduce the incidence of thrombus propagation [8]. The maximal benefit of early ambulation was achieved with the use of low-molecular-weight-heparins (LMWH) in the outpatient setting. A meta-analysis of seven trials compared home treatment with LMWH and inpatient treatment predominantly with UFH showed no difference in bleeding risk and mortality, but a significant reduction of VTE recurrence by 42% with LMWH [9].

Later, direct oral anticoagulants (DOACs: rivaroxaban, apixaban, edoxaban, dabigatran) were introduced. In comparison with conventional treatment (LMWH/VKA) they provided a similar efficacy but increased safety [10]. Also, DOACs do not require an individual dose adjustment or laboratory monitoring, and some of them (rivaroxaban and apixaban) could be initiated since the VTE confirmed. All these advantages are very useful for treatment in outpatient settings. However, in most trials, therapy with DOACs was started in the hospital.

Several retrospective claims analyzes were published recently. They suggested that treatment of DVT with rivaroxaban in comparison with conventional therapy is associated with a lower rate of hospitalization [11], shorter hospital stay [12], less cost [13—15], and a smaller number of further hospital admissions if therapy was initiated at outpatient setting [15]. However, there is a lack of prospective data on the outpatient use of rivaroxaban [16].

The aim of this study was to assess the efficacy and safety of DVT treatment with rivaroxaban started and continued in the outpatient facility.

This is a retrospective analysis of prospectively collected data extracted from the electronic medical records (EMRs) in a private outpatient clinic MedSwiss (Moscow, Russia). The clinic provides medical care for patients who have one kind of paid medical insurance. It represents the first-line facility for primary medical access of any kind and secondary admission after discharge from the hospital. All relevant medical information is stored in the EMR and available for analysis. Patients with suspected or verified VTE or after discharge from the hospital can be admitted to phlebologist (KL, AV, LL) or non-phlebologist (general surgeon, orthopedic surgeon, cardiologist, pulmonologist or another internalist). Duplex ultrasound scan (DUS) can be performed in the office by phlebologist (KL and AV) or by regular specialist in ultrasound diagnostics. The decision on hospitalization is taken individually by each specialist; any local recommendations are currently unavailable.

We have searched for EMRs of patients who were admitted to the medical center with the diagnosis of DVT or PE according to the International Classification of Diseases version 10 (ICD-10) in 2017—2019 and selected those, who had no inpatient period of treatment, received rivaroxaban during the first 24 hours after DVT verification and had clearly documented outcomes in the EMR. The methodology of the search is represented in .

We studied eligible EMRs for the following outcomes: death, unscheduled hospitalization, recurrent DVT (symptomatic and asymptomatic; on anticoagulation and after cessation) and symptomatic PE, major, clinically relevant non-major (CRNM) and minor bleeding. If the patient had not attended the clinic for three months and more he was interviewed by phone to find out the continued use of anticoagulants, any episodes of recent hospitalizations, any evidence of recurrent VTE, or bleeding events. If the subject was not available by phone, the attempts to contact his employer and relatives to clarify the current status must be done. Death should be confirmed by appropriate medical documentation received from relatives or other medical facilities. Unscheduled hospitalization was defined as any emergent or urgent hospital admission for acute surgical or medical illness. Symptomatic DVT recurrence was defined as an appearance of new symptoms in the affected or unaffected lower limb and should be confirmed by DUS. Asymptomatic DVT recurrence was defined as the appearance of new lesions on unaffected vein segments or re-occlusion of previously recanalized venous segments as reported in EMR. Symptomatic PE was defined as the appearance of standard symptoms and should be confirmed by the appropriate radiological imaging as reported in EMR and attached hospital discharge summary. Major and clinically relevant non-major bleeding was defined according to the ISTH (International Society on Thrombosis and Hemostasis) criteria [17, 18]. Minor bleeding was defined as any other hemorrhagic complication reported in the EMR but did not fulfill the requirements of major or CRNM bleeding. In case of any reported bleeding event, the fact of anticoagulation interruption was analyzed.

The study on medical records does not require informed consent and Ethical approval according to the verification by Institutional Review Board of Pirogov Russian National Research Medical University. The study was performed without any funding.

. Due to the retrospective character of observation, preliminary sample size calculation was not required. The absolute values are represented as mean and standard deviation (mean±SD) in the normal data distribution or as median with an interquartile range of 25—75 percentile (IQR) in the abnormal data distribution. Relative values are represented as a percent with 95% confidential interval (CI) calculated by the Wilson method. Time-to-event represented with Kaplan-Meier curves. All calculations were performed in SPSS v.26.

Data covering for the period of 2017 to 2019 were extracted in January 2020, 118 EMRs of patients with VTE admitted to the clinic were identified. Isolated DVT was reported in 98 (83%) cases and DVT with PE — in 20 (17%) cases. Prior inpatient treatment was identified in 75 (64%) of 118 patients. 20 (27%) of 75 were diagnosed with PE. The decision for hospitalization was made by phlebologist in 3 (7%) of 46 admissions for DVT (no admissions for PE); by non-phlebologist in 48 of 48 admissions for VTE (16 of them for PE); by ambulance physician or physician from other facilities in 24 of 24 admissions for VTE (4 of them for PE). The only three patients who were hospitalized by phlebologists had an iliofemoral DVT with severe symptoms and were candidates for thrombus extraction. So the total rate of hospital admission for DVT without PE accounted for 55 (56%) of 98 patients.

