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Cătălina Liliana Andrei,1 Andreea Catană,1 Crina Julieta Sinescu,1 Andreea Mirică,2 Octavian Ceban,2 Valentin Puiu Chioncel,1 Roxana Oana Darabont1 1University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania; 2The Bucharest University of Economic Studies, Bucharest, RomaniaCorrespondence: Andreea Catană, University of Medicine and Pharmacy “Carol Davila”, Dionisie Lupu Street, no. 37, Bucharest, 020021, Romania, Tel +40-745469489, Email catanaandreea91@yahoo.com; andreea.catana@drd.umfcd.roPurpose: Despite all medical efforts and discoveries, heart failure (HF) remains one of the most important and common public health problems, with high mortality and hospitalization rates, due to decompensation of HF. In the present study, we aimed to identify a predictive factor through which we can evaluate the risk of readmission and mortality in the first year, given the initial admission of a patient with decompensated heart failure.Patients and Methods: The parameter we have investigated is the mean platelet volume (MPV). Studies have shown that there is a significant correlation between the value of MPV and the risk of cardiovascular disease (CVD) and cardiovascular (CV) death. In this study, we enrolled 130 patients hospitalized for decompensated chronic HF (NYHA class IV HF or acute pulmonary edema) and analyzed whether there is a relationship between the value of the MPV at admission and 6-month rehospitalization, and 1-year mortality, respectively.Results: The statistical analysis revealed significantly different values (p = 0.041) for MPV at admission between the group of patients without decompensated chronic HF compared to the group of patients with decompensated chronic HF (8.74 fl vs 9.08 fl). Also, the results of our study revealed that patients with decompensated chronic heart failure who were readmitted at 6 months and died at 1 year, respectively, had a higher MPV at admission (> 9 fl), compared to those without the above-mentioned events, with a statistical significance.Conclusion: A higher MPV at admission can be considered in our study as an independent predictor for rehospitalization and 1-year mortality of patients with decompensated chronic HF.Graphical Abstract: Keywords: decompensated heart failure, mean platelet volume, 6-month rehospitalization, 1-year mortality

Cardiovascular diseases (CVDs) are the leading cause of mortality in Europe, with potentially more than 60 million deaths per year, with an age-standardized rate of morbidity-mortality higher in men than women, exceeding deaths from cancer. Heart attacks and strokes account for more than four out of every five CVD fatalities globally. After a patient overcomes an acute cardiovascular event, they are referred for rehabilitation to help them to restore most of their normal cardiac functions. One effective way to provide this activity regimen is via virtual models or telerehabilitation, where the patient can avail themselves of the rehabilitation services from the comfort of their homes at designated timings. Under the funding of the European Union’s Horizon 2020 Research and Innovation program, grant no 769807, a virtual rehabilitation assistant has been designed for elderly patients (vCare), with the overall objective of supporting recovery and an active life at home, enhancing patients’ quality of life, lowering disease-specific risk factors, and ensuring better adherence to a home rehabilitation program. In the vCare project, the Carol Davila University of Bucharest (UMFCD) was in charge of the heart failure (HF) and ischemic heart disease (IHD) groups of patients. By creating a digital environment at patients’ homes, the vCare system’s effectiveness, use, and feasibility was evaluated. A total of 30 heart failure patients and 20 ischemic heart disease patients were included in the study. Despite the COVID-19 restrictions and a few technical difficulties, HF and IHD patients who performed cardiac rehabilitation using the vCare system had similar results compared to the ambulatory group, and better results compared to the control group.

