Atrial Fibrillation in Decompensated Heart Failure: Associated Factors and In-Hospital Outcome

Background: Studies on atrial fibrillation (AF) in decompensated heart failure (DHF) are scarce in Brazil. Objectives: To determine AF prevalence, its types and associated factors in patients hospitalized due to DHF; to assess their thromboembolic risk profile and anticoagulation rate; and to assess the impact of AF on in-hospital mortality and hospital length of stay. Methods: Retrospective, observational, cross-sectional study of incident cases including 659 consecutive hospitalizations due to DHF, from 01/01/2006 to 12/31/2011. The thromboembolic risk was assessed by using CHADSVASc score. On univariate analysis, the chi-square, Student t and Mann Whitney tests were used. On multivariate analysis, logistic regression was used. Results: The prevalence of AF was 40%, and the permanent type predominated (73.5%). On multivariate model, AF associated with advanced age (p < 0.0001), non-ischemic etiology (p = 0.02), right ventricular dysfunction (p = 0.03), lower systolic blood pressure (SBP) (p = 0.02), higher ejection fraction (EF) (p < 0.0001) and enlarged left atrium (LA) (p < 0.0001). The median CHADSVASc score was 4, and 90% of the cases had it ≥ 2. The anticoagulation rate was 52.8% on admission and 66.8% on discharge, being lower for higher scores. The group with AF had higher in-hospital mortality (11.0% versus 8.1%, p = 0.21) and longer hospital length of stay (20.5 ± 16 versus 16.3 ± 12, p = 0.001). Conclusions: Atrial fibrillation is frequent in DHF, the most prevalent type being permanent AF. Atrial fibrillation is associated with more advanced age, non-ischemic etiology, right ventricular dysfunction, lower SBP, higher EF and enlarged LA. Despite the high thromboembolic risk profile, anticoagulation is underutilized. The presence of AF is associated with longer hospital length of stay and high mortality.

Diabetes Mellitus and Glucose as Predictors of Mortality in Primary Coronary Percutaneous Intervention

Background: Diabetes mellitus and admission blood glucose are important risk factors for mortality in ST segment elevation myocardial infarction patients, but their relative and individual role remains on debate. Objective: To analyze the influence of diabetes mellitus and admission blood glucose on the mortality of ST segment elevation myocardial infarction patients submitted to primary coronary percutaneous intervention. Methods: Prospective cohort study including every ST segment elevation myocardial infarction patient submitted to primary coronary percutaneous intervention in a tertiary cardiology center from December 2010 to May 2012. We collected clinical, angiographic and laboratory data during hospital stay, and performed a clinical follow-up 30 days after the ST segment elevation myocardial infarction. We adjusted the multivariate analysis of the studied risk factors using the variables from the GRACE score. Results: Among the 740 patients included, reported diabetes mellitus prevalence was 18%. On the univariate analysis, both diabetes mellitus and admission blood glucose were predictors of death in 30 days. However, after adjusting for potential confounders in the multivariate analysis, the diabetes mellitus relative risk was no longer significant (relative risk: 2.41, 95% confidence interval: 0.76 - 7.59; p-value: 0.13), whereas admission blood glucose remained and independent predictor of death in 30 days (relative risk: 1.05, 95% confidence interval: 1.02 - 1.09; p-value ≤ 0.01). Conclusion: In ST segment elevation myocardial infarction patients submitted to primary coronary percutaneous intervention, the admission blood glucose was a more accurate and robust independent predictor of death than the previous diagnosis of diabetes. This reinforces the important role of inflammation on the outcomes of this group of patients.

Relationship between Neutrophil-To-Lymphocyte Ratio and Electrocardiographic Ischemia Grade in STEMI

