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BACKGROUND: The current incidence and outcomes of structural transcatheter procedures in heart transplant (HTx) recipients and left-ventricular assist devices (LVAD) carriers is unknown. AIMS: To provide insights on structural transcatheter procedures performed across HTx and LVAD patients in Spain. METHODS: Multicenter, ambispective, observational nationwide registry. RESULTS: Until May/2023, 36 percutaneous structural interventions were performed (78% for HTx and 22% for LVAD) widely varying among centers (0%-1.4% and 0%-25%, respectively). Percutaneous mitral transcatheter edge-to-edge (TEER) was the most common (n = 12, 33.3%), followed by trancatheter aortic valve replacement (n = 11, 30.5%), and tricuspid procedures (n = 9, 25%). Mitral TEER resulted in mild residual mitral regurgitation in all but one case, mean gradient was <5 mmHg in 75% of them at 1-year, with no mortality and 8.3% re-admission rate. Tricuspid TEER resulted in 100% none/mild residual regurgitation with a 1-year mortality and readmission rates of 22% and 28.5%, respectively. Finally, trancatheter aortic valve replacement procedures (n = 8 in LVADs due to aortic regurgitation and n = 3 in HTx), were successful in all cases with one prosthesis degeneration leading to severe aortic regurgitation at 1-year, 18.2% mortality rate and no re-admissions. Globally, major bleeding rates were 7.9% and 12.5%, thromboembolic events 3.7% and 12.5%, readmissions 37% and 25%, and mortality 22% and 25%, in HTx and LVADs respectively. No death was related to the implanted transcatheter device. CONCLUSIONS: Most centers with HTx/LVAD programs perform structural percutaneous procedures but with very inconsistent incidence. They were associated with good safety and efficacy, but larger studies are required to provide formal recommendations.
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INTRODUCTION AND OBJECTIVES: Heart transplant (HT) represents a major physiological stress, resulting in elevated levels of analytical biomarkers. This study aimed to determine whether changes in biomarker levels after HT can identify patients with a poor prognosis. METHODS: A prospective longitudinal noninterventional study was conducted in 149 consecutive patients undergoing HT from July 2017 to July 2023. Biomarkers were assessed before HT and at 6, 24, 48, 72, and 96hours after HT. The biomarkers analyzed were high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine, and lactic acid. The primary outcome was a composite of death and severe primary graft failure (PGF). RESULTS: NT-proBNP and troponin levels remained highly elevated throughout the period and stabilized from the first 24hours post-HT. Lactate levels stabilized after the first 24hours, and creatinine from the second day onward. Exitus occurred in 23 (15%) of the patients, and severe PGF in 26 (17%). All biomarkers were significantly associated with the incidence of the combined event (P <.0001). Receiver operating characteristic curve analysis at 24hours showed significant areas under the curve (P=.0001). The greatest discriminatory power was observed for the NT-proBNP curve. A value of 10 000 pg/mL had a sensitivity of 90% and specificity of 80%. CONCLUSIONS: A significant elevation of post-HT analytical biomarkers was associated with mortality and/or severe PGF. Among the biomarkers analyzed, NT-proBNP was the most accurate in classifying patients.
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Background: In heart failure (HF), not all episodes of decompensation are alike. The study aimed to characterize the clinical groups of decompensation and perform a survival analysis. Methods: A retrospective study was conducted on patients consecutively admitted for HF from 2018 to 2023. Patients who died during admission were excluded (final number 1,668). Four clinical types of HF were defined: low cardiac output (n:83), pulmonary congestion (n:1,044), mixed congestion (n:353), and systemic congestion (n:188). Results: The low output group showed a higher prevalence of reduced left ventricular ejection fraction (93%) and increased biventricular diameters (p < 0.01). The systemic congestion group exhibited a greater presence of tricuspid regurgitation with dilatation and right ventricular dysfunction (p:0.0001), worse renal function, and higher uric acid and CA125 levels (p:0.0001). Diuretics were more commonly used in the mixed and, especially, systemic congestion groups (p:0.0001). The probability of overall survival at 5 years was 49%, with higher survival in pulmonary congestion and lower in systemic congestion (p:0.002). Differences were also found in survival at 1 month and 1 year (p:0.0001). Conclusions: Mortality in acute HF is high. Four phenotypic profiles of decompensation differ clinically, with distinct characteristics and varying prognosis in the short, medium, and long term.
