Dose Reduction Criteria Research Articles

Off-label underdosed apixaban use in Asian patients with non-valvular atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Background In Asian patients with atrial fibrillation (AF), off-label underdosed prescriptions of direct oral anticoagulants (DOACs) are common Purpose We aimed to compare the effectiveness and safety of off-label underdosed apixaban with on-label standard dose apixaban in Asian patients with AF. Methods Using the Korean nationwide claims database, we identified patients who prescribed apixaban and did not fulfill the dose reduction criteria of apixaban between January 2015 and December 2017. Multivariable Cox hazard regression model was performed and hazard ratios (HRs) for ischemic stroke, major bleeding (MB), all-cause death, and the composite clinical outcome were analyzed. Results Compared to patients prescribed on-label standard dose apixaban (n = 4,194), patients prescribed off-label underdosed apixaban (n = 2,890) were associated with higher risks of ischemic stroke (adjusted HR [aHR] 1.38, 95% confidence interval [CI] 1.06-1.81), all-cause death (aHR 1.19, 95% CI 1.01-1.39) and the composite clinical outcome (aHR 1.17, 95% CI 1.03-1.34), but with no significant differences in MB between the two groups (Figure). In patients without any dose reduction criteria, off-label underdosed apixaban use was associated with a significantly higher risk of ischemic stroke than on-label standard dose apixaban use (aHR 1.85, 95% 1.25-2.73); however, in patients who had single dose reduction criteria (age ≥80 years, serum creatinine ≥1.5mg/dL, or bodyweight ≤60 kg), off-label underdosed apixaban use did not show a significant overall benefit in the composite clinical outcome compared with on-label standard dose apixaban, but was associated with a higher risk of all-cause death (aHR 1.32, 95% CI 1.07-1.64). Conclusion Off-label underdosed apixaban use was associated with higher risks of ischemic stroke, all-cause death, and composite clinical outcome and comparable risk of MB compared with on-label standard dose apixaban use. Label-adherence of apixaban dosing should be emphasized to achieve the best clinical outcome for Asian patients with non-valvular AF, especially in those without any dose reduction criteria. Abstract Figure.

Factors associated with the dosing of edoxaban for stroke prevention in patients with atrial fibrillation from South Korea and Taiwan: 1-year data from the Global ETNA-AF Program.

Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the standard of care for stroke prevention in patients with atrial fibrillation (AF). However, DOAC prescriptions at dosages that do not adhere to labeling are common in daily practice. This analysis from the observational Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program focuses on edoxaban-treated patients from South Korea and Taiwan to identify patient baseline characteristics that may be associated with non-recommended dosing. We report baseline data from ETNA-AF, including patient demographics, clinical characteristics, and bleeding/stroke history of patients receiving recommended or non-recommended edoxaban dosing. A total of 2677 patients were enrolled. Among 1543 patients who did not meet dose-reduction criteria, 1033 (66.9%) were prescribed the recommended 60-mg dose, and 510 (33.1%) were prescribed the non-recommended 30-mg dose. Among 1134 patients meeting ≥1 of the dose-reduction criteria, 863 (76.1%) were prescribed the recommended 30-mg dose; 271 (23.9%) were prescribed the nonrecommended 60-mg dose. Compared with the recommended 60-mg group, the nonrecommended 30-mg group had a higher proportion of patients aged ≥75 years, higher stroke and bleeding risks, and a history of major bleeding. The non-recommended 60-mg group had a lower proportion of patients aged ≥75 years, a higher history of stroke, and lower history of bleeding compared with the recommended 30-mg group. The baseline data from ETNA-AF indicate that physicians take patient clinical characteristics (e.g., bleeding risks) into consideration when deviating from the dosing recommendation per label.