Background: Neutrophil-to-lymphocyte ratio (NLR) has been found to be a good predictor of future adverse cardiovascular outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Changes in the QRS terminal portion have also been associated with adverse outcomes following STEMI. Objective: To investigate the relationship between ECG ischemia grade and NLR in patients presenting with STEMI, in order to determine additional conventional risk factors for early risk stratification. Methods: Patients with STEMI were investigated. The grade of ischemia was analyzed from the ECG performed on admission. White blood cells and subtypes were measured as part of the automated complete blood count (CBC) analysis. Patients were classified into two groups according to the ischemia grade presented on the admission ECG, as grade 2 ischemia (G2I) and grade 3 ischemia (G3I). Results: Patients with G3I had significantly lower mean left ventricular ejection fraction than those in G2I (44.58 ± 7.23 vs. 48.44 ± 7.61, p = 0.001). As expected, in-hospital mortality rate increased proportionally with the increase in ischemia grade (p = 0.036). There were significant differences in percentage of lymphocytes (p = 0.010) and percentage of neutrophils (p = 0.004), and therefore, NLR was significantly different between G2I and G3I patients (p < 0.001). Multivariate logistic regression analysis revealed that only NLR was the independent variable with a significant effect on ECG ischemia grade (odds ratio = 1.254, 95% confidence interval 1.120–1.403, p < 0.001). Conclusion: We found an association between G3I and elevated NLR in patients with STEMI. We believe that such an association might provide an additional prognostic value for risk stratification in patients with STEMI when combined with standardized risk scores.

Subclinical Ventricular Dysfunction Detected by Speckle Tracking Two Years after Use of Anthracycline

Background: Heart failure is a severe complication associated with doxorubicin (DOX) use. Strain, assessed by two-dimensional speckle tracking (2D-STE), has been shown to be useful in identifying subclinical ventricular dysfunction. Objectives: a) To investigate the role of strain in the identification of subclinical ventricular dysfunction in patients who used DOX; b) to investigate determinants of strain response in these patients. Methods: Cross-sectional study with 81 participants: 40 patients who used DOX ±2 years before the study and 41 controls. All participants had left ventricular ejection fraction (LVEF) ≥55%. Total dose of DOX was 396mg (242mg/ms2). The systolic function of the LV was evaluated by LVEF (Simpson), as well as by longitudinal (εLL), circumferential (εCC), and radial (εRR) strains. Multivariate linear regression (MLR) analysis was performed using εLL (model 1) and εCC (model 2) as dependent variables. Results: Systolic and diastolic blood pressure values were higher in the control group (p < 0.05). εLL was lower in the DOX group (-12.4 ±2.6%) versus controls (-13.4 ± 1.7%; p = 0.044). The same occurred with εCC: -12.1 ± 2.7% (DOX) versus -16.7 ± 3.6% (controls; p < 0.001). The S’ wave was shorter in the DOX group (p = 0.035). On MLR, DOX was an independent predictor of reduced εCC (B = -4.429, p < 0.001). DOX (B = -1.289, p = 0.012) and age (B = -0.057, p = 0.029) were independent markers of reduced εLL. Conclusion: a) εLL, εCC and the S’ wave are reduced in patients who used DOX ±2 years prior to the study despite normal LVEF, suggesting the presence of subclinical ventricular dysfunction; b) DOX was an independent predictor of reduced εCC; c) prior use of DOX and age were independent markers of reduced εLL.

Depression as a Clinical Determinant of Dependence and Low Quality of Life in Elderly Patients with Cardiovascular Disease

Background:The aging process promotes a progressive increase in chronic-degenerative diseases. The effect of these diseases on the functional capacity has been well recognized. Another health parameter concerns “quality of life related to health”. Among the elderly population, cardiovascular diseases stand out due to the epidemiological and clinical impact. Usually, these diseases have been associated with others. This set of problems may compromise both independence and quality of life in elderly patients who seek cardiologic treatment. These health parameters have not been well contemplated by cardiologists.Objective:Evaluating, among the elderly population with cardiovascular disease, which are the most relevant clinical determinants regarding dependence and quality of life.Methods:This group was randomly and consecutively selected and four questionnaires were applied: HAQ, SF-36, PRIME-MD e Mini Mental State.Results:The study included 1,020 elderly patients, 63.3% women. The group had been between 60 and 97 years-old (mean: 75.56 ± 6.62 years-old). 61.4% were independent or mild dependence. The quality of life total score was high (HAQ: 88.66 ± 2.68). 87.8% of patients had a SF-36 total score > 66. In the multivariate analysis, the association between diagnoses and high degrees of dependence was significant only for previous stroke (p = 0.014), obesity (p < 0.001), lack of physical activity (p = 0.016), osteoarthritis (p < 0.001), cognitive impairment (p < 0.001), and major depression (p < 0.001). Analyzing the quality of life, major depression and physical illness for depression was significantly associated with all domains of the SF-36.Conclusion:Among an elderly outpatient cardiology population, dependence and quality of life clinical determinants are not cardiovascular comorbidities, especially the depression.