Of the last 43 subjects who initiated and continued therapy in the outpatient setting, everyone was eligible for the final analysis . All of them were accessed by phlebologists. DVT was confirmed by DUS and anticoagulation was started immediately in the office with the only injection of enoxaparin (1 mg per kg of body weight). Twelve hours after that, patients were first switched to rivaroxaban 15 mg bid for three weeks, followed by 20 mg qd. They were followed with clinical and ultrasound examinations according to the standard schedule of one week, one, three, and six months, and every six months thereafter. After six months of therapy, the dose of rivaroxaban could be reduced to 10 mg. Compression therapy with above or below knee compression stocking (pressure of 23—32 mm Hg at the ankle) was recommended to all patients for at least six months. Longer compression was used in subjects who developed postthrombotic syndrome. The standard schedule of DVT assessment and treatment is represented in .

The analyzed data include outcomes in 26 men and 17 women with a mean age of 45.6±12.4; their clinical characteristics are represented in . Nine of 43 (21%) patients had an asymptomatic DVT that was revealed accidentally by DUS after trauma with plaster cast immobilization (=5), after surgical repair of leg bone fracture (=2), after major surgery (=1) and due to thrombotic alertness of the patient (=1). In symptomatic ones the duration of symptoms varied from several days to one month and more. About one-third of patients represented symptoms for less than one week, and about half — for less than one month. Of twelve subjects with an unidentified duration of symptoms, nine had an occult thrombus and three suffered from non-specific leg symptoms (pain and edema) for the period they could not define. Personal history for VTE was reported by 7 (16%) patients; none of them received antithrombotic therapy at the moment of admission; the persistent inferior vena cava filter was observed in one woman; time to previous VTE event varied from seven months to more than ten years. No patient had more than one VTE episode in the past.

Provoked DVT was observed in 29 (67%) of 43 patients. It was caused mainly by a transient major risk factor (trauma, immobilization, surgery). Cancer-associated thrombosis was revealed in two cases. One lady reported surgery for breast cancer two years before DVT manifestation and at the time of admission received hormonal treatment. Another male patient was diagnosed with colon cancer within one month after DVT verification. Distal and proximal thrombi were detected in 28 (65%) and 15 (35%) patients, respectively. The free-floating head was revealed on the popliteal vein (length of 18 mm) in one case and on the iliac vein (length of 22 mm) in another one. The last patient had a persistent IVC filter in the absence of severe symptoms of iliofemoral DVT, so it was decided to avoid hospitalization. The main comorbidities are represented in . No case of chronic renal insufficiency was reported. Twenty-two of 43 (51%) patients had no reported chronic diseases, 7 (16%) had only one comorbidity, and 14 (33%) had two to three comorbidities.

DVT — deep vein thrombosis; VTE — venous thromboembolism; IQR — interquartile range; SD — standard deviation.

The duration of treatment with rivaroxaban varied from 3 to 24 months (median of 3; the interquartile range 3—6 months). Anticoagulation for a limited time period was used in 36 (84%) patients and for unlimited in seven subjects (16%). Reduced doses of rivaroxaban were started in 7 (16%) patients at 3—18 months after index DVT. The duration of follow-up ranged from 3 to 26 months (median of nine; interquartile range 3—14 months).

No death, symptomatic PE, unscheduled hospitalization, or major bleeding was reported during the period of observation . Two of 43 patients developed CRNM bleeding (4.7%; 95% CI 1.3—15.2%), and three had minor bleeding (7.0%; 95% CI, 2.4—18.6%). Four of five bleeding events appeared in women and were represented by menometrorrhagia that repeated every month, and the last one — with minor spontaneous skin ecchymosis during the first month of treatment. Time-to-event is represented in . Two ladies with CRNM bleeding temporary interrupted anticoagulation to stop menstruation, and one developed previously unreported chronic anemia after three months of treatment. The anticoagulation was stopped at three months in both women. However, the lady with chronic anemia developed DVT recurrence within one month after cessation of therapy, so the anticoagulation was restarted and the intrauterine system with levonorgestrel was implanted to control the bleeding. After that, she is being under observation for 18 months without new hemorrhagic complications. The last two cases of metrorrhagia did not require interruption of anticoagulation. In one patient therapy was finished at three months, but another one requires treatment of undefined duration due to the personal history of VTE. She was referred to the gynecologist for the decision on hormonal control for bleeding.

DVT recurrence was observed in four patients (9.3%; 95% CI 3.7—21.6%). One DVT developed during temporary interruption of anticoagulation for cancer surgery and was represented with the occult previously undetected venous lesion of the contralateral limb revealed by the scheduled DUS. Three other events appeared at 1 to 12 months after anticoagulation cessation. It was one occult DVT on the contralateral limb revealed by scheduled DUS at two months after finishing therapy, and one symptomatic ipsilateral DVT in the lady with uterine bleeding who was mentioned above. The last recurrent DVT was provoked by pregnancy in a woman who had a previously unprovoked event and finished treatment at three months. Rivaroxaban was restarted in all patients except pregnant women. However, the last one decided to abort her pregnancy and was switched from LMWH to oral therapy. Time-to-event is represented in .