ANTIHYPERTENSIVE EFFECTS AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH MODERATE KIDNEY DYSFUNCTION

Objective: Mineralocorticoid receptor blockers (MRB) adding to renin–angiotensin system (RAS) inhibitors should be an effective treatment option for the strict blood pressure (BP) control of the hypertensive patients with moderate kidney dysfunction. Esaxerenone is a novel, first non-steroidal MRB with a dose-dependent antihypertensive effect and renal protective potential. We investigated the efficacy and safety of esaxerenone in Japanese hypertensive patients with moderate kidney dysfunction. Design and method: Two multicenter, open-label, non-randomized, dose-escalation studies were conducted to assess the efficacy and safety of esaxerenone monotherapy and add-on therapy to RAS inhibitor. Esaxerenone therapy started from 1.25 mg/day, titrated to 5 mg/day and continued until 12 weeks. Primary endpoint was change from baseline in sitting BP. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also evaluated. Results: Of 91 patients, 33 received monotherapy and 58 received add-on therapy; mean baseline estimated glomerular filtration rates were 52 and 51 mL/min/1.73m2, respectively. The esaxerenone dose was increased to 2.5 mg/day and above in 100% (n = 33) and 93% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. After the initiation of treatment, significant reduction in sitting SBP/DBP at the end of treatment was observed in both studies (monotherapy: 19/9 mmHg; add-on therapy: 18/8 mmHg; both P < 0.001); 64% and 48% of patients achieved target blood pressure (<140/90 mmHg). The antihypertensive effects were consistent across patient subgroups by age, BMI, and eGFR. The UACR decreased significantly from baseline to Week 12: by 26% in the monotherapy study (P < 0.01) and 29% in the add-on therapy study (P < 0.001). An increased serum K+ level of 5.5 mEq/L and above occurred in 7 patients (12%) receiving add-on therapy, but in none receiving monotherapy. All increases in serum K+ were transient and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment due to kidney function decline. Conclusions: Esaxerenone demonstrated sufficient antihypertensive effects and was well tolerated in hypertensive patients with moderate kidney dysfunction, both as monotherapy and add-on therapy to a RAS inhibitor.

Clinical outcomes according to dose reduction criteria of apixaban in Japanese elderly patients with atrial fibrillation: J-ELD AF Registry subanalysis.

Dose reduction of apixaban is applied in atrial fibrillation (AF) patients fulfilling ≥ 2 of the following criteria: (1) age ≥ 80years, (2) body weight ≤ 60kg and (3) serum creatinine ≥ 1.5mg/dL. However, the clinical significance of each criterion remains unclear. The J-ELD AF Registry is a prospective observational study of elderly (≥ 75years) Japanese AF patients receiving on-label dose of apixaban. In patients receiving the standard dose (5mg bid, n = 1243), the incidence rates (% per patient-year) of stroke or systemic embolism in those fulfilling none [n = 516] or one of the above criteria (1) [n = 328], (2) [n = 378] and (3) [n = 21] were 1.24, 2.32, 1.41 and 4.93 (log-rank P = 0.422), respectively, and those of bleeding requiring hospitalization were 1.03, 0.99, 1.98 and 4.93 (P = 0.318), respectively. In patients receiving a reduced dose (2.5mg bid, n = 1,515), the incidences of stroke or systemic embolism in those fulfilling (1)/(2) [n = 1,331], (1)/(3) [n = 65], (2)/(3) [n = 23] and all three criteria [n = 96] were 1.38, 1.64, 4.67 and 3.51 (P = 0.295), respectively, and those of bleeding requiring hospitalization were 2.04, 1.64, 0.00 and 4.71 (P = 0.318), respectively. Univariate analysis demonstrated that the types or combinations of each criterion was not significantly associated with the incidence of thromboembolic or bleeding events. The types or combinations of the three apixaban dose reduction criteria did not have significant impact on effectiveness and safety in Japanese elderly AF patients receiving on-label dose of apixaban, although the impact of the creatinine criterion remains uncertain due to the few number of the patients.

Off-label underdosed apixaban use in Asian patients with non-valvular atrial fibrillation.