Purpose: Using a data and machine learning approach, from classical to complex, we aim to approximate the relationship between factors such as behavioral, social or comorbidity and the ejection fraction for hospitalized patients. To measure how much the independent variables influence the left ventricular ejection fraction (LVEF), classification models will be made and the influences of the independent variables will be interpreted. Through the data obtained, it is desired to improve the management of patients with heart failure (treatment, monitoring in primary medicine) in order to reduce morbidity and mortality. Patients and Methods: In this study, we enrolled 201 patients hospitalized with decompensated chronic heart failure. The models used are extreme gradient boosting (XGB) and logistic regression (LR). To have a deeper analysis of the independent variables, their influences will be analyzed in two ways. The first is a modern technique, Shapley values, from game theory, adapted in the context of Machine Learning for XGB; and the second, the classical approach, is by analysis of Logistic Regression coefficients. Results: The importance of several factors related to behavior, social and diabetes are measured. Smoking, low education and obesity are the most harmful factors, while diabetes controlled by diet or medication does not significantly affect LVEF, indeed, there is a tendency to increase the LVEF. Conclusions: Using machine learning techniques, we can better understand to what extent certain factors affect LVEF in this sample. Following further studies on larger groups and from different regions, prevention could be better understood and applied.

Tracheal stenosis is a rare complication of tracheal intubation, which usually becomes symptomatic after some time after detubation, with typical superior airway obstruction signs and symptoms. This is a case of a 62-yearold female with post intubation tracheal stenosis, with interesting problems of differential diagnosis until the final diagnostic was found. Clinical and imagistic investigations led us to our final diagnosis of iatrogenic post intubation tracheal stenosis.

Purpose. The study aims to determine the impact of dysthyroidism on the severity and type of coronary lesion, on vascular function, as well as on the morbidity and mortality of patients with acute coronary syndrome, by finding predictive markers that can be translated into preventive measures that contribute substantially to reduce the number of newly diagnosed patients with coronary heart disease. Methods. We introduced in the study 100 patients recently diagnosed with acute coronary syndrome, without history of ischemic heart disease or thyroid disease, hospitalized in the Cardiology Clinic of the “Bagdasar-Arseni“ Emergency Clinical Hospital Bucharest, for the interventional treatment of acute coronary syndrome. The studied patients were hospitalized between November 2014 and April 2015, with regular follow-up of up to 5 years (telephone or direct interview, conducted at 6 months, 12 months, 24 months, 36 months, 48 months, 60 months), with an average period follow-up of 1006 days, evaluated clinically, bio-humorally, by echocardiography, explored with coronary angiography with the calculation of the SYNTAX score and with the performance of electrocardiogram and pulse wave. The obtained data were integrated in Excel sheets and statistically processed with the Python program. Results. The mortality rate in the patient group was 7% (7 deaths). Descriptively, of the deceased, 6 patients (86%) were male, and as thyroid status 1 hyperthyroid patient (14%), 3 hypothyroid patients (43%) and 3 patients (43%) normothyroid. There were 4 deaths (8%) in the group of patients with unstable angina and 3 deaths (8%) in the group of patients with myocardial infarction without ST-segment elevation. There were no deaths in the group of patients with acute myocardial infarction with ST-segment elevation. At follow-up, 41 patients (41%) were readmitted. Re-hospitalization was influenced by elevated values of mean blood pressure, diastolic blood pressure and C-reactive protein, unicoronary atherosclerotic disease and unstable angina at admission. At follow-up, the development of noncardiac events was noted in the evolution of patients, diabetes mellitus occurring in the majority, in almost a quarter of patients (22 patients, respectively 24% developed diabetes over time), 34% (19 patients) in euthyroidism and 8% (3 patients) dysthyroidism. Discussions. Predictive factors for the readmission of the patient with acute coronary syndrome are highlighted the following: increased level of C-reactive protein (p = 0.017), tricoronary vascular damage (p = 0.01), diastolic blood pressure greater than 80 mmHg (p = 0.025), and euthyroid status (p = 0.04). The probability of death for the patient with acute coronary syndrome rises to 66% in the presence of severe systolic dysfunction of the left ventricle (p = 0.006), and to 61% in the case of elevated values of hs troponin I (p = 0.008). In our study, the presence of dysthyroidism in the patient with acute coronary syndrome has a protective role in the development of diabetes in the first 5 years (p = 0.025). Conclusion. Dysthyroidism is associated with increased morbidity and mortality from cardiovascular disease.

