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Aims Patients with atrial fibrillation (AF) treated with oral anticoagulation still suffer from cardiovascular complications including cardiovascular death, stroke, and major bleeding. To identify risk factors for predicting stroke and bleeding outcomes in anticoagulated patients, we assessed 2-year outcomes in patients with AF treated with edoxaban in routine care. We also report the age-adjusted risk predictors of clinical outcomes. Methods and results The Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular Atrial Fibrillation (ETNA-AF) Europe (NCT02944019) is a prospective, multi-centre, post-authorisation, observational study with an overall 4-year follow-up conducted in 825 centres enrolling edoxaban-treated patients in 10 European countries. Of the 13 133 patients with AF (mean age: 73.6 ± 9.5 years), 5682 (43.3%) were female. At the 2-year follow-up, 9017/13 133 patients were still on edoxaban; 1830 discontinued treatment including 937 who died (annualised event rate of all-cause death was 3.87%). 518 (2.14%) patients died of cardiovascular causes; 234 (0.97%) experienced major bleeding and 168 (0.70%) experienced stroke or systemic embolic events (SEE). Intracranial haemorrhage was noted in 49 patients (0.20%). History of transient ischaemic attack (TIA) at baseline was the strongest predictor of ischaemic stroke or SEE (Wald χ2: 73.63; P Conclusion Patients treated with edoxaban in ETNA-AF-Europe reported low 2-year event rates in unselected AF patients. Prior stroke, reduced kidney function, and HF identify patients at high risk of stroke, bleeding and all-cause/cardiovascular death, respectively.

Background: The Tenosynovial giant cell tumor Observational Platform Project (TOPP) registry is an international prospective study that -previously described the impact of diffuse-type tenosynovial giant cell tumour (D-TGCT) on patient-reported outcomes (PROs) from a baseline snapshot. This analysis describes the impact of D-TGCT at 2-year follow-up based on treatment strategies. Material and Methods: TOPP was conducted at 12 sites (EU: 10; US: 2). Captured PRO measurements assessed at baseline, 1-year, and 2-year follow-ups were Brief Pain Inventory (BPI), Pain Interference, BPI Pain Severity, Worst Pain, EQ-5D-5L, Worst Stiffness, and -Patient-Reported Outcomes Measurement Information System. Treatment interventions were no current/planned treatment (Off-Treatment) and systemic treatment/surgery (On-Treatment). Results: A total of 176 patients (mean age: 43.5 years) were included in the full analysis set. For patients without active treatment strategy -(Off-Treatment) at baseline (n = 79), BPI Pain Interference (1.00 vs. 2.86) and BPI Pain Severity scores (1.50 vs. 3.00) were numerically favorable in patients remaining Off-Treatment compared with those who switched to an active treatment strategy at year 1. From 1-year to 2-year -follow-ups, patients who remained Off-Treatment had better BPI Pain Interference (0.57 vs. 2.57) and Worst Pain (2.0 vs. 4.5) scores compared with patients who switched to an alternative treatment strategy. In addition, EQ-5D VAS scores (80.0 vs. 65.0) were higher in patients who remained -Off-Treatment between 1-year and 2-year follow-ups compared with patients who changed treatment strategy. For patients receiving systemic treatment at baseline, numerically favorable scores were seen in patients remaining on systemic therapy at 1-year follow-up: BPI Pain Interference (2.79 vs. 5.93), BPI Pain Severity (3.63 vs. 6.38), Worst Pain (4.5 vs. 7.5), and Worst Stiffness (4.0 vs. 7.5). From 1-year to 2-year follow-up, EQ-5D VAS scores (77.5 vs. 65.0) were higher in patients who changed from systemic treatment to a different treatment strategy. Conclusion: These findings highlight the impact D-TGCT has on patient quality of life, and how treatment strategies may be influenced by these outcome measures. (ClinicalTrials.gov number: NCT02948088)The TOPP registry is an international prospective study that previously described the impact of diffuse-type tenosynovial giant cell tumor on patient-reported outcomes from a baseline snapshot. This article reports a 2-year follow-up based on treatment strategies and could represent a benchmark for future clinical trials.

BACKGROUND The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P���=���0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P���=���0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).

Aims Non-vitamin K oral anticoagulants are safe and effective for stroke prevention in patients with atrial fibrillation (AF). Data on the safety and efficacy of edoxaban in routine care are limited in Europe. We report 1-year outcomes in patients with AF treated with edoxaban in routine care. Methods and results ETNA-AF-Europe is a prospective, multicentre, post-authorization, observational study enrolling patients treated with edoxaban in 10 European countries, the design of which was agreed with the European Medicines Agency as part of edoxaban’s post-approval safety plan. Altogether 13 092 patients in 852 sites completed the 1-year follow-up [mean age: 73.6 ± 9.5 years; 57% male, mean follow-up: 352 ± 49 days (median: 366 days)]. Most patients had associated comorbidities (mean CHA2DS2-VASc score: 3.1 ± 1.4). Stroke or systemic embolism was reported in 103 patients (annualized event rate: 0.82%/year), and major bleeding events were reported in 132 patients (1.05%/year). Rates of intracranial haemorrhage were low [30 patients (0.24%/year)]. Death occurred in 442 patients (3.50%/year); cardiovascular (CV) death occurred in 206 patients (1.63%/year). The approved dosing of edoxaban was chosen in 83%. All-cause and CV mortality were higher in patients receiving edoxaban 30 mg vs. 60 mg, in line with the higher age and more frequent comorbidities of the 30 mg group. Major bleeding was also numerically more common in patients receiving edoxaban 30 mg vs. 60 mg. Conclusion The rates of stroke, systemic embolism, and major bleeding are low in this large unselected cohort of high-risk AF patients routinely treated with edoxaban.