Post-Acute Coronary Syndrome Alcohol Abuse: Prospective Evaluation in the ERICO Study

Background:Some studies have indicated alcohol abuse as one of the contributors to the development of cardiovascular disease, particularly coronary heart disease. However, this relationship is controversial.Objective:To investigate the relationship between post-acute coronary syndrome (ACS) alcohol abuse in the Acute Coronary Syndrome Registry Strategy (ERICO Study).Methods:146 participants from the ERICO Study answered structured questionnaires and underwent laboratory evaluations at baseline, 30 days and 180 days after ACS. The Alcohol Use Disorders Identification Test (AUDIT) was applied to assess harmful alcohol consumption in the 12 months preceding ACS (30 day-interview) and six months after that.Results:The frequencies of alcohol abuse were 24.7% and 21.1% in the 12 months preceding ACS and six months after that, respectively. The most significant cardiovascular risk factors associated with high-risk for alcohol abuse 30 days after the acute event were: male sex (88.9%), current smoking (52.8%) and hypertension (58.3%). Six months after the acute event, the most significant results were replicated in our logistic regression, for the association between alcohol abuse among younger individuals [35-44 year-old multivariate OR: 38.30 (95% CI: 1.44-1012.56) and 45-54 year-old multivariate OR: 10.10 (95% CI: 1.06-96.46)] and for smokers [current smokers multivariate OR: 51.09 (95% CI: 3.49-748.01) and past smokers multivariate OR: 40.29 (95% CI: 2.37-685.93)].Conclusion:Individuals younger than 54 years and smokers showed a significant relation with harmful alcohol consumption, regardless of the ACS subtype.

Metabolic Syndrome and Importance of Associated Variables in Children and Adolescents in Guabiruba - SC, Brazil

Background:The risk factors that characterize metabolic syndrome (MetS) may be present in childhood and adolescence, increasing the risk of cardiovascular disease in adulthood.Objective:Evaluate the prevalence of MetS and the importance of its associated variables, including insulin resistance (IR), in children and adolescents in the city of Guabiruba-SC, Brazil.Methods:Cross-sectional study with 1011 students (6–14 years, 52.4% girls, 58.5% children). Blood samples were collected for measurement of biochemical parameters by routine laboratory methods. IR was estimated by the HOMA-IR index, and weight, height, waist circumference and blood pressure were determined. Multivariate logistic regression models were used to examine the associations between risk variables and MetS.Results:The prevalence of MetS, IR, overweight and obesity in the cohort were 14%, 8.5%, 21% and 13%, respectively. Among students with MetS, 27% had IR, 33% were overweight, 45.5% were obese and 22% were eutrophic. IR was more common in overweight (48%) and obese (41%) students when compared with eutrophic individuals (11%; p = 0.034). The variables with greatest influence on the development of MetS were obesity (OR = 32.7), overweight (OR = 6.1), IR (OR = 4.4; p ≤ 0.0001 for all) and age (OR = 1.15; p = 0.014).Conclusion:There was a high prevalence of MetS in children and adolescents evaluated in this study. Students who were obese, overweight or insulin resistant had higher chances of developing the syndrome.

Left Atrial Volume Determinants in Patients with Non-Ischemic Dilated Cardiomyopathy