To compare the effectiveness and safety of off-label underdosed apixaban with on-label standard dose apixaban in Asian patients with atrial fibrillation (AF). Using the Korean nationwide claims database, we identified patients who were prescribed apixaban and did not fulfil the dose reduction criteria for apixaban between January 2015 and December 2017. A multivariable Cox hazard regression model was performed, and hazard ratios (HRs) for ischaemic stroke, major bleeding (MB), all-cause death, and composite outcome were analysed. Compared to patients prescribed on-label standard dose apixaban (n = 4194), patients prescribed off-label underdosed apixaban (n = 2890) showed a higher risk of ischaemic stroke [adjusted HR (aHR) 1.38, 95% confidence interval (CI) 1.06-1.81], all-cause death (aHR 1.19, 95% CI 1.01-1.39), and the composite outcome (aHR 1.17, 95% CI 1.03-1.34), but with no significant differences in MB between the two groups. Among the patients who did not meet any dose reduction criteria, off-label underdosed apixaban use was associated with a significantly higher risk of ischaemic stroke than on-label standard dose apixaban use (aHR 1.85, 95% CI 1.25-2.73). Among the patients who met a single dose reduction criterion, off-label underdosed apixaban use was associated with a higher risk of all-cause death than on-label standard dose apixaban (aHR 1.32, 95% CI 1.07-1.64). The off-label underdosed apixaban group showed higher risks of ischaemic stroke, all-cause death, and composite clinical outcomes than the on-label standard dose apixaban group, but both showed comparable risks of MB. Label adherence to apixaban dosing should be emphasized to achieve the best clinical outcomes for Asian patients with AF.

Characteristics of patients with atrial fibrillation prescribed edoxaban in Belgium and the Netherlands: insights from the ETNA-AF-Europe study.

BackgroundStudies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban.MethodsWith data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15–50 ml/min, weight ≤60 kg, and/or use of strong p‑glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC).ResultsOf all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA2DS2-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC.ConclusionThere were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation.Trial registrationNCT02944019; Date of registration 24 October 2016Electronic supplementary materialThe online version of this article (10.1007/s12471-020-01518-7) contains supplementary material, which is available to authorized users.

Characteristics of patients with atrial fibrillation prescribed edoxaban in Belgium and The Netherlands: insights from the ETNA-AF-Europe study

Background Studies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban. Methods With data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15–50 mL/min, weight ≤60 kg, and/or use of strong p-glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC). Results Of all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA2DS2-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC. Conclusion There were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation. Trial registration NCT02944019; Date of registration: October 24, 2016.

Rationale and design of the ADAPT-TAVR trial: a randomised comparison of edoxaban and dual antiplatelet therapy for prevention of leaflet thrombosis and cerebral embolisation after transcatheter aortic valve replacement

IntroductionOptimal antithrombotic strategy following transcatheter aortic valve replacement (TAVR) is still unknown. We hypothesised that the direct factor Xa inhibitor edoxaban can potentially prevent subclinical leaflet thrombosis and cerebral embolisation...

Non-Vitamin K Antagonist Oral Anticoagulants and Factors Influencing the Ischemic and Bleeding Risk in Elderly Patients With Atrial Fibrillation: A Review of Current Evidence.

:Non–vitamin K antagonist oral anticoagulants (NOACs) are a widely prescribed treatment to prevent stroke in patients with nonvalvular atrial fibrillation, and a therapy and preventative measure to prevent recurrences following venous thromboembolism. Optimal use of NOACs requires a thorough knowledge of the pharmacology of these drugs, as well as an understanding of patient factors affecting their use. The 4 NOACs—dabigatran, apixaban, edoxaban, and rivaroxaban are available in a range of doses suitable for differing indications and with a variety of dose reduction criteria. Identification of the correct dose is one of the key challenges in the individualization of treatment. Elderly patients with atrial fibrillation are at a greater risk of both ischemic and bleeding events than younger patients. Consequently, it is essential to achieve balance in anticoagulation strategies. Medication adherence to NOACs is important for safe and effective treatment, particularly in elderly populations. A growing body of evidence shows that once-daily dosing improves adherence and persistence to therapy, without having an impact on bleeding risk.

Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction

Renin–angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin–angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: −18.5/−8.8 mmHg; add-on therapy: −17.8/−8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.

