Rivaroxaban for the treatment of venous thromboembolism in real life: A single-center prospective study.

The clinical profile, evolution and complications of treatment with rivaroxaban in a cohort of patients presenting with venous thromboembolism (VTE) were analyzed in an observational, non-interventional and prospective study.A total of 111 patients were included in the study. Clinical data were collected from the medical history of the patients and recorded in a specific database.Mean age was 63.8 ± 17.4 years, 53.2% of patients were men, 55.9% had at least another concomitant condition, and 40.9% at least 1 VTE risk factor. 54.1% of patients presented with deep venous thrombosis, 32.4% with pulmonary embolism and 13.5% with both conditions simultaneously. The 61% of patients were admitted to hospital and mean hospital length-of-stay was 8.8 ± 9.9 days. After a mean follow-up 530 ± 464 days (median follow-up of 405 days), 3.9% of patients died and VTE recurrence occurred in 2.9% of patients. While receiving rivaroxaban, a first bleeding complication occurred in 8.1%; all events were minor bleeding.Our study supports the current literature data and confirms the similar results of real-life VTE patients with those enrolled in the rivaroxaban pivotal clinical trials. Rivaroxaban may facilitate outpatient treatment and might be considered as a first-line therapy for the management of VTE patients.

Introduction

Venous thromboembolism (VTE), that include deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major health care problem. Although the exact incidence of VTE is unknown, the estimated annual incidence rates of VTE among people of European ancestry range from 104 to 183 per 100,000 person-years.[ In addition, VTE is the third cause of vascular death after myocardial infarction and stroke.[ Moreover, the risk of recurrence among survivors is approximately 10% per patient during the first year after the event and the costs associated with VTE are considerable.[

The treatment of choice for VTE is anticoagulation.[ Traditionally, standard therapy comprised low-molecular-weight heparin (LMWH) followed by vitamin K antagonists (VKA).[ However, the introduction of direct oral anticoagulants (DOACs) in clinical practice may have changed this pattern,[ due to the advantages of DOACs over VKA.[

Rivaroxaban is a once-daily direct factor Xa inhibitor indicated for the management of VTE.[ In the EINSTEIN-DVT study, rivaroxaban was as effective and safe as standard therapy for acute treatment of symptomatic DVT.[ In the continued-treatment study, compared with placebo, rivaroxaban 20 mg once daily was superior in terms of efficacy, without a significant increase in the risk of major bleeding.[ In the EINSTEIN-PE study that included patients with acute symptomatic PE with or without DVT, rivaroxaban was noninferior to standard therapy (enoxaparin followed by VKA) with regard to the risk of symptomatic recurrent VTE. However, treatment with rivaroxaban was associated with a lesser risk of major bleeding.[ In the pooled analysis of both studies, rivaroxaban had a similar efficacy than standard therapy, but importantly, with a lesser risk of major bleeding.[ Besides, lower doses of rivaroxaban have shown efficacy in the prevention of VTE in the extended phase (beyond the first 3–6 months).[

The strict inclusion/exclusion criteria of clinical trials may limit the external validity of these studies.[ In this context, observational studies may provide relevant information and may help to establish the effectiveness and safety of a drug in routine practice. To date, only a small number of studies, many of them with a retrospective design, analyzing the use of rivaroxaban in VTE patients in clinical practice have been published and more information is warranted.[

The objective of this study was to analyze the clinical profile, evolution, and complications of treatment with rivaroxaban in a cohort of patients presented with VTE.

Methods

This was an observational, non-interventional and prospective study. All patients with a diagnosis of VTE treated with rivaroxaban and admitted in the VTE unit of the Internal Medicine department of University Hospital Gregorio Marañon between January 2014 and September 2017 were consecutively included. The local Clinical Research Ethics Committee of the hospital approved this study. Informed consent was obtained from patients prior to the inclusion in the study.

Clinical data were collected from the medical history of the patients and recorded in a specific database. Biodemographic data, cardiovascular risk factors, cardiovascular disease, other concomitant conditions, type of VTE (DVT, PE or both) and VTE risk factors were recorded. In addition, dose and duration of treatment with rivaroxaban were also collected. Diagnosis of VTE was established with venous doppler ultrasound or computed tomography (CT) for DVT and CT contrast angiography or ventilation/perfusion scintigraphy for PE. Patients follow-up was performed in the VTE clinic.

Data about hospitalizations, VTE recurrence, bleeding (severity and origin) and mortality during the follow-up were analyzed. The risk of bleeding was calculated according to the RIETE (0 points: low risk; 1 to 4 points: intermediate risk; >4 points: high risk) and the HAS-BLED scores (0 points: low risk; 1 to 2 points: intermediate risk; ≥3 points: high risk).[ Whether patients met inclusion criteria for the EINSTEIN studies was also analyzed.[

The dose of rivaroxaban was adjusted to the recommendations for patients with VTE according to the drug data sheet.