Background:Left atrial volume (LAV) is a predictor of prognosis in patients with heart failure.Objective:We aimed to evaluate the determinants of LAV in patients with dilated cardiomyopathy (DCM).Methods:Ninety patients with DCM and left ventricular (LV) ejection fraction ≤ 0.50 were included. LAV was measured with real-time three-dimensional echocardiography (eco3D). The variables evaluated were heart rate, systolic blood pressure, LV end-diastolic volume and end-systolic volume and ejection fraction (eco3D), mitral inflow E wave, tissue Doppler e´ wave, E/e´ ratio, intraventricular dyssynchrony, 3D dyssynchrony index and mitral regurgitation vena contracta. Pearson´s coefficient was used to identify the correlation of the LAV with the assessed variables. A multiple linear regression model was developed that included LAV as the dependent variable and the variables correlated with it as the predictive variables.Results:Mean age was 52 ± 11 years-old, LV ejection fraction: 31.5 ± 8.0% (16-50%) and LAV: 39.2±15.7 ml/m2. The variables that correlated with the LAV were LV end-diastolic volume (r = 0.38; p < 0.01), LV end-systolic volume (r = 0.43; p < 0.001), LV ejection fraction (r = -0.36; p < 0.01), E wave (r = 0.50; p < 0.01), E/e´ ratio (r = 0.51; p < 0.01) and mitral regurgitation (r = 0.53; p < 0.01). A multivariate analysis identified the E/e´ ratio (p = 0.02) and mitral regurgitation (p = 0.02) as the only independent variables associated with LAV increase.Conclusion:The LAV is independently determined by LV filling pressures (E/e´ ratio) and mitral regurgitation in DCM.

Development and Validation of Predictive Models of Cardiac Mortality and Transplantation in Resynchronization Therapy

AbstractBackground:30-40% of cardiac resynchronization therapy cases do not achieve favorable outcomes.Objective:This study aimed to develop predictive models for the combined endpoint of cardiac death and transplantation (Tx) at different stages of cardiac resynchronization therapy (CRT).Methods:Prospective observational study of 116 patients aged 64.8 ± 11.1 years, 68.1% of whom had functional class (FC) III and 31.9% had ambulatory class IV. Clinical, electrocardiographic and echocardiographic variables were assessed by using Cox regression and Kaplan-Meier curves.Results:The cardiac mortality/Tx rate was 16.3% during the follow-up period of 34.0 ± 17.9 months. Prior to implantation, right ventricular dysfunction (RVD), ejection fraction < 25% and use of high doses of diuretics (HDD) increased the risk of cardiac death and Tx by 3.9-, 4.8-, and 5.9-fold, respectively. In the first year after CRT, RVD, HDD and hospitalization due to congestive heart failure increased the risk of death at hazard ratios of 3.5, 5.3, and 12.5, respectively. In the second year after CRT, RVD and FC III/IV were significant risk factors of mortality in the multivariate Cox model. The accuracy rates of the models were 84.6% at preimplantation, 93% in the first year after CRT, and 90.5% in the second year after CRT. The models were validated by bootstrapping.Conclusion:We developed predictive models of cardiac death and Tx at different stages of CRT based on the analysis of simple and easily obtainable clinical and echocardiographic variables. The models showed good accuracy and adjustment, were validated internally, and are useful in the selection, monitoring and counseling of patients indicated for CRT.

Predictors of Arrhythmic Events Detected by Implantable Loop Recorders in Renal Transplant Candidates

AbstractBackground:The recording of arrhythmic events (AE) in renal transplant candidates (RTCs) undergoing dialysis is limited by conventional electrocardiography. However, continuous cardiac rhythm monitoring seems to be more appropriate due to automatic detection of arrhythmia, but this method has not been used.Objective:We aimed to investigate the incidence and predictors of AE in RTCs using an implantable loop recorder (ILR).Methods:A prospective observational study conducted from June 2009 to January 2011 included 100 consecutive ambulatory RTCs who underwent ILR and were followed-up for at least 1 year. Multivariate logistic regression was applied to define predictors of AE.Results:During a mean follow-up of 424 ± 127 days, AE could be detected in 98% of patients, and 92% had more than one type of arrhythmia, with most considered potentially not serious. Sustained atrial tachycardia and atrial fibrillation occurred in 7% and 13% of patients, respectively, and bradyarrhythmia and non-sustained or sustained ventricular tachycardia (VT) occurred in 25% and 57%, respectively. There were 18 deaths, of which 7 were sudden cardiac events: 3 bradyarrhythmias, 1 ventricular fibrillation, 1 myocardial infarction, and 2 undetermined. The presence of a long QTc (odds ratio [OR] = 7.28; 95% confidence interval [CI], 2.01–26.35; p = 0.002), and the duration of the PR interval (OR = 1.05; 95% CI, 1.02–1.08; p < 0.001) were independently associated with bradyarrhythmias. Left ventricular dilatation (LVD) was independently associated with non-sustained VT (OR = 2.83; 95% CI, 1.01–7.96; p = 0.041).Conclusions:In medium-term follow-up of RTCs, ILR helped detect a high incidence of AE, most of which did not have clinical relevance. The PR interval and presence of long QTc were predictive of bradyarrhythmias, whereas LVD was predictive of non-sustained VT.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio are Predictors of Heart Failure