Management of Secondary Prevention in Venous Thromboembolism: Use of Reduced Doses of Rivaroxaban and Apixaban in Extended Therapy

BACKGROUND After a standard anticoagulation period (3-6 months), the risk of venous thromboembolism recurrence (RVTER) needs to be considered. Such risk is higher in unprovoked events and patients with persistent risk factor. The increase of D-dimer (DD) levels during the therapy seems to be strongly associated to RVTER. The use of rivaroxaban 10 mg/day and apixaban 2.5mg/12h as an extended therapy (ET) after the standard anticoagulation period has been proven to be an effective strategy to prevent recurrence without increasing bleeding events. AIM To assess the effectiveness and safety of reduced doses of rivaroxaban and apixaban as ET in patients with RVTER and to compare their DD levels with those of a control group on anticoagulant therapy at a standard dose. METHODS From April 2016 to June 2020, we included patients with venous thromboembolism (VTE) who received ET with rivaroxaban and apixaban with/at reduced doses. Dose reduction was performed following the clinical algorithm of our unit (Fig. 1). The DD values were determined using HemosIl D-Dimer HS-500 and the cut-off value was established at 500 µg/L DD levels were compared with a control group of 235 patients with VTE who received ET with standard doses of anticoagulation. DD levels were measured at the time of diagnosis (D1), initiation of treatment (D2) and 3 months after treatment (D3). RESULTS From a total of 116 patients (65.5% women), 77.6% (n=90) received rivaroxaban 10 mg/24h and 22.4% received apixaban 2.5 mg/12h as an ET. The mean duration of the initial anticoagulant therapy was 12 +/- 8.8 months. The mean DD value prior to the ET was 388 µg/L. In this group, 63.8% (n=74) was an unprovoked VTE and 17.2% (20) had hereditary thrombophilia. The mean of follow-up time was 6.9 +/- 8.3 months. No recurrences of VTE were observed during the follow-up and only one major bleeding event was reported in a high-bleeding risk patient. We observed a progressive decrease of DD levels from the VTE diagnosis to the last visit, with D1, D2, and D3 values of 987 µg/L ± 324, 388 µg/L ± 134, and 288 µg/L ± 98, respectively. There were no differences in d-dimer concentrations between patients with reduce doses of rivaroxaban or apixaban and the control group with standard doses (D1: 85.6% vs 81%, p =0.22; D2: 10.2% vs 8.0%, p =0.14; and D3: 9.1% vs 9.5%, p =0.18). CONCLUSIONS Our data indicated that an ET strategy with reduced doses of rivaroxaban or apixaban is effective and safe. We did not observe significant differences in DD levels at follow-up compared to the control group receiving a standard dose of anticoagulation. Further studies are needed in order to select and standardize dose reduction criteria in secondary prevention. Figure 1 Disclosures Campoy: boehringer ingelheim: Consultancy; Daiichi Sankyo: Speakers Bureau. Sierra:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Olivera:Daiichi Sankyo: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Boehringer Ingelheim: Consultancy, Speakers Bureau; BAYER: Consultancy.

Edoxaban for the Long-Term Therapy of Venous Thromboembolism: Should the Criteria for Dose Reduction be Revised?

Edoxaban is used for venous thromboembolism (VTE) treatment. Real‐life data are lacking about its use in long‐term therapy. We aimed to assess the efficacy and the safety of edoxaban for long‐term VTE treatment in a real‐life setting. Patients with VTE included in the Registro Informatizado Enfermedad TromboEmbólica (RIETE) registry, receiving edoxaban 60 or 30 mg daily were prospectively followed up to validate the benefit of using different dosages. The main outcome was the composite of VTE recurrences or major bleeding in patients with or without criteria for dose reduction. Multivariable analysis to identify predictors for the composite outcome was performed. From October 2015 to November 2019, 562 patients received edoxaban for long‐term therapy. Most (94%) of the 416 patients not meeting criteria for dose reduction received 60 mg daily, and 92 patients meeting criteria (63%) received 30 mg daily. During treatment, two patients developed recurrent VTE, six had major bleeding and nine died (2 from fatal bleeding). Among patients not meeting criteria for dose reduction, those receiving 30 mg daily had a higher rate of the composite event (hazard ratio (HR) 8.37; 95% confidence interval (CI) 1.12–42.4) and a significant higher mortality rate (HR 31.1; 95% CI 4.63–262) than those receiving 60 mg. Among patients meeting criteria for dose reduction, those receiving 60 mg daily had no events, and a nonsignificantly higher mortality rate (HR 5.04; 95% CI 0.54–133) than those receiving 30 mg daily. In conclusion, edoxaban seems to be effective and safe for long‐term VTE treatment in real life. Criteria for dose reduction should be reformulated.