Previous trials of the III phase have shown that long-term treatment for VTE with rivaroxaban of 15 mg twice daily for three weeks switched to 20 mg once daily up to 12 months in comparison with proper controlled conventional treatment with LMWH/VKA demonstrated the same efficacy with reduced risk of major bleeding [19]. The prolonged treatment of DVT over 6—12 months with rivaroxaban 20 mg in comparison with placebo provided further risk reduction of recurrent DVT by 82% without increasing the risk of major bleeding [20]. In comparison with aspirin, both doses of 20 and 10 mg of rivaroxaban demonstrated a significant risk reduction of recurrent VTE by 66 and 74% respectively without increasing risk of major or CRNM bleeding during prolonged therapy [21]. The studies of real clinical practice have confirmed good efficacy and safety profiles of rivaroxaban and demonstrated a trend to the benefits of direct oral anticoagulants over conventional therapy in the lack of proper control [22—24]. However, all these trials suggested the initiation of anticoagulation in a hospital and did not allow us to reveal all the advantages of DOACs.

Evidence on the DVT treatment in an outpatient setting with DOACs is still lacking. A retrospective claims analysis demonstrated that introducing of rivaroxaban led to reduction of hospital admissions by 27% in propensity-score matched patients with DVT [11]. The other retrospective claims analysis revealed 512 subjects with DVT treated as outpatients and compared the results with a matched cohort of LMWH/VKA-treated patients according to the mean numbers of hospitalizations for all causes and VTE [15]. The results were in favor of rivaroxaban: the number of all-cause and VTE related hospital admissions was significantly lower. The only prospective trial has demonstrated the opportunity to use rivaroxaban in the outpatient facility [16]. Of 78 patients with confirmed DVT, 53 were treated as outpatients, and rivaroxaban was prescribed in 31 cases. The follow up was limited with three months and only 47% of patients were assessed by phone call. The hemorrhagic complications were recorded in 5 (9%) of 53 subjects.

Thus, our study is one of the few prospective observations on DVT outpatient treatment with rivaroxaban. The obtained figures correspond with the previously published results of DVT treatment with rivaroxaban or LMWH in the hospital or at home . However, our practice has some specifications. We do not use evaluation for the clinical probability of DVT with a combination of Wells score and D-dimer [25] due to the absence of express tests for D-dimer, that’s why we exclude any DVT by DUS. Due to the high alertness of traumatologists and orthopedic surgeons for possible VTE complications, we can observe a high rate of occult thrombosis and thrombus of unidentified duration among trauma patients. Our phlebologists usually see patients with isolated DVT, because subjects with suspected PE are usually referred to cardiologists, pulmonologists or another internists. As a result, the rate of hospitalization of DVT patients, prescribed by phlebologists, was very low compared with other physicians. Today we are working on the local protocol that suggests evaluation for the clinical probability of DVT by Wells score and D-dimer, start of anticoagulation by any physician before thrombus verification by DUS and referral of all patients with a high probability of DVT to phlebologist after receiving initial anticoagulation. That should allow to reduce the number of unnecessary hospital admissions.

Our approach for treating selected patients with rivaroxaban in outpatients facility seems to be safe and effective. Our selection criteria are quite similar to previously reported [26, 27]. We suggested hospital admission in patients with symptoms of PE or high risk for PE (proximal DVT with the history of PE, excessive free-floating thrombus), iliofemoral DVT with severe symptoms and who are candidates for surgical intervention, high risk for bleeding, severe comorbidities, projected low compliance with suggested therapy, social factors. We should highlight that our population contains highly socialized non-disabled patients of middle age with a low rates of comorbidities. Also, we started anticoagulation immediately after confirmation of DVT, and the first dose of enoxaparin was injected in the office under a physician’s control. Treated patients were able to contact the doctor in any case of emergency. And we have enough resources for frequent clinical and ultrasound follow up examination.

. The study is limited by its retrospective character, analysis of previously undesigned data from EMRs, low number of participants, high level of provoked distal DVT with unknown duration, a small amount proximal DVT cases, domination of patients with a low risk of complications. The results obtained could be supported by the fact that the medical center involved is a first-line clinic that provides medical care to outpatients having a single form of paid medical insurance. Thus, treatment of any complication would be carried out in this facility as an outpatient or after discharge and the EMRs would contain all relevant information with low risk of missing data.

Treatment for DVT with rivaroxaban in the outpatient settings may be safe and effective for selected patients without symptoms of PE. We need more studies to evaluate medical, and pharmaco-economical benefits of DVT treatment started at the outpatient facility and to identify patients who can utilize this approach without any additional risks.

Research concept and design — K.L., I.S., L.L.

Collection and processing of material — A.V., A.B.

Statistical data processing — K.L.

Writing a text — K.L.

Editing — I.S., L.L.