Abstract Background: Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are inflammatory markers used as prognostic factors in various diseases. The aims of this study were to compare the PLR and the NLR of heart failure (HF) patients with those of age-sex matched controls, to evaluate the predictive value of those markers in detecting HF, and to demonstrate the effect of NLR and PLR on mortality in HF patients during follow-up. Methods: This study included 56 HF patients and 40 controls without HF. All subjects underwent transthoracic echocardiography to evaluate cardiac functions. The NLR and the PLR were calculated as the ratio of neutrophil count to lymphocyte count and as the ratio of platelet count to lymphocyte count, respectively. All HF patients were followed after their discharge from the hospital to evaluate mortality, cerebrovascular events, and re-hospitalization. Results: The NLR and the PLR of HF patients were significantly higher compared to those of the controls (p < 0.01). There was an inverse correlation between the NLR and the left ventricular ejection fraction of the study population (r: -0.409, p < 0.001). The best cut-off value of NLR to predict HF was 3.0, with 86.3% sensitivity and 77.5% specificity, and the best cut-off value of PLR to predict HF was 137.3, with 70% sensitivity and 60% specificity. Only NLR was an independent predictor of mortality in HF patients. A cut-off value of 5.1 for NLR can predict death in HF patients with 75% sensitivity and 62% specificity during a 12.8-month follow-up period on average. Conclusion: NLR and PLR were higher in HF patients than in age-sex matched controls. However, NLR and PLR were not sufficient to establish a diagnosis of HF. NLR can be used to predict mortality during the follow-up of HF patients.

Hemorheological and Glycemic Parameters and HDL Cholesterol for the Prediction of Cardiovascular Events

Abstract Background: Hemorheological and glycemic parameters and high density lipoprotein (HDL) cholesterol are used as biomarkers of atherosclerosis and thrombosis. Objective: To investigate the association and clinical relevance of erythrocyte sedimentation rate (ESR), fibrinogen, fasting glucose, glycated hemoglobin (HbA1c), and HDL cholesterol in the prediction of major adverse cardiovascular events (MACE) and coronary heart disease (CHD) in an outpatient population. Methods: 708 stable patients who visited the outpatient department were enrolled and followed for a mean period of 28.5 months. Patients were divided into two groups, patients without MACE and patients with MACE, which included cardiac death, acute myocardial infarction, newly diagnosed CHD, and cerebral vascular accident. We compared hemorheological and glycemic parameters and lipid profiles between the groups. Results: Patients with MACE had significantly higher ESR, fibrinogen, fasting glucose, and HbA1c, while lower HDL cholesterol compared with patients without MACE. High ESR and fibrinogen and low HDL cholesterol significantly increased the risk of MACE in multivariate regression analysis. In patients with MACE, high fibrinogen and HbA1c levels increased the risk of multivessel CHD. Furthermore, ESR and fibrinogen were significantly positively correlated with HbA1c and negatively correlated with HDL cholesterol, however not correlated with fasting glucose. Conclusion: Hemorheological abnormalities, poor glycemic control, and low HDL cholesterol are correlated with each other and could serve as simple and useful surrogate markers and predictors for MACE and CHD in outpatients.

Predictors of Atrial Fibrillation Recurrence in Hyperthyroid and Euthyroid Patients

Background: Atrial fibrillation (AF) is the most common arrhythmia in adults, and is encountered in 10-15% of the patients with hyperthyroidism. Unless euthyroidism is restored, pharmacological or electrical cardioversion is controversial in patients with AF who remain hyperthyroid. Objective: The aim of this study was to assess the efficacy of electrical cardioversion and predictors of AF recurrence in hyperthyroid and euthyroid patients. Methods: The study included 33 hyperthyroid (21 males) and 48 euthyroid (17 males) patients with persistent AF. The patients were sedated with intravenous midazolam before undergoing electrical cardioversion delivered by synchronized biphasic shocks. Rates of AF recurrence were recorded. Results: Mean follow-up was 23.63 ± 3.74 months in the hyperthyroid group and 22.78 ± 3.15 months in the euthyroid group (p = 0.51). AF recurred in 14 (43.8%) and 21 (44.7%) patients in each group, respectively (p = 0.93). Multivariate regression analysis in each group showed that AF duration was the only predictor of AF recurrence, with odds ratios of 1.38 (95% confidence interval [CI] = 1.05 - 1.82, p = 0.02) in the hyperthyroid group and 1.42 (95% CI = 1.05 - 1.91, p= 0.02) in the euthyroid group. Conclusion: Rates of long-term AF recurrence were similar in successfully cardioverted hyperthyroid and euthyroid patients. The only predictor of AF recurrence in both groups was AF duration.

