Mariko Kajikawa

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

BackgroundThe global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban.MethodsWe conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5–2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding.ResultsEighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, -3.4–23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group.ConclusionsThe findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program.Trial registrationClinicaltrials.gov: NCT01516840 and NCT01516814.

Rivaroxaban versus Warfarin in Japanese Patients with Nonvalvular Atrial Fibrillation for the Secondary Prevention of Stroke: A Subgroup Analysis of J-ROCKET AF

BACKGROUND The overall analysis of the rivaroxaban versus warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial revealed that rivaroxaban was not inferior to warfarin with respect to the primary safety outcome. In addition, there was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban compared with warfarin. METHODS In this subanalysis of the J-ROCKET AF trial, we investigated the consistency of safety and efficacy profile of rivaroxaban versus warfarin among the subgroups of patients with previous stroke, transient ischemic attack, or non-central nervous system systemic embolism (secondary prevention group) and those without (primary prevention group). RESULTS Patients in the secondary prevention group were 63.6% of the overall population of J-ROCKET AF. In the secondary prevention group, the rate of the principal safety outcome (% per year) was 17.02 in rivaroxaban-treated patients and 18.26 in warfarin-treated patients (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.70-1.29), while the rate of the primary efficacy endpoint was 1.66 in rivaroxaban-treated patients and 3.25 in warfarin-treated patients (HR 0.51; 95% CI 0.23-1.14). There were no significant interactions in the principal safety and the primary efficacy endpoints of rivaroxaban compared to warfarin between the primary and secondary prevention groups (P=.090 and .776 for both interactions, respectively). CONCLUSIONS The safety and efficacy profile of rivaroxaban compared with warfarin was consistent among patients in the primary prevention group and those in the secondary prevention group.

Shortened length of hospital stay with rivaroxaban in patients with symptomatic venous thromboembolism in Japan: the J-EINSTEIN pulmonary embolism and deep vein thrombosis program

Abstract Background: In Japan, the standard of care for the treatment of pulmonary embolism (PE) and/or deep vein thrombosis (DVT) consists of intravenous unfractionated heparin (UFH) followed by warfarin, which was recently compared with rivaroxaban, an oral factor Xa inhibitor, in randomized trials. Aim: To examine the length of hospital stay in patients with PE and/or DVT receiving rivaroxaban compared to Japanese standard therapy in the Japanese (J)-EINSTEIN PE and DVT program. Methods: Open-label, randomized clinical trials that compared 3, 6, or 12 months of rivaroxaban with UFH and warfarin in patients with acute, confirmed symptomatic proximal PE and/or DVT. Decisions regarding hospital admission and/or discharge were left to the clinical judgment of attending physicians. Analyses were conducted in the intention-to-treat (ITT) population. Results: In the ITT population (N = 97), overall patient characteristics were similar in both treatment arms. The median length of stay in rivaroxaban patients was 10.0 days (interquartile range [IQR] 6.0 to 15.0 days) while it was 15.0 days (IQR 9.0 to 22.0) for patients on standard therapy (p = 0.016). All of the four DVT patients who were not hospitalized for the index event were in the rivaroxaban arm. Conclusions: Our results suggest that treatment with rivaroxaban may significantly reduce the length of hospital stay in patients hospitalized for PE and/or DVT compared with the current standard of care in Japan, thereby reducing the burden on patients and the healthcare system. The limitations of our study include small sample size and the generalizability of the findings to the real-world setting. Further research is warranted to identify PE and/or DVT patients in Japanese clinical practice who may potentially be managed as outpatients. Trial registration: Clinicaltrials.gov: NCT01516814 and NCT01516840.

Net Clinical Benefit of Rivaroxaban versus Warfarin in Japanese Patients with Nonvalvular Atrial Fibrillation: A Subgroup Analysis of J-ROCKET AF

BACKGROUND The risk factors that have been identified for bleeding events with rivaroxaban are predominantly the same as those predicting thromboembolic ones in patients with atrial fibrillation (AF). Our aim was to determine the net clinical benefit (NCB) from the results of the J-ROCKET AF trial, in which rivaroxaban was compared with warfarin in Japanese patients with AF. METHODS Two strategies were adopted to quantify the NCB. First, the NCB was calculated as the number of ischemic strokes avoided with anticoagulation minus the number of excess intracranial hemorrhage (ICH) with a weight of 1.5. Second, the composite end point of major bleeding events and secondary efficacy end points (stroke, noncentral nervous system systemic embolism, myocardial infarction and death) to ascertain the NCB were established. Subgroup analysis by CHADS2 score or creatinine clearance was also performed. RESULTS The adjusted NCB, which was given a weight of 1.5 for ICH, was nominally significant in favor of rivaroxaban therapy (difference in incidence rate -2.13; 95% confidence interval [CI]: -.26 to -3.99). Furthermore, the event rate of the composite end point tended to be lower in patients treated with rivaroxaban than in those treated with warfarin (rivaroxaban: 4.97% per year, warfarin: 6.11% per year; difference in incidence rate: -1.14; 95% CI: -3.40 to 1.12). The event rate of the composite end point tended to be consistently low in patients treated with rivaroxaban in the subanalysis by CHADS2 score and renal function. CONCLUSION Analysis of the NCB supports that rivaroxaban therapy provides clinical benefit for Japanese patients with AF.

