Clinical trial NCT02704598: Comparison Between Xarelto Versus Warfarin in the Recanalization Rate of Deep Venous Thrombosis in Patients Legs.
Official title: Comparison of the Recanalization Rate and Incidence of Postthrombotic Syndrome in Patients With Lower-limb Deep Venous Thrombosis Treated With Rivaroxaban or Warfarin
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Deep Venous Thrombosis
Lead sponsor: Hospital do Servidor Publico Estadual
Sponsor class: OTHER
First posted: 2016-03-10
Enrollment: 84
Sex: ALL
Minimum age (years): 21
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: This is a prospective, randomized study, aiming to evaluate patients with Deep Venous Thrombosis in lower limbs and the recanalization rates evaluated with DUPLEX ultrasound, as so the clinical outcomes in patients submitted to oral anticoagulation with Rivaroxaban versus Warfarin.

Detailed description: This study was approved by the Research Ethics Committee of the Hospital do Servidor Público Estadual, São Paulo, Brazil, and was registered at clinicaltrials.gov under NCT 02704598. This prospective, randomized, consecutive, double-blind cohort study included patients treated for acute iliofemoral and/or femoropopliteal DVT of a lower limb at the Division of Vascular and Endovascular Surgery, Hospital do Servidor Público Estadual, São Paulo, Brazil, between march 2016 and July 2018. The patient data were collected during an appointment at the routine follow-up, and recorded with the proper protocols. The data obtained included the patient's general and demographic characteristics, and the information recorded during the outpatient follow-up visits. This research received no specific funding.

The noninclusion criteria were: pregnancy, age \< 18 years or \> 80 years, chronic renal failure, chronic hepatic chronic failure, inferior vena cava thrombosis, contraindication for any type of anticoagulation, previous DVT on the ipsilateral affected limb, or any type of active cancer, and patients who refused to participate in the study.

The exclusion criteria were: several hemorrhagic complications that required the discontinuation of anticoagulation, death after \< 30 days, allergic reaction to any anticoagulant, a diagnosis of active cancer during follow-up, loss to follow-up, difficulty in achieving proper anticoagulation due to patient nonadherence to the treatment protocol, and incomplete data.

The diagnosis of DVT was made with clinical signs and symptoms, laboratory tests such as D-dimer, and routine DUS of the affected limb. The criteria used to confirm acute DVT with DUS were the absence or diminution of venous flow, incompressibility of the vessel, visible thrombus, enlarged vein diameter, immobility of the valves, and loss of respiratory phasicity.13 All the patients diagnosed with acute DVT were hospitalized and received initial anticoagulation with subcutaneous enoxaparin (1 mg/kg/dose) every 12 h (12/12 h) or intravenous unfractionated heparin (IUH) (loading dose 80 UI/kg, and 18 UI/kg/h) for at least 48-72 h. The infusion dose of IUH was adjusted to achieve the therapeutic activated partial thromboplastin time (APTT) established by the hospital laboratory within every 4-6 h period. After initial admission, the patients were randomized into two groups: group 1 patients received oral rivaroxaban, with a loading dose of 15 mg 12/12 h for 21 days after the initial dose, and 20 mg/day for 6 months; group 2 patients received oral warfarin, sufficient to maintain an INR of 2-3 for 6 months. The patients in group 2 were kept in hospital on subcutaneous enoxaparin or intravenous unfractionated heparin until their INR was 2-3. The patients were discharged after their INR achieved the therapeutic dose.

During the follow-up visits, all the patients were subjected to a DUS analysis by a physician blinded to the type of drug therapy, with defined protocols that assessed the compressibility of the external iliac vein, common femoral vein, superficial femoral vein, and popliteal vein. Flow recanalization was evaluated by confirming the total vein flow, the partial vein flow, or the absence of vein flow. All vessels evaluated were tested for the absence or presence of reflux and the grade of reflux.

