The management of acute venous thromboembolism in clinical practice - study rationale and protocol of the European PREFER in VTE Registry

BACKGROUND: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. METHODS/DESIGN: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. RESULTS: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. CONCLUSION: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. TRIAL REGISTRATION: Registered in DRKS register, ID number: DRKS0000479

The diffuse-type tenosynovial giant cell tumor (dt-TGCT) patient journey: a prospective multicenter study

[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. Most 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 prospectively explores the management of TGCT in tertiary sarcoma centers.[Methods] The TGCT Observational Platform Project 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, 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.[Name of registry] Tenosynovial Giant Cell Tumors (TGCT) Observational Platform Project (TOPP).[Trial registration number] NCT02948088.[Date of registration] 10 October 2016.[URL of Trial registry record] https://clinicaltrials.gov/ct2/show/NCT02948088?term=NCT02948088&draw=2.Sponsored by Daiichi Sankyo, Co., Ltd; ClinicalTrials.gov Number NCT02948088. The Department of Orthopaedics of the Leiden University Medical Center receives research funding from Daiichi Sankyo. All research funding for Memorial Sloan Kettering is supported in part by a grant from the National Institutes of Health/National Cancer Institute (#P30 CA008748).Peer reviewe

Characteristics of patients initiated on edoxaban in Europe:baseline data from edoxaban treatment in routine clinical practice for patients with atrial fibrillation (AF) in Europe (ETNA-AF-Europe)

Background: Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The available routine care data have demonstrated the safety of different NOACs; however, such data for edoxaban are scarce. Here, we report baseline characteristics of 13,638 edoxaban-treated patients with AF enrolled between November 2016 and February 2018. Methods: ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study conducted in 825 sites in 10 European countries. Patients will be followed up for four years. Results: Overall, 13,980 patients were enrolled of which 342 patients were excluded from the analysis. Mean patient age was 73.6 years with an average creatinine clearance of 69.4 mL/min. 56.6% were male. The calculated CHA2DS2-VASc and HAS-BLED mean scores were 3.1 and 2.6, respectively. Overall, 3.3, 14.6 and 82.0% of patients had low (CHA2DS2-VASc = 0), intermediate (CHA2DS2-VASc = 1) and high (CHA2DS2-VASc≥2) risks of stroke, respectively. High-risk patients (those with prior stroke, prior major bleeding, prior intracranial bleed or CHA2DS2-VASc ≥4) comprised 38.4% of the overall population. For 75.1% of patients edoxaban was their first anticoagulant prescription, whilst 16.9% switched from a VKA and 8.0% from another NOAC. A total of 23.4% of patients in ETNA-AF-Europe received the reduced dose of edoxaban 30 mg. Overall, 83.8% of patients received an edoxaban dose in line with the criteria outlined in the label. Conclusion: Edoxaban was predominantly initiated in older, often anticoagulation-naïve, unselected European patients with AF, with a good overall adherence to the approved label. Trial registration: NCT02944019; Date of registration: October 24, 2016

Efficacy and Safety of Triple Antihypertensive Therapy with the Olmesartan/Amlodipine/Hydrochlorothiazide Combination

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 <140/90 mmHg threshold achievement by Week 10 was over 70%. Across the triple and dual combination therapy groups, treatment was well tolerated and no safety concerns for either treatment were identified. Conclusion: Adding HCTZ to a range of OLM/AML dose combinations is well tolerated and improved BP control by significantly lowering DBP and SBP and significantly increasing BP threshold achievement in patients with moderate-to-severe hypertension

Open-Label Study Assessing the Long-term Efficacy and Safety of Triple Olmesartan/Amlodipine/Hydrochlorothiazide Combination Therapy for Hypertension

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, or < 130/80 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 to < 200 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 to < 200 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

Clinical risk predictors in atrial fibrillation patients following successful coronary stenting: ENTRUST-AF PCI sub-analysis

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

Routine clinical practice in the periprocedural management of edoxaban therapy is associated with low risk of bleeding and thromboembolic complications: The prospective, observational, and multinational EMIT-AF/VTE study

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.status: publishe

Clinical risk predictors in atrial fibrillation patients following successful coronary stenting: ENTRUST-AF PCI sub-analysis

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

Edoxaban for stroke prevention in atrial fibrillation in routine clinical care: One year follow up of the prospective observational ETNA-AF-Europe study

AIM Non-vitamin K oral anticoagulants (NOACs) 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 one-year outcomes in patients with AF treated with edoxaban in routine care. METHODS AND RESULTS ETNA-AF-Europe is a prospective, multi-centre, post-authorisation, 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 one-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 (annualised event rate: 0.82%/year), and major bleeding events was 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 death occurred in 206 patients (1.63%/year). The approved dosing of edoxaban was chosen in 83%. All-cause and cardiovascular mortality were higher in patients receiving edoxaban 30 mg versus 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 versus 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