BACKGROUND: Guidance for periprocedural anticoagulant management is mainly based on limited data from Phase III or observational studies and expert opinion. HYPOTHESIS: EMIT-AF/VTE was designed to document the risks of bleeding and thromboembolic events in more than 1000 patients on edoxaban undergoing diagnostic and therapeutic procedures in clinical practice. METHODS: Routine care in a multinational multicenter, prospective observational study. Participants were adult patients with atrial fibrillation and/or venous thromboembolism treated with edoxaban for stroke prevention or for secondary prevention in venous thromboembolic disease, undergoing a wide range of diagnostic and therapeutic procedures. Edoxaban therapy was interrupted periprocedurally at the treating physician's discretion. Patients were evaluated from 5 days pre- until 30 days postprocedure. Primary outcome was the incidence of International Society on Thrombosis and Haemostasis defined major bleeding; secondary outcomes included incidence of clinically relevant non-major bleeding, acute coronary syndrome, and acute thromboembolic events. RESULTS: Outcomes and management are reported for the first procedures in 1155 unselected patients. Five cases of major bleeding (0.4%) and eight of clinically relevant non-major bleeding (0.7%) were documented, five (38%) of which occurred outside the period of likely edoxaban effect (last edoxaban dose ≥3 days prior to bleeding). Five (0.4%) deaths from any cause, seven acute thromboembolic events (0.6%) including two cardiac deaths (0.2%) in six patients, and one acute coronary event (0.1%) occurred. CONCLUSIONS: The periprocedural bleeding and acute thromboembolic event risks for patients treated with edoxaban were low. This can help inform both clinical routine and guidelines for the periprocedural management of edoxaban. ispartof: CLINICAL CARDIOLOGY vol:43 issue:7 pages:769-780 ispartof: location:United States status: published

Background Tenosynovial Giant-Cell Tumour (TGCT) is a benign clonal neoplastic proliferation arising from the synovium, causing a variety of symptoms and often requiring repetitive surgery. This study aims to define the economic burden—from a societal perspective—associated with TGCT patients and their health-related quality of life (HRQOL) in six European countries. Methods This article analyses data from a multinational, multicentre, prospective observational registry, the TGCT Observational Platform Project (TOPP), involving hospitals and tertiary sarcoma centres from six European countries (Austria, France, Germany, Italy, the Netherlands, and Spain). It includes information on TGCT patients’ health-related quality of life and healthcare and non-healthcare resources used at baseline (the 12-month period prior to the patients entering the registry) and after 12 months of follow-up. Results 146 TGCT patients enrolled for the study, of which 137 fulfilled the inclusion criteria. Their mean age was 44.5 years, and 62% were female. The annual average total costs associated with TGCT were €4866 at baseline and €5160 at the 12-month follow-up visit. The annual average healthcare costs associated with TGCT were €4620 at baseline, of which 67% and 18% corresponded to surgery and medical visits, respectively. At the 12-month follow-up, the mean healthcare costs amounted to €5094, with surgery representing 70% of total costs. Loss of productivity represented, on average, 5% of the total cost at baseline and 1.3% at follow-up. The most-affected HRQOL dimensions, measured with the EQ-5D-5L instrument, were pain or discomfort, mobility, and the performance of usual activities, both at baseline and at the follow-up visit. Regarding HRQOL, patients declared a mean index score of 0.75 at baseline and 0.76 at the 12-month follow-up. Conclusion The results suggest that TGCT places a heavy burden on its sufferers, which increases after one year of follow-up, mainly due to the healthcare resources required—in particular, surgical procedures. As a result, this condition has a high economic impact on healthcare budgets, while the HRQOL of TGCT patients substantially deteriorates over time.

Annually 10% of patients with atrial fibrillation on oral anticoagulation undergo invasive procedures. Optimal peri-procedural management of anticoagulation, as judged by major bleeding and thromboembolic events, especially in the elderly, is still debated.Procedures from 1442 patients were evaluated. Peri-procedural edoxaban management was guided only by the experience of the attending physician. The primary safety outcome was the rate of major bleeding. Secondary outcomes included the peri-procedural administration of edoxaban, other bleeding events, and the main efficacy outcome, a composite of acute coronary syndrome, non-hemorrhagic stroke, transient ischemic attack, systemic embolic events, deep vein thrombosis, pulmonary embolism, and mortality.Of the 1442 patients, 280 (19%) were 65, 550 (38%) were 65-74, 514 (36%) 75-84, and 98 (7%) were 85 years old or older. With increasing age, comorbidities and risk scores were higher. Any bleeding complications were uncommon across all ages, ranging from 3.9% in patients 65 to 4.1% in those 85 years or older; major bleeding rates in any age group were ≤ 0.6%. Interruption rates and duration increased with advancing age. Thromboembolic events were more common in the elderly, with all nine events occurring in those 65, and seven in patients aged 75 years.Despite increased bleeding risk factors in the elderly, bleeding rates were small and similar across all age groups. However, there was a trend toward more thromboembolic complications with advancing age. Further efforts to identify the optimal management to reduce ischemic complications are needed.NCT# 02950168, October 31, 2016.

Aims To compare the safety and efficacy of edoxaban combined with P2Y12 inhibition following percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) presenting with an acute coronary syndrome (ACS) or chronic coronary syndrome (CCS). Methods and results In this pre-specified sub-analysis of the ENTRUST-AF PCI trial, participants were randomly assigned 1:1 to edoxaban- or vitamin K antagonist (VKA)-based strategy and randomization was stratified by ACS (edoxaban n = 388, VKA n = 389) vs. CCS (edoxaban n = 363, VKA = 366). Participants received edoxaban 60 mg once-daily plus a P2Y12 inhibitor for 12 months, or VKA combined with a P2Y12 inhibitor and aspirin 100 mg (for 1-12 months). The primary bleeding endpoint at 12 months occurred in 59 (15.2%) vs. 79 (20.3%) ACS patients [hazard ratio (HR): 0.73, 95% confidence interval (CI): 0.59-1.02, P = 0.063], and in 69 (19.0%) vs. 73 (19.9%) CCS patients (HR: 0.94, 95%CI: 0.68-1.31, P = 0.708) with edoxaban- and VKA-based therapy, respectively [P for interaction (P-int) = 0.2741]. The main secondary endpoint (composite of CV death, myocardial infarction, stroke, systemic embolic events, or definite stent thrombosis) in ACS patients was 33 (8.5%) vs. 28 (7.2%) (HR: 1.16, 95%CI: 0.70-1.92), compared with 16 (4.4%) vs. 18 (4.9%) (HR: 0.91, 95%CI: 0.47-1.78) CCS patients with edoxaban and VKA-based therapy, respectively (P-int = 0.5573). Conclusions In patients with AF who underwent PCI, the edoxaban-based regimen, as compared with VKA-based regimen, provides consistent safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation. This work was supported and funded by Daiichi Sankyo. Vranckx, P (corresponding author), Hasselt Univ, Fac Med & Life Sci, Dept Cardiol & Crit Care Jessaziekenhuis Hasselt, Hasselt, Belgium. pascal.vranckx@iccuhasselt.be