Statistical analysis

Qualitative variables were expressed as absolute and relative frequencies, and quantitative variables were expressed as measures of central tendency and dispersion (mean and standard deviation [SD] or median and interquartile range [IQR] in the case of variables with a non-normal distribution). To compare proportions, the chi-square test or Fisher test were used, according to the sample size. To compare 2 means, the Mann–Whitney U test was performed. Statistical significance was set at a P value < .05. The statistical analyses were performed using SPSS 19.0 (SPSS Inc., Chicago, IL).

Results

A total of 111 patients were included in the study (all patients had a history of VTE, received rivaroxaban at some point and were follow-up regardless patients remained on rivaroxaban). Mean age was 63.8 ± 17.4 years (53.2% men). The 54.1% of patients presented with DVT, 32.4% with PE, 13.5% with both conditions simultaneously. 61% of patients were admitted to hospital. VTE risk factors are presented in Table 1. The 40.9% of patients had at least one VTE risk factor with 59.1% of the events being unprovoked. Seven patients (6.3%) had cancer, all of them with a different origin. The origin of the cancer was as follows: breast, stomach, pancreas, bladder, prostate, hematologic, and biliary. Baseline characteristics of the sample are available in Table 1.

Table 1

Baseline clinical characteristics of the study population (n = 111).

Overall, 71.7% (n = 79) of patients received rivaroxaban during the acute phase (first 10 days) of VTE, 95.5% (n = 106) as long-term therapy (from day 10 onwards), and 10.8% (n = 12) after suffering complications (bleeding or recurrence). In 26.4% of patients low-molecular-weight heparin were used, mainly during the acute phase or after complications. Overall, mean duration of treatment with rivaroxaban was 5.5 ± 9.5 months. Patients were followed-up regardless of the duration of rivaroxaban therapy. In 10 patients, treatment with fibrinolytic drugs was required and in 1 patient mechanical thrombectomy and in other patient pulmonary embolectomy were performed.

After a mean follow-up 530 ± 464 days (median follow-up of 405 days), 3.9% of patients died. The causes of death were: infection (1.8%), heart failure (0.9%) and liver failure (0.9%). VTE recurrence was observed in 2.7% of patients (DVT in 2 patients and superficial vein thrombosis in 1 patient). None of the patients with VTE recurrence were receiving anticoagulants. As a result, VTE recurrence was not associated with failure of anticoagulant treatment.

A first bleeding complication occurred in 8.1% while receiving rivaroxaban; all events were minor bleeding. Bleeding events similarly occurred in DVT and PE patients, regardless treatment with rivaroxaban. Overall, major bleeding occurred in 2 cases during the study period (1 patient was taking acenocumarol and the other enoxaparin). The number of patients with a bleeding event according to the RIETE and HAS-BLED scores was shown in Table 2. Bleeding events were independent of the RIETE score (P = .52) or HAS-BLED score (P = .094). In 26.7% of the cases the bleeding had a gastrointestinal origin, in other 26.7% the urinary tract, in 13.3% epistaxis, and in other 13.3% menorrhagia. A second hemorrhage occurred in 3 patients (1 patient was taking rivaroxaban, another patient acenocumarol and the last one clopidogrel). None of these were major bleeding.

Table 2

Number of patients with a bleeding event according to the RIETE and HAS-BLED scores.

Overall, 91 patients (82%) met all the inclusion criteria for the EINSTEIN studies and 20 patients (18%) had at least 1 exclusion criteria. VTE recurrence (P = .48) and total bleeding events (P = .34) were independent of patients met inclusion criteria for the EINSTEIN studies. However, the 2 cases of major bleeding occurred in patients with any exclusion criteria (vs 0 in patients who met all the inclusion criteria; P = .057). None of the patients with major bleeding were taking rivaroxaban.

Discussion

In this prospective study, a wide cohort of patients presented with VTE, either DVT or PE, treated with rivaroxaban in a VTE unit of a tertiary hospital was analyzed. Mean age was 64 years and 56% of patients had at least another concomitant condition at the moment of VTE. Similarly, in other studies performed in “real-life” patients with VTE and treated with rivaroxaban, mean age was 58 to 62 years and patients had a low prevalence of concomitant diseases.[ Recent data from the RIETE study have shown that among patients with VTE, LMWH is the most frequently used drug as initial therapy in France, Italy and Spain.[ These data suggest that despite clinical trials have shown that rivaroxaban exhibit a better benefit-risk profile than standard therapy in a wide spectrum of the VTE population (only 18% of our patients did not meet criteria to be included in the EINSTEIN studies),[ and that in contrast to some other DOACs, rivaroxaban can be used in the acute setting without parenteral anticoagulation,[ the use of rivaroxaban in this context is still low and limited to some type of patients. This may be related with the lack of reimbursement of rivaroxaban for this indication in Spain.