Long-term safety and efficacy of high-dose controlled-release nifedipine (80 mg per day) in Japanese patients with essential hypertension

High-dose calcium channel blocker (CCB) shows strong blood pressure (BP) lowering effect. Currently available of controlled-release (CR) nifedipine 80 mg per day clinical data are limited to monotherapy and short-term or long-term retrospective studies. We report the safety and efficacy results of a 52-week, prospective open-label study, in which Japanese patients with essential hypertension were treated with CR nifedipine [80 mg per day; 40 mg bis in die (BID; twice daily)] in combination with other antihypertensive drugs. The patients with inadequate BP control despite treatment with CR nifedipine (40 mg once daily) in combination with other antihypertensive drugs were enrolled. The primary objective of this study was to assess the long-term safety of CR nifedipine (80 mg per day). Efficacy variables included changes in the mean sitting BP, the target BP achievement rate and the BP response rate. CR nifedipine (80 mg per day) was generally well tolerated, with the most common drug-related treatment-emergent adverse event being tachycardia (6.9% of patients). Serious treatment-emergent adverse events were reported in three (4.2%) patients. By week 52, the mean reductions in sitting systolic and diastolic BP were 19.4 and 13.6 mm Hg, respectively. The target BP achievement and BP response rates after 52 weeks of treatment were 32.4 and 63.4%, respectively. Based on these findings, long-term treatment with CR nifedipine at 40 mg BID in combination with antihypertensive drugs was well tolerated and effective in Japanese patients with essential hypertension.

Rivaroxaban versus warfarin in Japanese patients with non-valvular atrial fibrillation in relation to hypertension: a subgroup analysis of the J-ROCKET AF trial

The majority of the patients enrolled in the rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial had hypertension. In this subgroup analysis, we investigated differences in the safety and efficacy of rivaroxaban and warfarin in subjects with and without hypertension. The baseline blood pressure (BP) measurements of patients with hypertension in the rivaroxaban and warfarin groups were 130/77 mm Hg and 131/77 mm Hg, respectively, whereas those of patients without hypertension were 123/74 mm Hg and 124/73 mm Hg, respectively. The incidence rates of the principal safety outcomes in the rivaroxaban and warfarin groups were 18.39% per year and 16.81% per year, respectively, among patients with baseline hypertension (hazard ratio (HR): 1.10; 95% confidence interval (CI): 0.84–1.45) and 16.71% per year and 15.00% per year, respectively, among patients without hypertension at baseline (HR: 1.14; 95% CI: 0.66–1.97), indicating no significant interaction (P=0.933). The incidence rates of the primary efficacy endpoints in the rivaroxaban group and the warfarin group were 0.54% per year and 2.24% per year, respectively, in patients without baseline hypertension (HR: 0.25; 95% CI: 0.03–2.25), and 1.45% per year and 2.71% per year, respectively, in patients with baseline hypertension (HR: 0.54; 95% CI: 0.25–1.16), indicating no significant interaction (P=0.509). In conclusion, the safety and efficacy profile of rivaroxaban was similar to that of warfarin, independent of baseline hypertensive status.

Predictive factors for bleeding during treatment with rivaroxaban and warfarin in Japanese patients with atrial fibrillation – Subgroup analysis of J-ROCKET AF

BACKGROUND Results from the J-ROCKET AF study revealed that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcomes in patients with non-valvular atrial fibrillation. This subgroup analysis evaluated whether non-major clinically relevant bleeding (NMCRB) could be a predictive factor for major bleeding (MB). Other predictive factors for MB were also obtained in both rivaroxaban and warfarin treatment groups. METHODS The temporal incidence of MB was compared between the rivaroxaban and warfarin treatment groups. Assessment was made whether MB events were often preceded by NMCRB. Univariate and multivariate analyses were carried out to identify any independent predictive factors for MB in both treatment groups. RESULTS The incidences of MB and NMCRB were 18.04% (138/639 patients) in the rivaroxaban arm, and 16.42% in the warfarin arm (124/639 patients). NMCRB preceded MB in only four patients in each treatment group (rivaroxaban: 4/117 and warfarin: 4/98). Multivariate analysis identified predictive factors for bleeding events: anemia with warfarin treatment and concomitant use of antiplatelet agents with rivaroxaban treatment. CONCLUSIONS Results from this subgroup analysis, particularly the fact that there was no repeated or sequential pattern between NMCRB and MB occurrences in both treatment groups, suggests that NMCRB might not be a predictive factor for MB. On the contrary, anemia and concomitant use of antiplatelet therapy were likely predictive factors for bleeding with warfarin and rivaroxaban treatment, respectively.