Aim We aimed to compare the safety and efficacy of edoxaban in combination with P2Y12 inhibition in the setting of percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) presenting with an acute coronary syndrome (ACS) or stable coronary artery disease (SCAD). Methods and results This is a pre-specified sub-analysis of the ENTRUST-AF PCI trial. Participants were randomly assigned 1:1 to an edoxaban or vitamin K antagonist (VKA) based strategy and randomisation was stratified by ACS (edoxaban n=388, vitamin K n=389) vs. SCAD (edoxaban n=363, vitamin K=366). Participants received edoxaban 60mg once daily plus a P2Y12 inhibitor for 12 months; or VKA in combination with a P2Y12 inhibitor and aspirin 100mg (for 1–12 months). The primary bleeding endpoint, a composite of International Society on Thrombosis and Haemostasis (ISTH) major or clinical relevant non-major bleeding, at 12 months occurred in 59 (18.52%/year) vs 79 (26.21%/year) ACS patients (Hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.591–1.018, P=0.0631), and in 69 (23.11%/year) vs 73 (25.02%/year) SCAD patients (HR 0.94, 95% CI 0.676–1.305, P=0.7082) with edoxaban and VKA based therapies, respectively (P for interaction [P-int]=0.2741). The main efficacy endpoint (composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, or definite stent thrombosis) occurred in 33 (9.59%/year) vs 28 (8.21%/year) ACS-patients (HR 1.16, 95% CI 0.697–1.916) compared with 16 (4.84%/year) vs 18 (5.47%/year) SCAD-patients (HR 0.91, 95% CI 0.465–1.781) with edoxaban and VKA based therapy, respectively (P-int=0.5573). Conclusions An antithrombotic regimen consisting of edoxaban and a P2Y12-inhibitor without aspirin provides equal safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation with ACS or SCAD. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH

Introduction Edoxaban has proven its efficacy and safety in the ENGAGE AF-TIMI 48 and HOKUSAI-VTE clinical trials. Clinical practice patients, however, may differ from those enolled in clinical trials. We aimed to compare patients from the HOKUSAI-VTE clinical trial with those treated in clinical practice. Materials and Methods ETNA-VTE-Europe is a prospective, non-interventional post-authorisation safety study conducted in eight European countries. Results A total of 2,879 patients presenting with acute symptomatic venous thromboembolism (VTE) were enrolled at 339 sites. Of the 2,680 patients with complete data, 23.6% reported prior VTE and 2.8% had a history of bleeding. Patients in ETNA-VTE were older (65vs.57 years), more likely to be female (46.5vs.39.8%) and had a higher prevalence of chronic venous insufficiency (11.1vs.1.6%) than those in the European cohort of the HOKUSAI-VTE trial (n=1,512). Bodyweight and creatinine clearance were substantially lower in clinical practice. Edoxaban dosing was adherent to label in 90% of patients, with higher (60 mg) and lower than recommended doses (30 mg) used in 6.6% and 3.3% of the patients, respectively. Heparin lead-in was used in 84.7% of the patients overall, and was more frequently used in patients with PE than patients with DVT only (91.3% vs. 80.1%; p Conclusions These data reinforce the largely appropriate use of edoxaban in routine clinical practice, where the study population differs from those in prior randomised controlled trials. ClinicalTrials.gov Identifier NCT02943993

Introduction Edoxaban had a positive risk-benefit ratio for the treatment of venous thromboembolism (VTE) compared to conventional therapy with warfarin. The objective of this analysis of the ongoing ETNA-VTE Europe study was to assess the real-world benefits and risks of edoxaban during the first 3 months of treatment, the highest risk period for further VTE events. Methods ETNA-VTE Europe is a prospective, non-interventional, post-authorization study, conducted in eight European countries. Participants had initial or recurrent acute VTE (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) that occurred ≤2 weeks prior to enrolment and received edoxaban therapy. Results The analysis set included 2672 patients (PE ± DVT, n = 1117; DVT only, n = 1555); mean age 62.9 ± 16.0 years, bodyweight 81.9 ± 17.4 kg, estimated glomerular filtration rate 95.4 ± 42.8 mL/min; 46.4% were female. Overall, 66.4% of patients (PE ± DVT, 68.5%; DVT-only, 64.8%) received heparin lead-in treatment for at least 5 days. Most patients (87.7%) received edoxaban at a dose of 60 mg once daily. Event rates at 3 months were: recurrent VTE 0.34% (n = 9), major bleeding 0.97% (n = 26), all-cause mortality 0.79% (n = 21). Rates were numerically higher in the PE ± DVT group compared with the DVT-only group (recurrent VTE, 0.45% (n = 5) versus 0.26% (n = 4); major bleeding, 1.34% (n = 15) versus 0.71% (n = 11); and all-cause mortality 1.16% (n = 13) versus 0.51% (n = 8)). Conclusions The results support the safety and effectiveness of edoxaban in a general VTE population during the most critical time period, the first 3 months. The outcomes of this study extend the principal efficacy and safety data on edoxaban into the routine clinical practice setting.