Subject(s)
Humans , Adult , Cardiomyopathies , Therapeutics , Patients , Disease/genetics , Chromosome Aberrations , Incidence , Congenital Abnormalities , Cell MembraneABSTRACT
BACKGROUND: Heart failure is frequently associated with kidney disease, and patients with kidney disease are at increased risk of heart failure. The co-occurrence of both entities not only significantly increases morbidity and mortality but also complicates therapy. SUMMARY: Cardiorenal syndrome often requires a broad, comprehensive, and multidisciplinary approach. As a result, a need has arisen to create specialized cardiorenal units that allow for rigorous and personalized management of this condition. Moreover, in some cases, cardiorenal syndrome is more complex, owing to an acute and critical situation that requires the concept of the cardiorenal unit to be extended toward advanced diagnostic and therapeutic positions, thus confirming the need for an advanced cardiorenal unit. The creation of these units constitutes a real challenge, necessitating a specific multilevel action plan, covering governance and management, type of patient, personnel requirements, service portfolio, care process, information systems, and other resources. Specific lines of action must be proposed for each of the relevant points in order to facilitate development of these units, together with continuous evaluation of unit activity through specific indicators, and to detect areas for improvement. KEY MESSAGES: This study addresses the conditions and organizational characteristics that enable the creation, development, and continuous improvement of advanced cardiorenal units.
Subject(s)
Cardio-Renal Syndrome , Humans , Cardio-Renal Syndrome/therapy , Cardio-Renal Syndrome/physiopathology , Cardio-Renal Syndrome/diagnosis , Heart Failure/therapy , Hospital Units/organization & administrationABSTRACT
Introducción y objetivo En la insuficiencia cardíaca la congestión es el síntoma más frecuente y es habitual la resistencia diurética. El objetivo del estudio es analizar si la ultrafiltración (UF) ambulatoria de corta duración por vía periférica es útil y segura en estos pacientes. Material y métodos Se analizaron los 5 primeros pacientes ultrafiltrados por resistencia diurética en una unidad de gestión rápida de un hospital de referencia durante 12h. Resultados Estos pacientes estaban en tratamiento con al menos 3 diuréticos por vía oral; la UF permitió reducir y/o retirar algunos. El volumen extraído durante el procedimiento fue de 1520±271ml. Hubo cambios significativos en la diuresis (pre-UF: 1360±164; post-UF: 1670±254ml; p=0,035); peso (pre-UF: 69,6±14; post-UF: 66,2±15kg; p=0,0001) y creatinina (pre-UF: 2,1±0,3; post-UF: 1,8±0,4mg; p=0,023). Conclusiones En pacientes en régimen ambulatorio con insuficiencia cardíaca y resistencia a los diuréticos, la UF de corta duración por vía periférica resultó efectiva y segura (AU)
Introduction and objective In heart failure congestion is the most common symptom and diuretic resistance is frequent. This study aims to analyse whether short-term peripheral outpatient ultrafiltration (UF) is useful and safe in these patients. Material and methods The first 5 patients ultrafiltrated for diuretic resistance in a fast-track unit of a referral hospital for 12hours were analysed. Results These patients were on treatment with at least 3 oral diuretics; UF made it possible to reduce and/or withdraw some of them. The volume extracted during the procedure was 1520±271ml. There were significant changes in diuresis (PreUF: 1360±164, PostUF: 1670±254ml; P=.035), weight (PreUF: 69.6±14, PostUF: 66.2±15kg; P=.0001) and creatinine (PreUF: 2.1±0.3, PostUF: 1.8±0.4mg; P= 0.023). Conclusions In outpatients with heart failure and diuretic resistance, short-course peripheral UF was effective and safe (AU)
Subject(s)
Humans , Male , Female , Aged, 80 and over , Ultrafiltration/methods , Diuretics/administration & dosage , Heart Failure/therapy , Treatment Outcome , Retrospective StudiesABSTRACT
Heart failure is a major problem in developed countries, leading to a high number of hospitalizations and healthcare costs. The most common symptom of heart failure is congestion, which is also the primary reason for hospitalization. Diuretics, particularly loop diuretics, are the cornerstone of the treatment of congestion. Likewise, there are other types of diuretics with different pathways of action, bioavailability profiles, adverse reactions, and effects on the cardiovascular and renal systems. Moreover, in recent years, new therapeutic alternatives have been proposed for challenging cases of diuretic resistance, such as ultrafiltration through peripheral access or peritoneal dialysis. The main objective of this article is to provide a step-guided approach to the management of congestion in patients with heart failure in order to guide the medical practice. Despite the significant amount of research published in recent years, there are no clear algorithms for managing acute heart failure. Diuretics remain the primary treatment of acute heart failure, and nephron blockade is key, but new therapies are emerging, and ongoing research is needed to develop better strategies for managing this condition.