Oral Anticoagulant Use in Elderly Japanese Patients With Non-Valvular Atrial Fibrillation - Subanalysis of the ANAFIE Registry.

Background: Oral anticoagulants (OACs) are effective in preventing stroke in patients with atrial fibrillation (AF), but are challenging for elderly patients because of the higher risk of bleeding complications.Methods and Results: The ANAFIE Registry is a prospective multicenter observational study of elderly (≥75 years) Japanese AF patients. This subanalysis evaluated the current use of OACs. Of 32,713 patients (mean age 81.5 years), 30,068 (91.9%) were receiving OACs, including 8,354 (25.5%) on warfarin and 21,714 (66.4%) on direct OACs (DOACs); 2,645 (8.1%) were not receiving OACs. The most common prescribed dose was a reduced dose for all DOACs. A substantial proportion of patients receiving the reduced dose did not fulfill dose reduction criteria (underdosing): apixaban, 25.1%; rivaroxaban, 26.3%; and edoxaban, 13.7%. Some patients received a lower off-label dose rather than the reduced dose: apixaban, 5.9%; rivaroxaban, 0.3%; edoxaban, 5.3%; and dabigatran, 13.6%. In multivariate analyses, advanced age, history of hemorrhage, paroxysmal AF, and antiplatelet drug use were significantly associated with no OAC. Advanced age, persistent or permanent AF, chronic kidney disease, and concomitant antiplatelet drugs were associated with warfarin rather than DOAC use.Conclusions: In the ANAFIE Registry, >90% of elderly Japanese AF patients received OAC therapy, mostly DOACs. Inappropriate low doses of DOACs that did not fulfill dose reduction criteria were prescribed in 20–30% of patients.

Tailoring anticoagulant treatment of patients with atrial fibrillation using a novel bleeding risk score

ObjectivesCurrent international guidelines advocate the application of bleeding risk scores only to identify modifiable risk factors, but not to withhold treatment in patients at high risk of bleeding. VTE-BLEED (ActiVe...

Model-based Dose Individualization of Sunitinib in Gastrointestinal Stromal Tumors.

Various biomarkers have been proposed for sunitinib therapy in gastrointestinal stromal tumor (GIST). However, the lack of "real-life" comparative studies hampers the selection of the most appropriate one. We, therefore, set up a pharmacometric simulation framework to compare each proposed biomarker. Models describing relations between sunitinib exposure, adverse events (hand-foot syndrome, fatigue, hypertension, and neutropenia), soluble VEGFR (sVEGFR)-3, and overall survival (OS) were connected to evaluate the differences in survival and adverse events under different dosing algorithms. Various fixed dosing regimens [4/2 (weeks on/weeks off) or 2/1 (50 mg), and continuous daily dosing (37.5 mg)] and individualization approaches [concentration-adjusted dosing (CAD), toxicity-adjusted dosing (TAD), and sVEGFR-3-adjusted dosing (VAD)] were explored following earlier suggested blood sampling schedules and dose-reduction criteria. Model-based forecasts of biomarker changes were evaluated for predictive accuracy and the advantage of a model-based dosing algorithm was evaluated for clinical implementation. The continuous daily dosing regimen was predicted to result in the longest survival. TAD (24.5 months) and VAD (25.5 months) increased median OS as compared with a fixed dose schedule (19.9 and 21.5 months, respectively) and CAD (19.7 and 21.3 months, respectively), without markedly raising the risk of intolerable toxicities. Changes in neutrophil count and sVEGFR-3 were accurately forecasted in the majority of subjects (>65%), based on biweekly blood sampling. Dose adjustments based on the pharmacodynamic biomarkers neutrophil count and sVEGFR-3 can increase OS while retaining drug safety. Future efforts could explore the possibility of incorporating a model-based dose approach in clinical practice to increase dosing accuracy for these biomarkers.

Inappropriate dose of nonvitamin-K antagonist oral anticoagulants: prevalence and impact on clinical outcome in patients with nonvalvular atrial fibrillation.