Background: Tenosynovial giant cell tumor (TGCT) is a rare locally aggressive neoplasm arising from the synovium of joints, bursae, and tendon sheaths affecting small and large joints. It represents a wide spectrum ranging from minimally symptomatic to massively debilitating. The majority of findings to date are mainly from small, retrospective case series, and thus the morbidity and actual impact of this rare disease remain to be elucidated. This study explores prospectively the real-world management of TGCT.Methods: The TGCT Observational Platform Project (TOPP) registry was a multinational, multicenter, prospective observational study involving 12 tertiary sarcoma centers in 7 European countries, and 2 US sites. This study enrolled for 2 years all consecutive ≥ 18 years old patients, with histologically diagnosed primary or recurrent cases of diffuse-type TGCT. Patient demographic and clinical characteristics were collected at baseline and every 6 months for 24 months. Quality of life questionnaires (PROMIS-PF and EQ-5D) were also administered at the same time-points. Here we report baseline patient characteristics.Results: 166 patients were enrolled between November 2016 and March 2019. Baseline characteristics were: mean age 44 years (mean age at disease onset: 39 years), 139/166 (83.7%) had prior treatment, 71/166 patients (42.8%) had ≥ 1 recurrence after treatment of their primary tumor, 76/136 (55.9%) visited a medical specialist ≥ 5 times, and 66/116 (56.9%) missed work in the 24 months prior to baseline, and 17/166 (11.6%) changed employment status or retired prematurely due to disease burden. Prior treatment consisted of surgery (i.e., arthroscopic, open synovectomy) (128/166; 77.1%), and systemic treatments (52/166; 31.3%) with imatinib (19/52; 36.5%) or pexidartinib (27/52; 51.9%). Treatment strategies at baseline visits consisted mainly of watchful waiting (81/166; 48.8%), surgery (41/166; 24.7%), or targeted systemic therapy (37/166; 22.3%). Patients indicated for treatment reported more impairment compared to patients indicated for watchful waiting: worst stiffness NRS 5.16/3.44, worst pain NRS 6.13/5.03, PROMIS-PF 39.48/43.85, and EQ-5D VAS 66.54/71.85.Conclusion: This study confirms that diffuse-type TGCT can highly impact quality of life. A prospective observational registry in rare disease is feasible and can be a tool to collect curated-population reflective data in orphan diseases.

e23565 Background: Diffuse Tenosynovial Giant Cell Tumor (d-TGCT) is a rare, locally aggressive neoplasm of joint and tendon sheath synovia, which may severely affect patients (pts) QOL due to pain, limited joint function and destruction of bone and local tissues. This study analyzes real-world data to describe d-TGCT pt journey and QOL in the US. Methods: The TGCT Observational Platform Project (TOPP), the first non-interventional prospective disease registry, enrolled d-TGCT pts at 10 Western European (EU) and 2 US sarcoma centers from Nov 2016 to Mar 2019, with prospective follow-up of 24 mo. Pts demographics, disease history and ongoing medical treatment and pt-reported outcomes (PROs) (pain, stiffness, PROMIS Physical Function [PF] and EQ-5D) were collected at baseline and every 6 mo during follow-up periods. Descriptive analyses from baseline compared US pts with Western EU pts (Table). Results: Of 166 d-TGCT pts, 30 were enrolled in the US. Mean age was 40.6 ± 12.82 y, with 63.3% female and 66.7% with tumor in knee. Median time from first symptom to diagnosis was 12 mo (range; 0–153). 28 pts (93.3%) had surgery, 4 pts (13.3%) had tyrosine kinase inhibitors (TKI), no pts had radiotherapy. 18 pts (60%) experienced >1 locoregional recurrence. Median Pain Severity Score (PSS) and Pain Interference Score (PIS) were 2.8 and 3.0, respectively. Median PROMIS PF Score was 39.8. Mean EQ-5D index score and visual analogue scale (VAS) were 0.73 ±0.229 and 75.5 ±13.31, respectively. Compared with Western EU pts, US pts reported similar PROs and QOL, were younger, had shorter delay in diagnosis, and lower use of systemic therapy or radiotherapy (Table). Conclusions: d-TGCT affects a relatively young population in the US, similar to Western EU, resulting in serious impairment in daily activities and QOL. Shorter diagnostic delay and less frequent use of non–surgical approach was observed in the US. [Table: see text]

Aims This subgroup analysis of the ENTRUST-AF PCI trial (ClinicalTrials.gov Identifier: NCT02866175; Date of registration: August 2016) evaluated type of AF, and CHA2DS2-VASc score parameters as predictors for clinical outcome. Methods Patients were randomly assigned after percutaneous coronary intervention (PCI) to either edoxaban (60 mg/30 mg once daily [OD]; n = 751) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist [VKA] (n = 755) plus a P2Y12 inhibitor and aspirin (100 mg OD, for 1–12 months). The primary outcome was a composite of major/clinically relevant non-major bleeding (CRNM) within 12 months. The composite efficacy endpoint consisted of cardiovascular death, stroke, systemic embolic events, myocardial infarction (MI), and definite stent thrombosis. Results Major/CRNM bleeding event rates were 20.7%/year and 25.6%/year with edoxaban and warfarin, respectively (HR [95% CI]: 0.83 [0.654–1.047]). The event rates of composite outcome were 7.26%/year and 6.86%/year, respectively (HR [95% CI]): 1.06 [0.711–1.587]), and of overall net clinical benefit were 12.48%/year and 12.80%/year, respectively (HR [(95% CI]: 0.99 [(0.730; 1.343]). Increasing CHA2DS2-VASc score was associated with increased rates of all outcomes. CHA2DS2-VASc score ≥ 5 was a marker for stent thrombosis. Paroxysmal AF was associated with a higher occurrence of MI (4.87% versus 2.01%, p = 0.0024). Conclusion After PCI in AF patients, increasing CHA2DS2-VASc score was associated with increased bleeding rates and CHA2DS2-VASc score (≥ 5) predicted the occurrence of stent thrombosis. Paroxysmal AF was associated with MI. These findings may have important clinical implications in AF patients.

