Evaluation of Treatment Safety in Patients with Atrial Fibrillation on Edoxaban Therapy in Real-Life in Turkey Study: Design and Rationale.

OBJECTIVE: Safety and effectiveness of edoxaban was demonstrated in phase III, Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE-AF-TIMI 48) trial and is being confirmed in the post-authorization Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study in patients with atrial fibrillation. However, any post-authoriza tion safety study focusing on the safety of edoxaban treatment in Turkey with a prospective design has not been performed yet. The Evaluation of Treatment Safety in Patients with Atrial Fibrillation on Edoxaban Therapy in Real-Life in Turkey (ETAF-TR) study is designed to evaluate the safety and effectiveness of edoxaban treatment in atrial fibrillation in routine practice. The present article describes the design and rationale for the ETAF-TR Study. METHODS: The ETAF-TR (NCT04594915) is a national, multicenter, prospective, observational study that enrolled 858 patients from 32 centers. The primary outcome of the ETAF-TR study is any overt bleeding (consisting of major bleeding or clinically relevant nonmajor bleeding or any bleeding that does not meet this definition but is considered as overt bleeding by the par ticipating physician). Effectiveness, treatment persistence, and posology will also be evaluated in an explorative manner. The overall duration of follow-up will be 1 year; the first patient was enrolled in August 2020. CONCLUSIONS: Results of ETAF-TR will add data from clinical practice to those from ENGAGE-AF trial and also ETNA-AF study. Comparing their results will enable to test the external validity of ENGAGE-AF trial in the country conditions.

Evaluation of demographic and clinical characteristics of female patients presenting with MINOCA and differences between male patients: A subgroup analysis of MINOCA-TR registry.

OBJECTIVE: Although the prevalence and rate of myocardial infarction with non-obstructive coronary arteries (MINOCA) are higher in women than in men in previous cohorts, potential demographic and clinical differences between women who are diagnosed with MINOCA versus myocardial infarction with obstructive coronary arteries (MIOCA) have not been studied till date. In this study, we aimed to document these characteristics and to compare them between female patients with MINOCA and MIOCA. METHODS: The study was a subgroup analysis of the MINOCA-TR study. The study was a multi-center, observational cohort study that was conducted in Turkey between March 2018 and October 2018. In this study, 477 (29.3%) female patients who had been diagnosed with acute myocardial infarction were evaluated. RESULTS: Of these women, 49 (10.3%) were diagnosed with MINOCA (mean age 58.9±12.9 years) and 428 (89.7%) had a final diagnosis of MIOCA (mean age 67.4±11.8 years). The prevalence of hypertension, hyperlipidemia, and diabetes mellitus was significantly lower in the MINOCA group than in the MIOCA group. In addition, the MINOCA group had higher rates of recent flu history and non-ST elevation myocardial infarction (NSTEMI) presentation than the MIOCA group. There were significant clinical differences in patients with MINOCA in terms of sex. The female patients were older, had higher systolic blood pressures, and lower hemoglobin levels than male patients. CONCLUSION: The study revealed that the prevalence of traditional coronary artery disease risk factors was lower in female patients with MINOCA than in those who had final diagnosis of MIOCA.

Dabigatran for stroke prevention in real life in a sample of population from Turkey: D-SPIRIT registry.

OBJECTIVE: The D-SPIRIT registry is designed to investigate the safety and effectiveness of dabigatran etexilate in patients with atrial fibrillation in routine clinical practice. METHODS: D-SPIRIT is the first national, multicenter, prospective, observational, postmarketing registry that investigates the usage of dabigatran in real life. A total of 326 noveloral anticoagulant-eligible patients with atrial fibrillation who have been taking dabigatran etexilate therapy for stroke prevention at least 6 months from 9 different centers were enrolled into the registry. Patients were followed up for 2 years to evaluate the effectiveness and safety of the treatment. All adverse clinical events including bleeding, thromboembolic events, stroke, systemic embolism, transient ischemic attack, myocardial infarction, and all-cause death were recorded. RESULTS: The mean age was 71.1±9.6 years, and 57.4% of the study participants were female. The mean CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack [TIA], vascular disease, age 65-74 years, sex category) score was 3.4±1.6. The cumulative adverse clinical events rate was 6.30% per year. The rate for embolic events including TIA, ischemic stroke, and peripheral embolism was 1.26% per year. The rate for major bleeding was 2.20% per year, and the mortality rate was 0.94% per year. CONCLUSION: This registry obtained an important overview of the current safety and effectiveness of the dabigatran etexilate in Turkey. Our results indicate similar rates of thromboembolic and bleeding events with pivotal phase 3 trial and other real-life registries. However, rate of undertreatment usage of dabigatran etexilate in real life was found to be considerable.