Prognostic Value of Pulmonary Vascular Resistance by Magnetic Resonance in Systolic Heart Failure

Abstract Background: Pulmonary hypertension is associated with poor prognosis in heart failure. However, non-invasive diagnosis is still challenging in clinical practice. Objective: We sought to assess the prognostic utility of non-invasive estimation of pulmonary vascular resistances (PVR) by cardiovascular magnetic resonance to predict adverse cardiovascular outcomes in heart failure with reduced ejection fraction (HFrEF). Methods: Prospective registry of patients with left ventricular ejection fraction (LVEF) < 40% and recently admitted for decompensated heart failure during three years. PVRwere calculated based on right ventricular ejection fraction and average velocity of the pulmonary artery estimated during cardiac magnetic resonance. Readmission for heart failure and all-cause mortality were considered as adverse events at follow-up. Results: 105 patients (average LVEF 26.0 ±7.7%, ischemic etiology 43%) were included. Patients with adverse events at long-term follow-up had higher values of PVR (6.93 ± 1.9 vs. 4.6 ± 1.7estimated Wood Units (eWu), p < 0.001). In multivariate Cox regression analysis, PVR ≥ 5 eWu(cutoff value according to ROC curve) was independently associated with increased risk of adverse events at 9 months follow-up (HR2.98; 95% CI 1.12-7.88; p < 0.03). Conclusions: In patients with HFrEF, the presence of PVR ≥ 5.0 Wu is associated with significantly worse clinical outcome at follow-up. Non-invasive estimation of PVR by cardiac magnetic resonance might be useful for risk stratification in HFrEF, irrespective of etiology, presence of late gadolinium enhancement or LVEF.

Risk Prediction of Cardiovascular Complications in Pregnant Women With Heart Disease

Abstract Background: Heart disease in pregnancy is the leading cause of non- obstetric maternal death. Few Brazilian studies have assessed the impact of heart disease during pregnancy. Objective: To determine the risk factors associated with cardiovascular and neonatal complications. Methods: We evaluated 132 pregnant women with heart disease at a High-Risk Pregnancy outpatient clinic, from January 2005 to July 2010. Variables that could influence the maternal-fetal outcome were selected: age, parity, smoking, etiology and severity of the disease, previous cardiac complications, cyanosis, New York Heart Association (NYHA) functional class > II, left ventricular dysfunction/obstruction, arrhythmia, drug treatment change, time of prenatal care beginning and number of prenatal visits. The maternal-fetal risk index, Cardiac Disease in Pregnancy (CARPREG), was retrospectively calculated at the beginning of prenatal care, and patients were stratified in its three risk categories. Results: Rheumatic heart disease was the most prevalent (62.12%). The most frequent complications were heart failure (11.36%) and arrhythmias (6.82%). Factors associated with cardiovascular complications on multivariate analysis were: drug treatment change (p = 0.009), previous cardiac complications (p = 0.013) and NYHA class III on the first prenatal visit (p = 0.041). The cardiovascular complication rates were 15.22% in CARPREG 0, 16.42% in CARPREG 1, and 42.11% in CARPREG > 1, differing from those estimated by the original index: 5%, 27% and 75%, respectively. This sample had 26.36% of prematurity. Conclusion: The cardiovascular complication risk factors in this population were drug treatment change, previous cardiac complications and NYHA class III at the beginning of prenatal care. The CARPREG index used in this sample composed mainly of patients with rheumatic heart disease overestimated the number of events in pregnant women classified as CARPREG 1 and > 1, and underestimated it in low-risk patients (CARPREG 0).