Introduction The appropriate strategy for initiating oral anticoagulant (OAC) therapy after an acute venous thromboembolism (VTE) depends on the intermediate-term anticoagulant to be used. While heparin bridging to vitamin K antagonists (VKA) is required, the direct oral anticoagulants (DOAC) rivaroxaban (30 mg/day) and apixaban (10 mg/day) can be initiated directly without parenteral anticoagulation. The objective was to evaluate OAC initiation patterns in clinical practice. Materials and methods PREFER in VTE was an international, non-interventional registry conducted between January 2013 and August 2015. Consecutive acute VTE patients were grouped based on their OAC treatment at 1 month after the index event (VKA or DOAC). Results At 1 month, 825 patients were receiving a VKA and 687 a DOAC (rivaroxaban in 685/687 cases). DOAC patients were significantly younger, less comorbid, at a lower bleeding risk, and less frequently diagnosed with pulmonary embolism (34.4% vs. 44.7%). During the first month after VTE, the most common treatment pattern was heparin-OAC overlap for VKA patents (69.6%), and OAC only for DOAC patients (49.1%). However, 28.8% of DOAC patients received a heparin-OAC overlap (median heparin duration: 3 days; IQR: 2–6) and 14.8% were switched from heparin to DOAC. For those on rivaroxaban at 1 month, only 29.7% had received the initial 30 mg/day recommended dose. Clinical event rates were comparable between the DOAC only, heparin-DOAC switch, and heparin-DOAC overlap subgroups at 1 and 6 months. Conclusions Guidelines for DOAC/rivaroxaban initiation after VTE are often not adhered to in clinical practice. This could result in adverse outcomes or suboptimal anticoagulation. Intervention programs to raise awareness amongst physicians may be merited.

Summary Background We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI). Methods ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1–12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15–50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed. Findings From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2–76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65–1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority). Interpretation In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events. Funding Daiichi Sankyo.

Background Randomized controlled trials showed the nonvitamin K oral anticoagulant (NOAC) edoxaban was effective and safe for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (AF) and for the prevention and treatment of venous thromboembolism (VTE; including pulmonary embolism and deep vein thrombosis). Additional research is needed to evaluate the effects of edoxaban in routine clinical practice. Therefore, the Edoxaban Treatment in routine cliNical prActice (ETNA) program is being conducted to provide routine clinical care data on characteristics and outcomes in patients with AF or VTE receiving edoxaban. Methods The Global ETNA program integrates prospectively collected data from edoxaban patients in regional ETNA noninterventional studies across Europe, Japan, and East and Southeast Asia into indication‐specific databases for AF and VTE. Targeted enrollment is >31 000 patients (AF >26 000; VTE >4500), with a follow‐up of 2 years for AF and 1 year for VTE. Data integration will be possible using consistent terminology, parameter definitions, and data collection across the regional noninterventional studies. Safety and effectiveness data will be assessed. Crude rates of outcomes including bleeding and thromboembolic events will be reported. Results Globally, enrollment began in early 2015 and is ongoing. Conclusions Global ETNA will generate the largest integrated prospective repository of routine clinical care data for a single NOAC in patients with AF or VTE. It will provide important information on the safety of edoxaban in routine clinical care and gather further information on its effectiveness.

Background Venous thromboembolism (VTE, including deep vein thrombosis [DVT] and pulmonary embolism [PE]) has an annual incidence rate of 104–183 per 100,000 person-years. After a VTE episode, the two-year recurrence rate is about 17%. Consequently, effective and safe anticoagulation is paramount. Edoxaban is a direct oral anticoagulant (DOAC) approved VTE treatment. Current safety and efficacy data are derived from clinical trials, and information about treatment durations beyond 12 months are not available. Methods ETNA-VTE-Europe is an 18-month prospective, single-arm, non-interventional, multinational post-authorisation safety study. Approximately 310 sites across eight European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Switzerland and the United Kingdom) will participate in the study, with the intention to represent the regional distributions of centres, healthcare settings and specialties. An estimated cohort of 2700 patients will be recruited, the only enrolment criteria being acute symptomatic VTE, no participation in an interventional study, and treating physician decision to prescribe edoxaban independently from the registry. Data from patient medical records and/or telephone interviews will be collected at baseline, 1, 3, 6, 12 and 18 months. The primary objective is to evaluate the 18-month rate of symptomatic VTE recurrence in patients with VTE treated with edoxaban outside a clinical trial. The co-primary objective is to evaluate the real-world rates of bleeding and adverse drug reactions. Secondary outcomes include rates of other patient-relevant safety events, adherence to and discontinuation of edoxaban. Furthermore, 12-month ETNA-VTE-Europe data will be considered in the context of those for patients receiving different anticoagulants in the PREFER in VTE registry and Hokusai-VTE clinical trial. Conclusions ETNA-VTE-Europe will allow the safety and effectiveness of edoxaban to be evaluated over an extended period in acute symptomatic VTE patients encountered in routine clinical practice. Findings will be informative for European practitioners prescribing edoxaban as part of real-world VTE treatment/prevention. Trial registration ClinicalTrials.gov Identifier: NCT02943993.

This randomized, parallel-group study in patients inadequately controlled on olmesartan medoxomil/amlodipine (OLM/AML) 40/10 mg assessed the effects of adding hydrochlorothiazide (HCTZ) 12.5 mg and 25 mg, using seated blood pressure (SeBP) measurements and ambulatory blood pressure (BP) monitoring. Enrolled patients were screened and tapered off of therapy if required. All patients received OLM/AML 40/10 mg and those with mean seated BP (SeBP) ≥140/90 mm Hg after 8 weeks (n=808) were randomized (1:1:1) to continue with OLM/AML 40/10 mg or receive OLM/AML/HCTZ 40/10/12.5 or 40/10/25 mg for a further 8 weeks. The primary endpoint was the change in seated diastolic BP (SeDBP) from the start to the end of the randomized treatment period. The addition of HCTZ 25 mg significantly reduced SeDBP (-2.8 mm Hg; P

Few studies describe oral anticoagulant (OAC) prescription practices in very elderly patients with atrial fibrillation (AF).In this sub-analysis of the PREFER in AF study, performed in 2012, patients were stratified according to age (80 [n=5565] and ≥80years [n=1660]) and OAC treatment. Factors associated with OAC prescription were analyzed in a multivariate logistic regression model with backward elimination of variables least associated with OAC use.Patients ≥80years presented with permanent AF more often (p0.0001) and reported fatigue and dyspnea more frequently (p0.0001) and palpitations less frequently (p0.0001) than patients80years. Hypertension, stroke, heart failure, coronary heart disease, peripheral arterial disease, cancer, chronic kidney disease, and prior major bleeding were significantly more frequent in ≥80years. Most patients were treated with OACs in both age groups. The overall use of vitamin K antagonists was similar in both groups (78.2% vs.78.2% p=0.98), while the use of non-vitamin K antagonist OACs was lower in the ≥80years old group than in the80years group (4.5% vs. 6.6% p=0.001). Among patients ≥80years, prior stroke and heart failure were significantly associated with OAC use, whereas higher age, prior bleeding, paroxysmal AF, chronic hepatic disease, and difficulties with self-care were associated with no OAC use.The current use of OAC in European AF patients was satisfactorily high in octogenarians, suggesting reasonable implementation of current guidelines. Interestingly, patients with poor quality of life were less often anticoagulated. This may warrant further studies.