Objective: The importance of the NT-proBNP value in detecting patients at risk of developing heart failure (HF) and its importance in guiding medical management to prevent the development of HF. Material and methods: The study is a prospective study and includes 314 patients who was presented at the Bagdasar-Arseni Emergency Hospital for cardiology consultation, by appointment, for a period of 3 years. The inclusion criteria were as follows: essential hypertension (diagnosed more than 5 years before), diabetes mellitus (insulin-deficient or under treatment with oral ant diabetics diagnosed more than 5 years before), ischemic heart disease, mild or moderate valvulopathy (mild or moderate mitral regurgitation and large or moderate aortic stenosis) and permanent or paroxysmal atrial fibrillation. Exclusion criteria were as follows: a previous diagnosis of heart failure or left ventricular systolic dysfunction, and the presence of signs or symptoms of heart failure at the time of enrollment in the study. Patients were randomized into 2 groups, a control group and a intervention group. Patients in the intervention group were managed according to the NT-proBNP value, and patients in the control group received the conventional intervention. Patients were monitored for 3 years and the following objectives were pursued: new diagnosis of heart failure, systolic or diastolic dysfunction of the left ventricle and hospitalization for cardiovascular pathology. Results: After 3 years, in the control group there were 40 patients (25.5%) who developed HF, compared to 28 patients (17.8%) in the intervention group. In the control group, 60 patients (38.2%) were diagnosed with left ventricular systolic dysfunction, compared to 43 patients (27.4%) in the intervention group. Regarding left ventricular diastolic dysfunction, in the control group there were 98 patients (62.4%), and in the intervention group there were 80 patients (51.0%). Also, the rate of hospitalizations for cardiovascular pathology was higher in the control group, 56 patients (35.7%), compared to 33 patients (21.0%) in the intervention group. Discussions: The incidence of heart failure, left ventricular systolic or diastolic dysfunction, or hospitalizations for cardiovascular events, was lower in the intervention group, in which patients were managed according to the NT-proBNP value, compared to patients in the control group who received conventional intervention. Conclusions: The NT-proBNP biomarker may be useful in the medical management of patients for the prevention of heart failure.

Purpose. The study aims to determine the impact of dystyroidism on the type of acute coronary syndrome, on vascular function and coronary impairment, as well as on the myocardium and last but not least the general biological resonance of these hormones, emphasizing the role of thyroid hormones in the cardiovascular system. Methods. We introduced in the study 100 patients recently diagnosed with acute coronary syndrome, without history of ischemic heart disease or thyroid disease, hospitalized in the Cardiology Clinic of the Emergency Clinical Hospital Bagdasar-Arseni Bucharest, for the interventional treatment of acute coronary syndrome. The studied patients were hospitalized between November 2014 - April 2015, with follow-up up to 5 years, evaluated clinically, bio-humorally, by echocardiography, coronary angiography with SYNTAX score calculation and electrocardiogram and pulse wave. The obtained data were integrated in Excel sheets and statistically processed with the Python program. Results. The prevalence of dystyroidism in the study group was 44% (44 patients). Hypothyroidism is predominant (34 patients; 77%), and subclinical hypothyroidism occurs in 20 (59%) of subjects with hypothyroidism. Unstable angina is the predominant type of acute coronary syndrome, both in the whole group (54 patients; 54%) and in the group of patients with hyperthyroidism (7 patients; 70%), while acute myocardial infarction without ST-segment elevation was the type majority of presentation in patients with hypothyroidism (19 patients, 56%). Coronary heart disease varied as follows: in the total group unicoronary lesion (31 subjects; 31%), in patients with hyperthyroidism unicoronary lesion (5 subjects; 50%), in patients with hypothyroidism bicoronary lesion (10 subjects; 29%). And the calculated SYNTAX score is higher in the group of patients with dysthyroidism compared to the group of patients with euthyroidism. Discussions. Unstable angina (p = 0.006) and ventricular wall hypertrophy (p = 0.008) are predictive factors for dysthyroidism. Hypothyroidism correlates with high LDL-cholesterol levels (p = 0.0176) and hyposideremia (p = 0.0083), while hyperthyroidism correlates with thrombocytosis (p = 0.0122) and a significant nonspecific inflammatory syndrome (p = 0.0043). Dystyroidism has a direct correlation with the presence of kinetic disorders (Person correlation coefficient 0.21). Conclusion. Thyroid disease, with hypothyroidism or hyperthyroidism, can also be a risk factor for cardiovascular disease, and especially for ischemic heart disease.