Demographic, Clinical, and Angiographic Characteristics of Atrial Fibrillation Patients Suffering From de novo Acute Myocardial Infarction: A Subgroup Analysis of the MINOCA-TR Study Population.

BACKGROUND: Atrial fibrillation (AF) prevalence in patients with acute myocardial infarction (MI) ranges from 3% to 25%. However demographic, clinical, and angiographic characteristics of AF patients who admitted with de novo MI are unclear. The aim of this study was to investigate the prevalence of patients presenting with de novo MI with AF. METHODS: The study was performed as a sub-study of the MINOCA-TR (Myocardial Infarction with Non-obstructive Coronary Arteries in Turkish Population) Registry, a multicenter, cross-sectional, observational, all-comer registry. MI patients without a known history of stable coronary artery disease and/or prior coronary revascularization were enrolled in the study. Patients were divided into AF and Non-AF groups according to presenting cardiac rhythm. RESULTS: A total of 1793 patients were screened and 1626 were included in the study. The mean age was 61.5 (12.5) years. 70.7% of patients were men. The prevalence of AF was 3.1% (51 patients). AF patients were older [73.4 (9.4) vs. 61.0 (12.4) years, p<0.001] than non-AF patients. The proportion of women to men in the AF group was also higher than in the non-AF group (43.1% vs. 28.7%, p=0.027). Only 1 out of every 5 AF patients (10 patients, 19.6%) was using oral anticoagulants (OAC). CONCLUSIONS: AF prevalence in patients presenting with de novo MI was lower than previous studies that issued on AF prevalence in MI cohorts. The majority of AF patients did not have any knowledge of their arrhythmia and were not undergoing OAC therapy at admission, emphasizing the vital role of successful diagnostic strategies, patient education, and implementations for guideline adaptation.

Current clinician perspective on non-vitamin K antagonist oral anticoagulant use in challenging clinical cases.

OBJECTIVE: The evolution of non-vitamin K antagonist anticoagulants (NOACs) has changed the horizon of stroke prevention in atrial fibrillation (SPAF). All 4 NOACs have been tested against dose-adjusted warfarin in well-designed, pivotal, phase III, randomized, controlled trials (RCTs) and were approved by regulatory authorities for an SPAF indication. However, as traditional RCTs, these trials have important weaknesses, largely related to their complex structure and patient participation, which was limited by strict inclusion and extensive exclusion criteria. In the real world, however, clinicians are often faced with complex, multimorbid patients who are underrepresented in these RCTs. This article is based on a meeting report authored by 12 scientists studying atrial fibrillation (AF) in diverse ways who discussed the management of challenging AF cases that are underrepresented in pivotal NOAC trials. METHODS: An advisory board panel was convened to confer on management strategies for challenging AF cases. The article is derived from a summary of case presentations and the collaborative discussions at the meeting. CONCLUSION: This expert consensus of cardiologists aimed to define management strategies for challenging cases with patients who underrepresented in pivotal trials using case examples from their routine practice. Although strong evidence is lacking, exploratory subgroup analysis of phase III pivotal trials partially informs the management of these patients. Clinical trials with higher external validity are needed to clarify areas of uncertainty. The lack of clear evidence about complex AF cases has pushed clinicians to manage patients based on clinical experience, including rare situations of off-label prescriptions.

Prevalence and clinical profile of patients with myocardial infarction with non-obstructive coronary arteries in Turkey (MINOCA-TR): A national multi-center, observational study.

OBJECTIVE: Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) is a relatively new term that is characterized by clinical evidence of MI with normal or near-normal coronary arteries on coronary angiography (QCA). To date, there have been no population-based studies on the prevalence of MINOCA in Turkey. The aim of this nationwide study was to document the prevalence and demographics of MINOCA in a Turkish population. METHODS: MINOCA-TR is national, multi-center, prospective, all-comer study that was conducted in 32 hospitals. All consecutive patients who were ≥18 years old, diagnosed with MI according to the Third Universal Definition of Myocardial Infarction, and had undergone QCA were included in the study. Patients with stable coronary artery disease, unstable angina pectoris, a history of revascularization, and type 4/5 MI were excluded. RESULTS: A total of 1793 patients who were diagnosed with MI and had undergone QCA were screened between March 2018 and October 2018, of whom 1626 (mean age: 61.5±12.5 years, 70.7% male) were enrolled from 32 centers. The prevalence of MINOCA was 6.7% (n=109) in the overall study population. Compared with non-MINOCA patients, those with MINOCA were younger, had a higher prevalence of the female gender, and had a history of flu. The percentages of current smokers, ST-segment elevated myocardial infarction patients, and those with a history of hypertension, diabetes mellitus, and hyperlipidemia were significantly lower in MINOCA patients (p<0.05, for all). Also, the median left ventricular ejection fraction as seen on echocardiography and the ratio of Killip Class I status at presentation was significantly higher in MINOCA patients than in non-MINOCA patients (p<0.001). Patients with MINOCA received a preload dose of P2Y12 antagonist before QCA less often than non-MINOCA patients (p<0.001). CONCLUSION: The prevalence of MINOCA in Turkey is 6.7% in patients who were admitted with MI. Also, as compared to non-MINOCA patients, the MINOCA patients were exposed to fewer traditional risk factors of coronary artery disease.