The following ultrasound criteria were used to determine absence of recanalization flow: partial compressibility of the vein, diminution of the vessel diameter, heterogeneous and hyperechoic thrombus, multiple channels of flow inside the veins, reflux, and collateral circulation.13 All the patients were followed-up with outpatient visits at 1, 3, 6, and 12 months after discharge. The following information was recorded at each visit: physical examination, DUS and laboratory tests, such as D-dimer, for all patients, and INR for patients receiving warfarin. The patients in group 2 were seen once a week to ensure that their INR remained at 2-3 and to confirm adequate anticoagulation. At the physical examination, the thigh was measured with a tape measure in the medium segment and the legs in the proximal segments, to record their diameters, in order to objectively assess the improvement in the swelling and edema of the leg.

A diagnosis of PTS was made with the Villalta scale when the patient's symptoms had remained unresolved for 6 months after treatment.9 The scale's components (five symptoms and six signs) are each rated on a 4-point severity scale, and the points are summed to produce a total score. A score \> 4 indicates PTS. The five symptoms (pain, cramps, heaviness, pruritus, and paresthesia) were assessed by patient self-report, and the six signs (edema, skin induration, hyperpigmentation, venous ectasia, redness, and pain during calf compression) by a clinician. The severity of each symptom and sign was rated as 0 (absent), 1 (mild), 2 (moderate), or 3 (severe). These were summed to yield the total Villalta PTS score: 0-4, no PTS; 5-9, mild PTS; 10-14, moderate PTS; ≥ 15 or presence of an ulcer, severe PTS.

The purpose of this study was to examine the long-term outcomes (after 12 months) in two groups of patients after treatment for DVT, by comparing the DUS-detected recanalization rates and the occurrence of PTS. The secondary end-points of the analysis were the prevalence of pulmonary embolism, death, complications of treatment, and DVT relapse.

The statistical analyses were performed with SPSS 15.0 for Windows® (SPSS Inc., Chicago, IL), as percentages of patients and descriptive statistics. The χ2 test and Student's t test were used to compare univariate data and differences between groups. Linear and Cox's regressions were used in the univariate and multivariable analyses, and the results are reported as adjusted hazard ratios (HRs) with the accompanying 95% confidence intervals (CIs). ANOVA and a post hoc test were used in the analysis of groups. In all analyses, p values of \< 0.05 were considered statistically significant.

Eligibility criteria: The noninclusion criteria were: pregnancy, age \< 18 years or \> 80 years, chronic renal failure, chronic hepatic chronic failure, inferior vena cava thrombosis, contraindication for any type of anticoagulation, previous DVT on the ipsilateral affected limb, or any type of active cancer, and patients who refused to participate in the study.

The exclusion criteria were: several hemorrhagic complications that required the discontinuation of anticoagulation, death after \< 30 days, allergic reaction to any anticoagulant, a diagnosis of active cancer during follow-up, loss to follow-up, difficulty in achieving proper anticoagulation due to patient nonadherence to the treatment protocol, and incomplete data.

Primary outcomes:
measure: the long-term outcomes (after 12 months) in two groups of patients after treatment for DVT, by comparing the DUS-detected recanalization rates and the occurrence of PTS.
timeFrame: 6 months after the diagnosis of deep venous thrombosis.
Secondary outcomes:
measure: Clinical Signs and Symptoms in 84 patients..
timeFrame: 6 months the diagnosis of deep venous thrombosis.
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: Hospital do Servidor Público Estadual de São Paulo
state: SP
Study officials:
affiliation: Hospital do Servidor Publico Estadual
name: Rafael Athayde Soares, MD, Dr/
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rivaroxaban (Xarelto): Treatment of Venous Thromboembolic Events (Deep Vein Thrombosis [DVT], Pulmonary Embolism [PE]) and Prevention of Recurrent DVT and PE [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2015 Aug. Available from http://www.ncbi.nlm.nih.gov/books/NBK344331/
citation: Isaacs AN, Doolin M, Morse C, Shiltz E, Nisly SA. Medication utilization evaluation of dabigatran and rivaroxaban within a large, multi-center health system. Am J Health Syst Pharm. 2016 Mar 1;73(5 Suppl 1):S35-41. doi: 10.2146/sp150031.
citation: Finks SW, Trujillo TC, Dobesh PP. Management of Venous Thromboembolism: Recent Advances in Oral Anticoagulation Therapy. Ann Pharmacother. 2016 Jun;50(6):486-501. doi: 10.1177/1060028016632785. Epub 2016 Feb 25.