Purpose. NT proBNP is routinely used in the diagnosis and prognosis of HF. The study aimed to determine whether the value of NT proBNP can be used in hypertensive patients to detect patients at risk of developing HF and whether in these patients medical management guided by NT proBNP can prevent the development of HF. Material and methods. We included 275 hypertensive patients who presented to the Bagdasar-Arseni Emergency Hospital for cardiological consultation for a period of 3 years. Patients diagnosed with heart failure or left ventricular systolic dysfunction and patients with symptoms of heart failure at enrollment were excluded. We divided the patients into 2 groups, a control group and an intervention group. Patients in the intervention group were managed according to the NT proBNP value, and patients in the control group received standard treatment. Results. The objectives pursued at 3 years were: diagnosis of heart failure, systolic or diastolic dysfunction of the left ventricle and hospitalization for cardiovascular pathology. After 3 years, in the control group there were 34 patients (25.4%) who developed HF, compared to 24 patients (17.0%) in the intervention group. In the control group, 51 patients (38.1%) were diagnosed with LV systolic dysfunction compared to 37 patients (26.2%) in the intervention group. Regarding diastolic LV dysfunction, in the control group there were 83 patients (61.9%), and in the intervention group there were 73 patients (51.8%). Also, the rate of hospitalizations for cardiovascular pathology was higher in the control group 47 patients (35.1%) compared to 27 patients (19.1%) in the intervention group. Discussions. Hypertensive patients in the intervention group, who were managed according to the NT proBNP value, had a lower incidence rate of heart failure, LV systolic or diastolic dysfunction, or hospitalizations for cardiovascular events than in the control group. Conclusions. The value of NT proBNP may be useful for detecting hypertensive patients at risk of developing HF, and NT proBNP-guided medical management may prevent or delay the onset of HF.

Hypertension frequently coexists with obesity, diabetes, hyperlipidemia, or metabolic syndrome, anditsassociation with cardiovascular disease is well established. The identification and management of these risk factors is an important part of overall patient management. In this paper, we find the most relevant patterns of hospitalized patients with cardiovascular diseases, consideringaspects of their comorbidities, such as triglycerides, cholesterol, diabetes, hypertension, and obesity. To find the most relevant patterns, several clusterizations were made, playing with the dimensions of comorbidity and the number of clusters. There are three main patient types who require hospitalization: 20% whose comorbidities are not so severe, 44% with quite severe comorbidities, and 36% with fairly good triglycerides, cholesterol, and diabetes but quite severe hypertension and obesity. The comorbidities, such as triglycerides, cholesterol, diabetes, hypertension, and obesity, were observed in different combinations in patients upon hospital admission.