In our study, 61% of patients with VTE were admitted to hospital. Despite in the last years it has been reported an increase in the incidence of hospitalized PE patients,[ in a recent study of VTE patients treated with rivaroxaban, only 48% of patients were hospitalised.[ In addition, different studies have shown that treatment with rivaroxaban could be associated with a reduction of hospital length-of-stay among VTE patients compared with standard therapy.[ These data suggest that treating VTE patients with rivaroxaban could facilitate outpatient management and in case of admission, hospital length-of-stay could significantly be reduced and secondarily, this translates into cost savings.

In our study, after a mean follow-up of 530 days, only 3.9% of patients died, and VTE recurrence occurred in 2.9% of patients. Remarkably, among anticoagulated patients, no VTE recurrence occurred. While receiving rivaroxaban, a first bleeding complication occurred in 8.1%, with no major bleeding events. Remarkably, bleeding events were independent of the RIETE or HAS-BLED scores, and no major bleeding occurred while taking rivaroxaban. Data from the RIETE registry have shown that risk-adjusted rates of all-cause mortality have decreased from 6.6% in the first period (2001–2005) to 4.9% in the last period (2010–2013), mainly due to improvements in the management of these patients,[ However, there is much room for improvement, and rivaroxaban could be of help in this context. Thus, in XALIA, a multicenter, prospective, noninterventional, and observational study, the risk of major bleeding (0.8%) and VTE recurrences (1.4%) with rivaroxaban was low.[ In addition, it has been shown that in routine practice, VTE patients who continue rivaroxaban therapy after the initial 3- or 6-month treatment period have a significantly lower risk for VTE recurrence without significant increased risk for major bleeding.[ Other studies have confirmed the good results in clinical practice of rivaroxaban regarding effectiveness and safety in VTE patients, that are in accordance with those reported in the pivotal clinical trials.[

This study has some limitations due to the absence of a control group. Since this was an observational study, some bias could have not been controlled. However, in this prospective study, all patients presented with VTE in the unit were consecutively included. The main strength of this real-life survey is that the patients studied represent the actual population that will receive rivaroxaban in clinical practice. In addition, as all patients were treated in the same VTE unit, this may increase the homogeneity in the management of these patients. On the other hand, since this was a unicenter study, our results cannot necessarily be extended to other populations with a different clinical profile or management.

In this cohort of patients presented with VTE, either DVT or PE and treated with rivaroxaban, only 61% of patients were admitted to hospital and mean hospital length-of-stay was 8.8 days. After a mean follow-up of 530 days, only 3.9% of patients died and VTE recurrence occurred in 2.9% of patients. Among anticoagulated patients, no VTE recurrence occurred. Overall, a first bleeding complication occurred in 13.5% of patients during the whole follow-up period. In patients receiving rivaroxaban, a first bleeding complication occurred in 8.1%; all events were minor bleeding.

In conclusion, our study supports the current literature data and the similar results of real-life VTE patients with those enrolled in the rivaroxaban pivotal clinical trials. Rivaroxaban may facilitate outpatient treatment and should be considered as a first-line therapy for the management of VTE patients.

Author contributions

Conceptualization: Pablo Demelo-Rodríguez, Francisco Galeano-Valle, Irene García-Fernández-Bravo, Sandra Piqueras-Ruiz, Luis Álvarez-Sala-Walther, Jorge del Toro-Cervera.

Data curation: Pablo Demelo-Rodríguez, Francisco Galeano-Valle, Irene García-Fernández-Bravo, Sandra Piqueras-Ruiz.

Formal analysis: Pablo Demelo-Rodríguez, Francisco Galeano-Valle, Irene García-Fernández-Bravo.

Investigation: Pablo Demelo-Rodríguez, Francisco Galeano-Valle, Irene García-Fernández-Bravo, Sandra Piqueras-Ruiz, Luis Álvarez-Sala-Walther, Jorge del Toro-Cervera.

Methodology: Pablo Demelo-Rodríguez, Francisco Galeano-Valle, Irene García-Fernández-Bravo.

Project administration: Pablo Demelo-Rodríguez, Francisco Galeano-Valle, Irene García-Fernández-Bravo, Sandra Piqueras-Ruiz, Luis Álvarez-Sala-Walther, Jorge del Toro-Cervera.

Resources: Pablo Demelo-Rodríguez, Francisco Galeano-Valle, Irene García-Fernández-Bravo, Sandra Piqueras-Ruiz, Luis Álvarez-Sala-Walther, Jorge del Toro-Cervera.

Software: Pablo Demelo-Rodríguez, Francisco Galeano-Valle, Irene García-Fernández-Bravo.

Supervision: Pablo Demelo-Rodríguez, Jorge del Toro-Cervera.

Validation: Luis Álvarez-Sala-Walther.

Writing – original draft: Pablo Demelo-Rodríguez, Francisco Galeano-Valle, Irene García-Fernández-Bravo, Sandra Piqueras-Ruiz.

Writing – review & editing: Luis Álvarez-Sala-Walther, Jorge del Toro-Cervera.