Objective The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study was a double-blind trial in patients with hypertension at increased cardiovascular risk with carotid wall thickening and a defined atherosclerotic plaque that used non-invasive 2- and 3-dimensionaL (D) ultrasound (US), to compare the effects of a 2-year treatment based on either olmesartan medoxomil or atenolol on common carotid (CC) intima-media thickness (IMT) and plaque volume (PV). Methods A total of 165 patients (with systolic/diastolic blood pressure 140—180/ 90—105 mmHg) were randomized to receive either olmesartan (20—40 mg/day) or atenolol (50—100 mg/day). US was performed at baseline and 28, 52 and 104 weeks. The primary efficacy outcome was the change from baseline ( Δ) in CC-IMT assessed by 2D US. Secondary outcomes included Δ PV assessed by 3D US and blood pressure (BP). Results Olmesartan and atenolo produced comparable significant reductions in CC-IMT; mean Δ IMT (SEM) was -0.090 (0.015) mm for oLmesartan and -0.082 (0.014) mm for atenolol. Mean Δ PV was -4.4 (2.3) µl and 0.1 (1.5) µl in the olmesartan and atenolol treated subjects, respectively, without significant between-treatment differences. In the subgroup of patients with baseLine PV ≥ median (33.7 µl), significant between-treatment differences existed in Δ PV ( p = 0 .023), because PV regressed significantly with olmesartan ( Δ PV: -11.5 (4.4) µl) but not with atenolol ( Δ PV: 0.6 (2.5) µl). In these patients BP reductions were comparabLe. Conclusions Carotid IMT and BP decreased similarly with olmesartan and atenolol, but only olmesartan reduced the volume of larger atherosclerotic plaques.

The prevalence of isolated systolic hypertension (ISH) is high in the elderly, and the objective of this study was to compare the antihypertensive efficacy of olmesartan medoxomil with that of nitrendipine in elderly (65-74 years) and very elderly (/= 75 years) male and female patients with ISH.Patients were randomized to 24 weeks of treatment with either olmesartan medoxomil 20 mg daily (n = 256) or nitrendipine 20 mg (n = 126) twice daily, with possible dose increase (to 40 mg daily) and addition of hydrochlorothiazide (HCTZ) 12.5 or 25 mg daily if required.On the primary endpoint [reduction in mean sitting systolic blood pressure (SBP) after 12 weeks of treatment], the two treatments were similar (olmesartan medoxomil, -30.0 mmHg; nitrendipine, -31.4 mmHg). No significant difference between the treatment groups was observed, and non-inferiority of olmesartan medoxomil to nitrendipine was demonstrated using an analysis of covariance (ANCOVA) model. Reductions in mean sitting and standing SBP and diastolic blood pressure (DBP) up to week 24 were also similar with both treatments. Blood pressure (BP) goal attainment rates (sitting SBP/= 135 mmHg) increased consecutively, and were higher with olmesartan medoxomil (62.5%) than with nitrendipine (56.0%) at week 24 (not significant). Both treatments were well tolerated.In elderly patients with ISH, the mean reduction in SBP produced by olmesartan is similar to that produced by nitrendipine.

OBJECTIVE To test whether adding hydrochlorothiazide (HCTZ) (12.5 or 25 mg) to olmesartan 20 mg improves 24-h blood pressure in patients whose conventional diastolic blood pressure is inadequately controlled by olmesartan monotherapy. PATIENTS Male and female patients > or = 18 years with mean sitting diastolic blood pressure (DBP) of 100-115 mmHg, mean sitting systolic blood pressure (SBP) greater than 150 mmHg, mean 24-h DBP of at least 84 mmHg, and at least 30% of DBP daytime readings > 90 mmHg. INTERVENTIONS Four weeks of single-blind treatment with olmesartan 20 mg once daily, followed in non-responders by 8 weeks of randomized double-blind treatment with placebo or HCTZ (12.5 or 25 mg) once-daily, added to olmesartan. RESULTS HCTZ 25 mg added to olmesartan 20 mg decreased mean daytime DBP significantly more (P = 0.0012) than placebo added to olmesartan 20 mg. Compared to olmesartan monotherapy, mean 24-h DBP and SBP were significantly reduced by combination therapy with olmesartan/HCTZ 20/12.5 mg (-1.9 mmHg, P = 0.0167 and -3.9 mmHg, P = 0.0018, respectively) and 20/25 mg (-3.7 and -7.4 mmHg respectively, P < 0.0001 for both). Mean 24-h DBP and SBP and mean night-time SBP reductions were significantly greater for HCTZ 25 mg than for HCTZ 12.5 mg. Response rates (mean daytime DBP assessed by ambulatory blood pressure measurement < or = 85 mmHg) approximately doubled following the addition of HCTZ (12.5 mg = 57.6% and 25 mg = 69.5%). CONCLUSION Combination of olmesartan 20 mg with HCTZ provides significantly better 24-h blood pressure reduction than olmesartan monotherapy in patients with mild-to-moderate hypertension. Moreover, increasing the dose of HCTZ from 12.5 to 25 mg is a reasonable step to reach better daytime and night-time blood pressure control.