Limited real-world data are available regarding the outcome of patients treated with inappropriate dose of nonvitamin-K antagonist oral anticoagulants (NOACs). To assess the prevalence and factors associated with inappropriate dose prescription of NOACs and to evaluate adverse events that come from this inappropriate prescription. Single-center multidisciplinary registry including nonvalvular atrial fibrillation patients treated with NOACs. Based on guidelines criteria for dose reduction, two subcohorts were defined as treated with appropriate or inappropriate NOACs dose. Primary efficacy endpoint was 2-year rate of thromboembolic events. Primary safety endpoint was 2-year rate of major bleeding. Event-free survival curves among groups were compared using Cox-Mantel test. A total of 760 nonvalvular atrial fibrillation patients were included; 32% patients were treated with dabigatran, 34% with apixaban, 24% with rivaroxaban and 10% with edoxaban. An inappropriate dose was prescribed in 96 patients (12.6%), and in most cases (68%) it was too low. Rivaroxaban (15%) and apixaban (18.5%) were the most frequently prescribed with an inappropriate dose. Patients treated with an inappropriate dose were elderly people, with low-creatinine clearance value, who had experienced previous bleeding and with a high CHADS2 VASc score. In 2 years, a trend for higher numbers of thromboembolic events (5.2 vs. 3.3%, P = 0.348) and less major bleeding (2.1 vs. 4.2%, P = 0.316) has been observed in patients with inappropriate NOACs prescriptions. Nearly 13% of patients were treated with an inappropriate dose of NOACs, in this single-center study. A trend for higher numbers of thromboembolic events was observed in these patients. The results should be considered as hypothesis generating.

A single-arm confirmatory trial of pazopanib in patients with paclitaxel-pretreated primary cutaneous angiosarcoma: Japan Clinical Oncology Group study (JCOG1605, JCOG-PCAS protocol)

BackgroundPaclitaxel is a standard of care for patients with primary cutaneous angiosarcoma of the scalp and face. However, no standard second-line treatment for paclitaxel-resistant patients has ever been established. Since primary cutaneous angiosarcoma expresses a high level of vascular endothelial growth factor receptor, the multitargeted tyrosine kinase inhibitor pazopanib seemed to be the most promising agent, and several retrospective studies have demonstrated its activity against this disease. However, the efficacy and safety of pazopanib in paclitaxel-resistant patients with primary cutaneous angiosarcoma have never been evaluated in a clinical trial.MethodsIn February 2018 the Dermatologic Oncology Group of Japan Clinical Oncology Group started a single-arm confirmatory trial to evaluate the efficacy and safety of pazopanib as a second-line treatment for patients with primary cutaneous angiosarcoma whose disease was resistant to paclitaxel or who were unable to tolerate paclitaxel (JCOG1605, JCOG-PCAS). Patients with primary cutaneous angiosarcoma not associated with lymphedema or radiation, progressing despite first-line paclitaxel monotherapy are included in the study. No prior systemic chemotherapy other than paclitaxel is permitted. Pazopanib is administered orally at an initial dosage of 800 mg once daily. Dose modifications for adverse events are made according to the dose reduction criteria described in the protocol. Treatment is continued until recurrence, disease progression, unacceptable toxic effects, patient refusal, or death. The primary endpoint is progression-free survival, secondary endpoints include overall survival, response rate, disease control rate, adverse events, and serious adverse events. We plan to recruit 30 participants in 5.5 years from 23 Japanese institutions. The follow-up period is set as 1 year after completion of accrual. The study protocol was approved by the Japan Clinical Oncology Group Protocol Review Committee in December 2017. Ethical approval for this study was granted by Ethics Committee of each institute.DiscussionIf the primary endpoint is met, pazopanib will be regarded as a standard of care for paclitaxel-resistant patients for whom no standard second-line treatment is established.Trials registrationRegistry number: UMIN000031438 [http://www.umin.ac.jp/ctr/index.htm]. Date of Registration: 23/Feb/2018. Date of First Participant Enrollment: 8/Mar/2018.

Novel anticoagulants in an older and frail population with atrial fibrillation: the effect of inappropriate dosing on clinical outcomes.