Due to population aging, we are currently confronted with an increased number of chronic heart failure patients. The primary purpose of this study was to implement a noncontact system that can predict heart failure exacerbation through vocal analysis. We designed the system to evaluate the voice characteristics of every patient, and we used the identified variations as an input for a machine-learning-based approach. We collected data from a total of 16 patients, 9 men and 7 women, aged 65–91 years old, who agreed to take part in the study, with a detailed signed informed consent. We included hospitalized patients admitted with cardiogenic acute pulmonary edema in the study, regardless of the precipitation cause or other known cardiovascular comorbidities. There were no specific exclusion criteria, except age (which had to be over 18 years old) and patients with speech inabilities. We then recorded each patient’s voice twice a day, using the same smartphone, Lenovo P780, from day one of hospitalization—when their general status was critical—until the day of discharge, when they were clinically stable. We used the New York Heart Association Functional Classification (NYHA) classification system for heart failure to include the patients in stages based on their clinical evolution. Each voice recording has been accordingly equated and subsequently introduced into the machine-learning algorithm. We used multiple machine-learning techniques for classification in order to detect which one turns out to be more appropriate for the given dataset and the one that can be the starting point for future developments. We used algorithms such as Artificial Neural Networks (ANN), Support Vector Machine (SVM) and K-Nearest Neighbors (KNN). After integrating the information from 15 patients, the algorithm correctly classified the 16th patient into the third NYHA stage at hospitalization and second NYHA stage at discharge, based only on his voice recording. The KNN algorithm proved to have the best classification accuracy, with a value of 0.945. Voice is a cheap and easy way to monitor a patient’s health status. The algorithm we have used for analyzing the voice provides highly accurate preliminary results. We aim to obtain larger datasets and compute more complex voice analyzer algorithms to certify the outcomes presented.

BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention.METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; PCONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).

Cavernous haemangioma (cavernoma) is a benign vascular lesion, exceptionally located in cauda equina. We report a case, diagnosed and operated in the Department of Neurosurgery from Pitesti County Emergency Hospital, of a 60-year-old woman with history of lumbar region distress, who presented with low back pain, paravertebral muscle contracture, and bilateral lumbar radiculopathy, with sudden onset after lifting effort. The preoperative diagnosis was done using computed tomography (CT) and magnetic resonance imaging (MRI), and the patient underwent surgery—two level laminectomy, dural incision, and tumor dissection from the cauda equina nerve roots under operatory microscope. Histopathological examination confirmed the positive diagnosis of cavernoma of cauda equina. The patient's outcome was favorable, without postoperative neurological deficits.

Study design: Survey and long-term clinical post-trial follow-up (interviews/correspondence) on nine chronic, post spinal cord injury (SCI) tetraplegics. Objective: To assess feasibility of the use of Electroencephalography-based Brain-Computer Interface (EEG-BCI) for reaching/grasping assistance in tetraplegics, through a robotic arm. Settings: Physical and (neuromuscular) Rehabilitation Medicine, Cardiology, Neurosurgery Clinic Divisions of TEHBA and UMPCD, in collaboration with 'Brain2Robot' (composed of the European Commission-funded Marie Curie Excellence Team by the same name, hosted by Fraunhofer Institute-FIRST), in the second part of 2008. Methods: Enrolled patients underwent EEG-BCI preliminary training and robot control sessions. Statistics entailed multiple linear regressions and cluster analysis. A follow-up-custom questionnaire based-including patients' perception of their EEG-BCI control capacity was continued up to 14 months after initial experiments. Results: EEG-BCI performance/calibration-phase classification accuracy averaged 81.0%; feedback training sessions averaged 70.5% accuracy for 7 subjects who completed at least one feedback training session; 7 (77.7%) of 9 subjects reported having felt control of the cursor; and 3 (33.3%) subjects felt that they were also controlling the robot through their movement imagination. No significant side effects occurred. BCI performance was positively correlated with beta (13-30?Hz) EEG spectral power density (coefficient 0.432, standardized coefficient 0.745, P-value=0.025); another possible influence was sensory AIS score (range: 0?min to 224 max, coefficient ?0.177, standardized coefficient ?0.512, P=0.089). Conclusion: Limited but real potential for self-assistance in chronic tetraplegics by EEG-BCI-actuated mechatronic devices was found, which was mainly related to spectral density in the beta range positively (increasing therewith) and to AIS sensory score negatively.