This prespecified subgroup analysis of a phase III study examined the effect of adding hydrochlorothiazide (HCTZ) to olmesartan (OLM)/amlodipine (AML) in patients with moderate to severe hypertension stratified by age, sex, body mass index, and hypertension severity. A total of 2690 patients, aged 18 years and older, with seated blood pressure (SeBP) ≥160/100 mm Hg received placebo or OLM/AML 20/5 mg, 40/5 mg, or 40/10 mg during a 2-week, double-blind, run-in period, after which they were allocated to one of eight treatment groups with the same OLM/AML dose or with HCTZ 12.5 mg or 25 mg added for 8 weeks. By week 10, greater reductions in SeBP were observed in each OLM/AML/HCTZ group (P

To reduce cardiovascular risk associated with hypertension, the majority of patients require at least two drugs to control their blood pressure (BP), and many require three or more.An open-label extension of a 10-week double-blind study assessed the long-term efficacy and safety of olmesartan/amlodipine/hydrochlorothiazide (OLM/AML/HCTZ) triple combination treatment in 2,509 patients with Grade 2-3 hypertension. After 8 weeks of single-blind OLM/AML/HCTZ 20/5/12.5 mg treatment, patients at BP goal [seated systolic/diastolic BP (SeSBP/SeDBP)140/90 mmHg, or130/80 mmHg for patients with diabetes, or chronic kidney or cardiovascular disease] entered open-label treatment for 36 weeks. Patients not at goal received 8 weeks of randomized, double-blind treatment before entering open-label treatment. During open-label treatment, patients received OLM/AML/HCTZ 20/5/12.5, 40/5/12.5, 40/5/25, 40/10/12.5 or 40/10/25 mg with up- or down-titration as needed to achieve BP goals.During open-label treatment, mean SeSBP/SeDBP levels remained within the ranges 120-140 and 75-85 mmHg, respectively. At study end, significant reductions from baseline were seen in each group for SeSBP (37-43 mmHg) and SeDBP (22-27 mmHg), and 78.1% of patients overall achieved BP goal. Categorical analysis of patients by baseline SeSBP (150-159, 160-169, 170-179, 180-189, 190 to200 mmHg) correlated with changes in SeSBP. Patients in the lowest baseline category (150-159 mmHg) showed a reduction of 34.3 mmHg, and those in the highest category (190 to200 mmHg) showed a 59.4 mmHg reduction. At baseline, 90.8% of patients had Grade 2 or 3 hypertension, but at study end 91.9% had normal/high-normal BP. The incidence of adverse events was similar across the treatment groups.In patients with Grade 2-3 hypertension, long-term treatment with OLM/AML/HCTZ triple combination therapy was well tolerated and effective. A high level of BP control and a substantial reduction in the level of hypertension severity were achieved.

To assess the efficacy and safety of the novel angiotensin II antagonist olmesartan medoxomil in patients with mild to moderate essential hypertension, using a meta-analysis of the combined database from seven US and European clinical trials.Studies were randomized, double-blind, placebo-controlled and dose-finding (2.5-80 mg), with treatment duration of 6-52 weeks.Hospital outpatient clinics.A total of 3,095 patients in the safety population and 3,055 patients in the intent-to-treat (efficacy) population.All studies used conventional sphygmomanometry for blood pressure measurements at trough (end of the dosing interval). Three studies also used 24-h ambulatory blood pressure monitoring for the principal efficacy evaluations.Percentage of patients achieving diastolic blood pressure (DBP)or = 90 mmHg or decreaseor = 10 mmHg (responder rate), percentage of patients achieving a target DBPor = 90 mmHg or target systolic blood pressure (SBP)or = 140 mmHg (normalization rate), and mean decrease in DBP from baseline to last visit.Efficacy variables tended to be dose related up to the 40 mg dose level. All olmesartan medoxomil doses were statistically significantly more effective than placebo for responder rate, DBP and SBP normalization rates, and mean decrease in DBP. A clinically relevant decrease ofor = 5 mmHg from baseline in sitting DBP was also observed at doses of 20 mg and above after correction for placebo effect The safety profile of olmesartan medoxomil was similar to that of placebo and was not dose related.Olmesartan medoxomil was safe and highly effective in lowering blood pressure in patients with mild to moderate essential hypertension in these studies.

Orally administered olmesartan medoxomil was rapidly absorbed from the gastrointestinal tract and converted during absorption to olmesartan, the pharmacologically active metabolite that was subsequently excreted without further metabolism. The medoxomil moiety was released as diacetyl that was rapidly cleared by further metabolism and excretion. Peak plasma concentrations of olmesartan occurred 1-3 h after administration, after which concentrations decreased quickly. The elimination half-life was 10-15 h. Olmesartan medoxomil was not measurable in plasma and excreta. The volume of distribution was low, consistent with limited extravascular tissue distribution. Bioavailability (Cmax and area under the curve) increased approximately in proportion with dose, after single and multiple daily oral doses, over the therapeutic dose range (up to 40-80 mg daily), above which systemic availability of olmesartan increased less than proportionally with increase in dose. Steady-state plasma concentrations of olmesartan were reached within the first few daily oral doses. On average, approximately 40% of systemically available olmesartan was excreted by the kidneys, the remainder being excreted in faeces, following secretion in bile. Renal clearance (0.5-0.7 l/h) was independent of dose, accounting for approximately 9-12% of an oral dose. The absolute bioavailability of olmesartan from olmesartan medoxomil tablets was 28.6%. Olmesartan exhibited little or no binding to blood cells. No clinically significant steady-state pharmacokinetic interactions were observed following co-administration of olmesartan medoxomil with digoxin, warfarin and aluminium magnesium hydroxide (antacid), supporting the low potential for clinically significant pharmacokinetic interactions to occur between olmesartan medoxomil and co-administered drugs.

Olmesartan medoxomil is a new angiotensin-II receptor antagonist for the treatment of hypertension. Olmesartan medoxomil is a pro-drug that is de-esterified to the active metabolite, olmesartan. Olmesartan has a dual method of elimination, with about 60% eliminated by the liver and the remainder by the kidney. In situations of impaired renal or hepatic function, the alternative excretion pathway can compensate for the compromised one. Olmesartan is not metabolized by the cytochrome P450 enzyme system and therefore has a low potential for metabolic drug interactions, a feature that may be of importance when treating patients on multiple drug regimens, such as the elderly. Olmesartan is well tolerated and has an excellent safety profile that is comparable to that of placebo. In addition, olmesartan provides 24-h blood pressure control with a once-daily dosing. In head-to-head studies, olmesartan delivered superior blood pressure reduction when compared with other angiotensin-II receptor antagonists at their recommended doses.