Point-of-Care Device for Warfarin Monitoring Used in the J-ROCKET AF Study

device recall would not be relevant. Conversely, PT-INRs performed while a patient had a RMC may exert an effect even after the AE/SAE stop date, until a subsequent (ie, unaffected) PT-INR was performed. Next, 2 physicians blinded to treatment assignments independently reviewed baseline medical history and AEs, identifying any conditions that matched those listed in the Alere letter. The 2 reviewers then compared their findings, and any discrepancies were discussed and resolved. Descriptions of the 3 sensitivity analyses are as follows. For sensitivity analysis no. 1, the safety outcome was the principal safety endpoint (composite of major and non-major clinically relevant bleeding), and the efficacy outcome was the primary efficacy endpoint (composite of stroke and non-central nervous system [CNS] systemic embolism). The trial population used was the safety population and the data scope was on-treatment. Patients who had a relevant chronic medical condition reported at baseline (ie, in their relevant medical history on the electronic case report form at the screening visit) were censored after the performance of their first PTINR of the study. For the remaining patients, the analysis also specified time intervals if they had a RMC, with censoring as defined by recall-related time of observation, as described above. For sensitivity analysis no. 2, the safety outcome was the principal safety endpoint and the efficacy outcome was the primary efficacy endpoint. The trial population used was the safety population, and the data scope was on-treatment. This analysis completely excluded patients who had recall-related time of observation before the endpoint event or censoring. In other words, the only patients included in this analysis were those who did not have any recall-related time of observation before the endpoint event or censoring. For sensitivity analysis no. 3, the safety outcome was the principal safety endpoint and the efficacy outcome was the primary efficacy endpoint. The trial population used was the safety population, and the data scope was on-treatment. As above, this analysis can be considered in terms of the occurrence of an endpoint or a censoring event (ie, reaching the end of treatment with the study drug). For this analysis, if the endpoint occurred or the end of treatment with the study drug was reached outside of a recall-related time of observation, the patient was included. What occurred before the event was not relevant, provided the event occurred outside of the period of recall-related time of observation. In all 3 analyses, rivaroxaban remained non-inferior to warfarin for the principal safety outcome of major and nonTo the Editor: In August 2012, we reported the safety and efficacy of oncedaily rivaroxaban for stroke and systemic embolism prevention in Japanese patients with atrial fibrillation (AF) as a result of the phase III J-ROCKET AF study.1 In December 2014, the United States Food and Drug Administration (FDA) issued a medical device recall notice for the AlereTM INRatio® Monitor System (formally known as the HemoSense INRatio device). The FDA reported that this whole-blood point-of-care device may provide an international normalized ratio (INR) result that is lower than an automated, plasma-based laboratory INR in patients with certain specific medical conditions, including abnormal hematocrit levels, conditions associated with raised fibrinogen levels, and bleeding or unusual bruising.2,3 In September 2015, Bayer Yakuhin Ltd (Bayer) identified that the recall notice of the Alere INRatio device was applicable to the HemoSense INRatio devices used in the J-ROCKET AF study. To evaluate the effect of possible device malfunction leading to lower INR values and inappropriately high doses of warfarin and bleeding events, Bayer and Johnson & Johnson performed 3 sensitivity analyses based on data from the J-ROCKET AF study. The sensitivity analyses were planned to exclude the effect of subsets of the study population listed in the Alere recall notice (relevant medical condition [RMC]) (Table 1),4 in order to provide a robust evaluation of the effect of the recall on the principal safety and primary efficacy endpoints. First, we defined the term “recall-related time of observation” to consider not only the presence of RMCs and adverse event (AE)/serious adverse event (SAE) start and stop dates but also the timing of prothrombin time (PT)-INR measurements performed with the device in association with these intervals. In brief, the mere presence of a RMC was not sufficient to warrant exclusion from observation because it was the performance of a PT-INR in association with this condition that was of most relevance. For example, if a patient developed a RMC but a PT-INR was not measured during that interval, the Point-of-Care Device for Warfarin Monitoring Used in the J-ROCKET AF Study