Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism – the J-EINSTEIN DVT and PE program

The J-EINSTEIN DVT and PE program had an open-label, randomized design and compared 3, 6, or 12 months of rivaroxaban with UFH and warfarin in patients older than 20 years who had acute, objectively confirmed symptomatic proximal DVT and/or PE. Patients were excluded if they had received heparin or fondaparinux treatment for longer than 48 hours or more than a single dose of warfarin. Other exclusion criteria were: thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent for the current episode; any contraindication listed in the local labeling of UFH or warfarin or another indication for the use of UFH or warfarin; a creatinine clearance <30 ml/min; significant hepatic disease or alanine aminotransferase >3 times the upper limit of normal; bacterial endocarditis; active bleeding or a high risk of bleeding contraindicating treatment with UFH or warfarin; a systolic blood pressure of more than 180 mm Hg or a diastolic blood pressure of more than 110 mm Hg; childbearing potential without proper contraceptive measures, pregnancy, or breast-feeding; concomitant use of strong cytochrome P450 3A4 inhibitors (i.e. azole-antimycotics or HIV protease inhibitors); and a life expectancy of less than 3 months.

The program was sponsored by Bayer Yakuhin Ltd, Japan. The protocols were approved by the local institutional review boards, and written informed consent was obtained from all patients. The data were collected and maintained by Bayer Yakuhin. An independent data and safety monitoring board periodically reviewed outcomes. A central independent committee whose members were unaware of treatment allocation assessed all baseline and repeat imaging tests and all suspected efficacy and bleeding events.

DVT-only patients received rivaroxaban 10 mg or 15 mg twice daily for a total of 3 weeks in a double-blind fashion, followed by open-label rivaroxaban 15 mg once daily. All PE patients (with or without DVT) received rivaroxaban 15 mg twice daily for 3 weeks followed by 15 mg once daily. Patients assigned to control treatment received intravenous UFH, with the dose adjusted to prolong the activated partial thromboplastin time to 1.5–2.5-fold that of controls, for at least 5 days, overlapping with and followed by INR (range 1.5–2.5)-titrated warfarin. UFH was discontinued when the INR was 1.5 or more for two consecutive measurements at least 24 hours apart. Initially, the INR was measured every 2–3 days and, when stable, at least once per month. Treatment was continued for 3, 6, or 12 months, as decided by the treating physician. The use of non-steroidal anti-inflammatory drugs and antiplatelet agents was discouraged [ 14]; however, both acetylsalicylic acid (up to 100 mg per day) and clopidogrel (up to 75 mg per day) were allowed.

Randomization was done centrally, using an interactive web response system, with a rivaroxaban to control ratio of 4:1. Randomization was stratified for DVT or PE and the intended treatment duration. In addition, rivaroxaban patients with DVT only were further allocated in a 1:1 ratio to the two different rivaroxaban regimens for the first 3 weeks.

Patients were followed-up for the intended treatment duration and seen at fixed intervals that were identical between treatment groups. At each visit, a checklist was used to elicit information on signs and symptoms of recurrent VTE, bleeding, and adverse events. Patients were instructed to report to the study center immediately if any of these events occurred. In case of clinically suspected recurrent VTE, objective testing was required. Venous compression ultrasound and spiral computed tomography (CT) were repeated at day 22 and at the end of the 3-, 6-, or 12-month intended treatment period.

Patients were assessed for the occurrence of symptomatic recurrent VTE or asymptomatic deterioration. Symptomatic VTE was defined as symptomatic DVT or symptomatic fatal or non-fatal PE, as previously described [ 12]. PE was considered as the cause of death if there was objective documentation, or if death could not be attributed to a documented cause and PE could not be ruled out.

Venous ultrasound and spiral CT performed at day 22 and at the end of intended treatment were compared with baseline for changes. To allow for a quantitative assessment of the venous ultrasound, the residual diameters of the common femoral, superficial femoral, and popliteal veins were measured under full compression. Diameters obtained at day 22 and at the end of intended treatment were compared with baseline and scored as normalized, improved (i.e. a decrease of 4 mm or more), unchanged, or deteriorated (i.e. an increase of 4 mm or more) [ 15- 17]. To allow for a quantitative assessment of CT and perfusion lung scans, the percentage of vascular obstruction was calculated as described earlier [ 18- 22]. For each scan, an estimate was made of the remaining perfusion of each of the six lobes, which was expressed as 0 (no perfusion), 0.25, 0.50, 0.75, and 1.0 (normal perfusion). The total perfusion score was the sum of the remaining perfusion of all lobes, corrected with a factor of 0.45 for the left lung and 0.55 for the right lung to reflect the difference in lung size. The lobe scores of the repeat scans were scored as normalized, improved (i.e. the perfusion defect has decreased by more than 50% compared to the baseline scan), unchanged, or deteriorated (i.e. the lobe score decreased by more than 0.25 for any individual lobe. The combined repeat ultrasound and spiral CT result at day 22 and at the end of intended treatment was considered as normalized (no thrombus in legs and lungs), improved (improved results for both legs and lungs, or improved for either legs or lungs without deterioration), unchanged (unchanged results for both legs and lungs), deteriorated (any deterioration in either legs or lungs), or not evaluable.

Bleeding was defined as major if it was clinically overt and associated with a decrease in hemoglobin levels of 2.0 g per deciliter or more or a transfusion of 2 or more units of red blood cells; or if bleeding was intracranial or retroperitoneal in nature, occurred in another critical site, or contributed to death. Clinically relevant non-major bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of a study drug, or discomfort or impairment of activities of daily life [ 12].

All analyses were performed on the intention-to-treat population, with the exception of bleeding outcomes, which were evaluated for the period that patients were on study medication, plus 2 days. Crude percentages and absolute differences and their 95% confidence intervals were calculated. Confidence intervals for proportions and for difference in proportions were calculated using exact methods. The mean percentage of time during which the INR was in the therapeutic range was also calculated.