Rationale and design of the Myocardial Infarction with Non-obstructive Coronary Arteries in Turkish Population (MINOCA-TR) study.

OBJECTIVE: Myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA) is a new term to define the syndrome of clinical evidence of MI occurring in the absence obstructive coronary artery disease. Given that there is believed to be a large number of MINOCA cases, effective diagnostic and therapeutic strategies are needed. Documentation of the demographic parameters and diagnostic methods used in existing cases is a first step. The purpose of this study is documentation of the prevalence, demographic details, and possible etiological causes, as well as inpatient and 1-year prognosis data of MINOCA patients in the Turkish population. METHODS: The MINOCA-TR Study is a national, multi-center, prospective, observational study. A sample of 1028 conse-cutive MI patients who undergo diagnostic angiography will be enrolled. This is a cohort study that will include patients from 32 different centers. After an initial screening/enrollment visit, follow-up will be performed at the time of hospital discharge for the overall MI study population. Patients diagnosed as MINOCA will be followed up with 3 prospective office or telephone visits as part of the Prospective MINOCA Registry. CONCLUSION: Demographic information, clinical characteristics, management strategies, and inpatient prognostic indicators will be documented in the cross-sectional portion of the registry. Additional diagnostic data, therapeutic strategies, and prognostic relevance will be recorded in the 12 months of the prospective research. The results are expected to inform future diagnostic and therapeutic strategies and enhance understanding of the condition by highlighting the national burden of the disease from a medical and a public health perspective, as well as stimulate future research focusing on the MINOCA population.

Remote monitoring with cardiac implantable electronic device to follow up pharmacodynamic effects of sacubitril/ valsartan treatment: A case report.

Cardiac implantable electronic devices include remote monitoring tools intended to guide heart failure management. These tools allow for observation of some physiological functions, such as intrathoracic impedance (ITI), patient activity (PA), and heart rate variability (HRV). Sacubitril/valsartan is recommended in the current guidelines as foundational therapy for patients with heart failure and reduced ejection fraction. However, the effects of sacubitril/valsartan treatment on these physiological parameters remain unclear. To the best of our knowledge, this is the first case objectively documenting improvements in ITI, PA, and HRV values with sacubitril/valsartan treatment.

Enhancing Solubility and Bioavailability of Rosuvastatin into Self Nanoemulsifying Drug Delivery System.

OBJECTIVE: The aim of this study was to develop new Rosuvastatin calcium (RCa) self nanoemulsifying drug delivery system (SNEDDS) and to evaluate the bioavailability and pharmacodynamic effect of RCa-SNEDDS in Yorkshire pigs. METHODS: Firstly, SNEDDS was developed and prepared then RCa was incorporated into SNEDDS which was evaluated regarding their characterization, stability properties, drug release profiles, permeation and cytotoxicity studies. Finally, in vivo performance of RCa-SNEDDS (F1-RCa-SNEDDS) was examined by pharmacokinetic and pharmacodynamics studies. The average droplet size of RCa- SNEDDS ranged between 200 and 250 nm. RCa-SNEDDS that contained 12.8% Oleic acid, 11 % Labrafil M, 3.3 % Labrasol and 4.4 % Transcutol HP were found to be stable and exhibited approximately 4-fold higher permeation than commercial tablet (Crestor® 20 mg tablet). RESULTS: In pharmacokinetic studies, when F1-RCa-SNEDDS and commercial tablet were administered orally, F1-RCa-SNEDDS showed higher bioavailability of RCa than commercial tablet. Respectively, in pharmacodynamic studies, triglyceride and total cholesterol levels were significantly reduced with F1- RCa-SNEDDS formulation by 37% and 19% when compared to baseline values. CONCLUSION: However, these decreases with commercial formulation were only 6% and 2% respectively. According to these findings, development formulation could be potentially used to enhance the oral absorption of RCa.