Objective This study was conducted to assess the dose-response relationship of the new angiotensin II (Ang II) antagonist CS-866 on blood pressure and on endocrine parameters in hypertensive patients with an activated renin-angiotensin system. Design Following a four-way crossover protocol, two groups of eight patients with mild-to-moderate hypertension received a sodium-restricted diet (60 mmol daily) and ingested single doses of 2.5, 10 and 40 mg or 5, 20 and 80 mg of CS-866, respectively, or placebo. Twenty-four hour ambulatory blood pressure measurements, plasma renin activity (PRA), Ang II and concentrations of RNH-6270, the pharmacologically active metabolite of CS-866, were monitored up to 24 h after medication. Results CS-866 was well tolerated. There was a significant decrease in 24 h diastolic blood pressure (DBP) at all doses of CS-866 above 5 mg. Increasing doses of CS-866 from 2.5 to 10 mg and from 5 to 20 mg lowered the mean 24 h DBP and DBP AUC 0-24h values considerably more than increasing doses from 10 to 40 mg and from 20 to 80 mg, respectively. The mean 24 h DBP was lowered by 6.9 and 8.4 mmHg after oral doses of 10 and 20 mg CS-866, respectively, compared with placebo and by 8.9 mmHg after 80 mg CS-866. The drug increased PRA and Ang II concentrations in plasma, maximum concentrations of which occurred within 3 h post-dose. The highest RNH-6270 concentrations were also found at the first post-dose measurement 3 h after administration of CS-866. Conclusion The new Ang II receptor antagonist CS-866 is effective and well tolerated. In salt-restricted hypertensive patients, CS-866 lowered blood pressure and increased PRA and Ang II concentrations at low doses. A single oral dose of 10-20 mg CS-866 resulted in almost maximal effects.

Background: European hypertension guidelines estimate that up to 15–20% of hypertensive patients are not controlled on a dual antihypertensive combination and require three or more different antihypertensive drug classes to achieve blood pressure (BP) control. Objective: This study in patients with moderate-to-severe hypertension assessed the efficacy and safety of adding hydrochlorothiazide (HCTZ) 12.5 mg and 25 mg to a range of olmesartan medoxomil (OLM)/amlodipine (AML) doses. Study Design: This phase III, multicentre study had a randomized, double-blind, parallel-group design that included a double-blind safety run-in and a double-blind treatment period. Intervention: Enrolled patients were screened and previous therapy was discontinued if required. During a 2-week, double-blind, safety run-in period (Weeks 0–2), patients were randomized to receive placebo, OLM/AML 20 mg/5 mg, OLM/AML 40 mg/5 mg or OLM/AML 40 mg/10 mg. During an 8-week, double-blind treatment period (Weeks 3–10), patients were allocated to eight groups depending on their initial treatment. They were either randomized to continue with the same dose of OLM/AML, or have HCTZ 12.5 mg or 25 mg added to treatment. Main Outcome Measure: The primary endpoint was formulated before data collection began. It was the change in mean diastolic BP (DBP) from baseline to Week 10 in groups with HCTZ added to OLM/AML, compared with the corresponding dual OLM/AML therapy. Results: Of 3195 patients who were screened, 2690 were randomized. Patients in every triple OLM/AML/HCTZ group had significantly greater mean reductions in DBP (p ≤ 0.032 for each comparison) and systolic BP (SBP) by Week 10 (p ≤ 0.0034 for each comparison), compared with patients on the corresponding OLM/AML therapy dose. The significant improvements in DBP and SBP reduction with triple OLM/AML/HCTZ therapy, compared with dual OLM/AML therapy, were observed after 4 and 6 weeks of therapy. Patients in each triple therapy group also had a significantly higher rate of BP < 140/90 mmHg threshold achievement (p ≤ 0.05 for each treatment comparison), compared with the dual OLM/AML groups. In three of the OLM/AML/HCTZ groups (40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg and 40 mg/10 mg/25 mg), BP

Olmesartan medoxomil was rapidly absorbed and converted to olmesartan in elderly hypertensive patients, and in patients with renal and hepatic dysfunction. No olmesartan medoxomil itself was detected in plasma. Pharmacokinetic steady state was reached within the first few days after oral dosing. In elderly (65-75 years old), after 80 mg olmesartan medoxomil once daily, and very elderly (or = 75 years old) hypertensive patients after 10 mg daily, steady-state Cmax and area under the curve (AUC(0-24 h)) values were up to 44% higher compared with young patients (46 years). Steady-state elimination half-life values were also longer in elderly (12.8 h) and very elderly patients (16.5 h) compared with young patients (10.6 and 12.3 h, respectively). At steady state after 10 mg olmesartan medoxomil daily in patients with renal impairment, both Cmax and AUC(0-24 h) increased as creatinine clearance (CLCR) decreased, and renal clearance (CLR) decreased with decreasing CLCR. Steady-state Cmax and AUC(0-24 h) values in patients with mild (CLCR, 40-59 ml/min) and moderate (CLCR, 20-30 ml/min) were up to 39 and 82% higher than the values in healthy subjects. After single oral doses of 10 mg olmesartan medoxomil daily to patients with mild (Child-Pugh scoreor = 6) and moderate (score 7-9) hepatic impairment, Cmax was generally similar to that in healthy matched subjects, but AUC increased by 30 and 48%, respectively, and was reflected in small increases in absolute bioavailability values compared with healthy subject controls. Excretion of olmesartan in urine also increased with the degree of hepatic impairment, indicating a compensatory excretion mechanism in this disease state. Since the increased plasma concentrations (Cmax and AUC(0-24 h)) in elderly and very elderly patients, and in mild and moderate renal and hepatic impairment, were several-fold lower than plasma concentrations observed in other studies after 80 mg olmesartan medoxomil daily that were well tolerated, a dosing adjustment in these groups is not considered necessary. In patients with severe renal impairment, however, consideration should be given to a lower starting dose, and it is recommended that the daily dose should not exceed 20 mg daily (compared with 40 mg daily for the general patient population).