An individualized approach should be taken regarding the use of novel oral anticoagulants (NOAC) in frail and older patients with atrial fibrillation (AF). We hypothesized that there would be a high proportion of underdosed patients among an older and frail population, where bleeding risk is higher. We retrospectively analyzed patients admitted to an Internal Medicine ward with a previous diagnosis of AF and discharged with a NOAC (n = 327). We compared survival and incidence of dosing-related events (stroke, systemic embolism, and major bleeding) at 1-year between inappropriately underdosed patients (dose reduction without a formal indication) and the rest of the population. A total of 167 patients (51%) received a reduced dose despite lacking formal criteria for dose reduction. Before adjustment, underdosed patients, in comparison with non-underdosed patients, had a higher mortality at 1 year (HR = 1.6, 95% CI 1.2-2.1, p = 0.003) and a higher combined stroke, systemic embolism, and major bleeding event rate at 1-year (HR = 3.2, 95% CI 1.3-8.0, p = 0.015). After adjustment, combined stroke, systemic embolism, and major bleeding event rate was higher in underdosed patients (HR 3.7, 95% CI 1.1-12.3, p = 0.030), but survival was not different in the adjusted model (HR 1.4, 95% CI 0.9-2.1, p = 0.110). Underdosed patients have a significant survival disadvantage and this may be due to clinician prescription bias, since this difference does not remain after adjusting for confounders. Combined stroke, systemic embolism, and major bleeding event rate was higher in underdosed patients.

Inappropriate direct oral anticoagulant dosing in atrial fibrillation patients is associated with prescriptions for outpatients rather than inpatients: a single-center retrospective cohort study

BackgroundInappropriate dosing of direct oral anticoagulants (DOACs) has been associated with clinical safety and efficacy; however, little is known about clinical data associated with an inappropriate DOAC dosing in Japan. In addition, there is no report in which the appropriateness of DOAC dosing between prescription for inpatients and for outpatients was examined. In this study, we aimed to investigate the prevalence and factors associated in the inappropriate dosing of DOACs in patients with atrial fibrillation (AF).MethodsThe retrospective cohort study was conducted at a single Japanese university hospital. Both inpatients and outpatients, who were diagnosed with AF and for whom treatment with either dabigatran, rivaroxaban, apixaban, or edoxaban was initiated between April 1, 2014 and March 31, 2018, were enrolled in the study. Appropriateness of DOAC dosing was assessed according to the manufacturer’s labeling recommendations (dose reduction criteria) of each DOAC. Inappropriate reduced dose, namely, underdosing, was defined as prescription of a reduced dose of DOAC despite the patient not meeting the dose reduction criteria. Inappropriate standard dose, namely, overdosing, was defined as prescription of a standard dose of DOAC despite the patient meeting the dose reduction criteria. Inappropriate DOAC dosing was defined as a deviation of the recommended dose (both underdosing and overdosing).ResultsA total of 316 patients (dabigatran, 28; rivaroxaban, 107; apixaban, 116; and edoxaban, 65) were included, with a median (interquartile range) age of 75 (66–81) years and 62.3% male. DOACs were prescribed at an appropriate standard dose in 39.2% of patients, an appropriate reduced dose in 36.7%, an inappropriate standard dose in 2.5%, and an inappropriate reduced dose in 19.3%. Multivariate analysis revealed that the inappropriate dosing of DOACs was significantly associated with prescriptions for outpatients (vs. inpatients; odds ratio [OR] 2.87, 95% confidence interval [CI] 1.53–5.62, p < 0.001) and those with higher HAS-BLED scores (OR 1.87, 95% CI 1.42–2.51, p < 0.001).ConclusionsOur results demonstrated that the inappropriate dosing of DOACs occurred in approximately 20% of AF patients, and was more frequent in outpatients (vs. inpatients) and in those with a higher risk of bleeding. It is recommended that pharmacists play a greater role in assisting in the prescription process to help physicians make better decisions.

Decline in renal function and oral anticoagulation dose reduction among patients with atrial fibrillation

ObjectiveNon-vitamin K oral anticoagulants (NOACs) require dose adjustment for renal function. We sought to investigate change in renal function over time in patients with atrial fibrillation (AF) and whether those...