The diabetic patients represent a population with a high risk of morbidity and mortality because of vascular complications. Out of them, all the patients with acute ST- elevation myocardial infarction have a more reserved prognostic than those without diabetes mellitus. Moreover, the patients with impaired glucose tolerance have a more severe evolution in case of a myocardial infarction. Aim: We wondered about the progress of patients with myocardial infarction and high blood glucose levels in admittance who had not been previously diagnosed with diabetes mellitus. Materials and methods: We took 128 patients (who did not have diabetes) with acute ST- elevation myocardial infarction and divided them into three groups, according to the blood glucose level in admittance ( 200mg/dL); we also analyzed a group of diabetics with acute myocardial infarction who were admitted in the same period in our clinic. We made a prospective analysis over a period of 30 days. We evaluated the mortality at 30 days (as primary objective), as well as the extent of the infarction and the change of the left ventricle systolic function (secondary objectives). Results: Both mortality and the mass of myocardial necrosis grew relative to the blood glucose level in admittance; instead, the ejection fraction varied inversely to the initial blood glucose level. Conclusion: The admittance blood glucose level represents a useful and available marker for the initial stratification of risks in patients with acute myocardial infarction, even in those undiagnosed with diabetes mellitus.

IMPORTANCE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme. OBJECTIVE: To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event. DESIGN, SETTING, AND PARTICIPANTS: SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13,026 participants within 30 days of hospitalization with an ACS (non-ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries. INTERVENTIONS: Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013. MAIN OUTCOMES AND MEASURES: The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years. RESULTS: During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%). CONCLUSIONS AND RELEVANCE: In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01000727.

Increasing costs of treatments have led to the apparition of the medical tourism. Patients in high-income countries seek to solve their health problems in developing countries where the cost of medical treatment is much lower. This cost difference has led to the medical tourism industry that is currently estimated with an annual growth rate of about 20%. Cardiovascular diseases are a leading cause of death worldwide. The high cost of treating these diseases cause many patients to seek treatment options abroad. This paper presents an analysis of the medical tourism industry highlighting the factors that led to its development, barriers to medical tourism, and the economic impact of this industry. Although Romania has highly appreciated doctors it hasn’t achieved yet the high level of other developing countries where medical tourism is more intense. Spa tourism is still far from Romania’s potential in this area due to the very small investments and the lack of necessary infrastructure. Using statistical and econometric techniques we examined key health indicators in Romania showing the lack of correlation between the prevalence of cardiovascular diseases, the development of the endowment of the health system in Romania, expenditures on health care and evolution of the number of foreign tourists coming to Romania to treat these diseases. We used statistical data series provided by N.S.I. that were processed using Eviews. We also tested whether there is a causal relationship in the Granger sense between the percentage of GDP allocated to the health care system and the number of nights spent by foreign tourists in resorts in Romania or the number of arrivals of foreign tourists.

Summary Background Ivabradine specifically inhibits the I f current in the sinoatrial node to lower heart rate, without affecting other aspects of cardiac function. We aimed to test whether lowering the heart rate with ivabradine reduces cardiovascular death and morbidity in patients with coronary artery disease and left-ventricular systolic dysfunction. Methods Between December, 2004, and December, 2006, we screened 12 473 patients at 781 centres in 33 countries. We enrolled 10 917 eligible patients who had coronary artery disease and a left-ventricular ejection fraction of less than 40% in a randomised, double-blind, placebo-controlled, parallel-group trial. 5479 patients received 5 mg ivabradine, with the intention of increasing to the target dose of 7·5 mg twice a day, and 5438 received matched placebo in addition to appropriate cardiovascular medication. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. We analysed patients by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00143507. Findings Mean heart rate at baseline was 71·6 (SD 9·9) beats per minute (bpm). Median follow-up was 19 months (IQR 16–24). Ivabradine reduced heart rate by 6 bpm (SE 0·2) at 12 months, corrected for placebo. Most (87%) patients were receiving β blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1·00, 95% CI 0·91–1·1, p=0·94). 1233 (22·5%) patients in the ivabradine group had serious adverse events, compared with 1239 (22·8%) controls (p=0·70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0·91, 95% CI 0·81–1·04, p=0·17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0·64, 95% CI 0·49–0·84, p=0·001) and coronary revascularisation (0·70, 95% CI 0·52–0·93, p=0·016). Interpretation Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater. Funding Servier, France.