Design and rationale of dabigatran's stroke prevention in real life in Turkey (D-SPIRIT).

OBJECTIVE: The D-SPIRIT registry is designed to investigate the safety and efficacy of dabigatran etexilate in patients with nonvalvular atrial fibrillation (NVAF) and to collect data on outcomes in clinical practice. METHODS: The D-SPIRIT is a national, prospective, observational, post-marketing registry involving patients with NVAF who have been taking dabigatran etexilate therapy for stroke prevention for a minimum of 6 months prior to enrollment. The registry will collect and analyze data from routine care, enrolling up to 600 patients in 9 centers. Patients will be followed up for 2 years to evaluate effectiveness and safety. A sample size of 600 subjects is proposed based on the following assumptions; Two-sided significance level of 0.05 (1-sided significance level of 0.025), ischemic stroke incidence rate of 0.768%-1.111%, hemorrhagic stroke incidence rate of 0.109%-0.130%, transient ischemic attack incidence rate of 0.722%-0.623%, therapy discontinuation incidence rate of 40% at day 730, and duration of enrollment period of 12 months with non-uniformed enrollment rate. Ethics approval was given by Dokuz Eylül University Ethics Committee of Clinical Research (2014/54) and approved by the Turkish Ministry of Health. CONCLUSION: Potential results of D-SPIRIT registry will add data from clinical practice to those from the RE-LY trial to expand knowledge of dabigatran etexilate treatment in patients with NVAF.

Evaluation of the impact of warfarin time in therapeutic range on outcomes of patients with atrial fibrillation in Turkey: perspectives from the observational, prospective WATER Registry.

BACKGROUND: Warfarin is highly efficacious in reducing stroke risk in patients with atrial fibrillation (AF). However, its safety and efficacy in stroke prevention is markedly influenced by its time in therapeutic range (TTR). The quality of anticoagulant therapy varies considerably among countries. Representative data concerning the quality of anticoagulant therapy and its effects on clinical outcomes in Turkey are lacking. METHODS: Warfarin in Therapeutic Range (WATER) registry is a prospective, observational study which followed 572 AF patients (mean age 67.3 ± 12 years; females 60%; 71% non-valvular AF) treated with warfarin. RESULTS: At a median of 22-month follow-up, the mean TTR value was 42.3 ± 18% (median: 40%) for the whole population and lower in non-valvular AF su group than valvular AF subgroup (40.3 ± 18 vs. 46.9 ± 19, respectively, p < 0.001). Death, cardiac hospital-ization and minor bleeding rates were higher in the group with TTR value < 40% than the group with > 40% (3.4% vs. 5.9%; 28.6% vs. 35.4%; 36.5% vs. 41.7%, respectively, all of them p < 0.001). A correlation analysis showed a negative correlation between age and TTR value (r = -0.178, p < 0.001). Mean CHA2DS2VASc score was 3.63 ± 1.5 and mean HASBLED score was 2.38 ± 1.01 in the non-valvular AF group. A negative correlation was observed between TTR levels and CHA2DS2VASc score. CONCLUSIONS: WATER provides insight into the anticoagulation control status of AF patients in Turkey. The quality of anticoagulation was poor. Strategies should be undertaken by clinicians and patients to improve TTR. New oral anticoagulant agents may be perfect alternatives for non-valvular AF patients.

Amiodarone-induced multiorgan toxicity with ocular findings on confocal microscopy.

Amiodarone is an antiarrhythmic medication that can adversely effect various organs including lungs, thyroid gland, liver, eyes, skin, and nerves. The risk of adverse effects increases with high doses and prolonged use. We report a 54-year-old female who presented with multiorgan toxicity after 8 months of low dose (200 mg/day) amiodarone treatment. The findings of confocal microscopy due to amiodarone-induced keratopathy are described. Amiodarone may cause multiorgan toxicity even at lower doses and for shorter treatment periods.

A new device for paravalvular leak closure.

Percutaneous closure of a prosthetic paravalvular leak (PVL) is a challenging procedure. Operators must use devices constructed for other applications. We present the use of a device which is specifically designed for PVL closure. To the best of our knowledge, there is no publication in MEDLINE reporting the use of the device.

Inadvertent implantation of pacemaker lead in the left ventricle: kill two birds with one stone.

We report an asymptomatic patient in whom the intravenous pacemaker (PM) lead was inadvertently implanted in LV through the perforated interventricular septum. He had no embolic events during the last 9 years after the implantation. Possible explanation of the uncomplicated follow-up period is that the patient had been taking warfarin because of mechanical mitral valve prosthesis.