Subject(s)
Diuretics , Heart Failure , Humans , Diuretics/therapeutic use , Heart Failure/drug therapy , Heart Failure/chemically induced , UltrafiltrationABSTRACT
INTRODUCTION AND OBJECTIVE: In heart failure congestion is the most common symptom and diuretic resistance is frequent. This study aims to analyse whether short-term peripheral outpatient ultrafiltration (UF) is useful and safe in these patients. MATERIAL AND METHODS: The first 5 patients ultrafiltrated for diuretic resistance in a fast-track unit of a referral hospital for 12hours were analysed. RESULTS: These patients were on treatment with at least 3 oral diuretics; UF made it possible to reduce and/or withdraw some of them. The volume extracted during the procedure was 1520±271ml. There were significant changes in diuresis (PreUF: 1360±164, PostUF: 1670±254ml; P=.035), weight (PreUF: 69.6±14, PostUF: 66.2±15kg; P=.0001) and creatinine (PreUF: 2.1±0.3, PostUF: 1.8±0.4mg; P= 0.023). CONCLUSIONS: In outpatients with heart failure and diuretic resistance, short-course peripheral UF was effective and safe.
Subject(s)
Heart Failure , Ultrafiltration , Humans , Ultrafiltration/methods , Diuretics/therapeutic use , Heart Failure/therapyABSTRACT
AIMS: Patients with heart failure (HF) admitted for decompensation often require high doses of intravenous diuretics. This study aims to analyse whether the use of peripheral ultrafiltration (UF) in patients hospitalized for acute HF with systemic-predominant congestion results in better hydric control, renal protection, and reduction of hospital stay compared with conventional treatment. METHODS AND RESULTS: This study was a retrospective, comparative, single-centre study of 56 patients admitted for HF with systemic congestion with a poor diuretic response after diuretic escalation. One group underwent peripheral UF (35 patients) and others were maintained on intense diuretic treatment (control group, 21 patients). The diuretic response and days of hospital stay were compared between and within groups. The baseline characteristics of both groups were similar: males with right ventricular failure and renal dysfunction. The inter-group analysis showed that patients who received UF had better glomerular filtration rate (GFR; UF: 39.2 ± 18.2 vs. control: 28.7 ± 13.4 mL/min; P = 0.031) and higher diuresis (UF: 2184 ± 735 vs. control: 1335 ± 297 mL; P = 0.0001) at hospital discharge despite less need for diuretic drugs. Days of hospital stay were shorter in the UF group (UF: 11.7 ± 10.1 vs. control: 19.1 ± 14.4 days; P = 0.027). Intra-group analysis showed that patients receiving UF improved GFR, increased diuresis, and reduced weight at discharge (P < 0.001), whereas patients on conventional treatment only experienced improved weight but worsening renal function at discharge. CONCLUSIONS: In patients with acute HF with systemic congestion and diuretic resistance, UF compared with conventional treatment produces greater decongestion and renal protection, reduces the total diuretic load, and shortens the length of hospital stay.
Subject(s)
Heart Failure , Ultrafiltration , Male , Humans , Ultrafiltration/methods , Diuretics/therapeutic use , Retrospective Studies , Heart Failure/drug therapy , KidneyABSTRACT
BACKGROUND: This study aims to analyse whether in acute heart failure (AHF) with iron deficiency (ID), the administration of ferric carboxymaltose (FCM) produces a greater benefit in renal dysfunction. METHODS: A total of 812 consecutive patients admitted for AHF and ID were studied. Untreated (n:272) and treated (n:540) patients were compared. The six-month prevalence of a combined event (readmission for HF, all-cause death, and emergency department visit for decompensation) was analysed. Three grades of renal dysfunction (KDIGO) were compared, Group 1 (grades 1 and 2), Group 2 (grades 3a and 3b), and Group 3 (grades 4 and 5). RESULTS: There were differences in sex distribution (untreated group: males 39.7% vs. treated group: males 51.9%; p < 0.001). Sex-adjusted combined event analysis showed a greater benefit in Group 1 (OR: 0.31, 95% CI:0.19-0.5; p < 0.001) and Group 2 (OR: 0.23, 95% CI:0.14-0.38; p < 0.001), but not in Group 3 (OR: 0.51, 95% CI:0.17-0.55; p: 0.237). CONCLUSIONS: The administration of FCM in patients with AHF and ID reduces the combined event analysed. The benefit is greater when renal dysfunction is present, except in very advanced degrees where no significant benefit is obtained.
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It is not clear to date whether a first admission in heart failure (HF) marks a worse evolution in patients not previously diagnosed with HF ("de novo HF") than those already diagnosed as outpatients ("acutely decompensated HF"). The aim of the study was to analyze whether survival in patients admitted for de novo HF differs from the survival in those admitted for a first episode of decompensation but with a previous diagnosis of HF. This study includes an analysis of 1,728 patients admitted for decompensated HF during 9 years. Readmissions and patients with left ventricular ejection fraction ≥50% were excluded (finally, 524 patients analyzed). We compared de novo HF (n = 186) in patients not diagnosed with HF, although their structural heart disease was defined, versus acutely decompensated HF (n = 338). The clinical profiles in both groups were similar. The de novo HF group more frequently presented with normal right ventricular function, with less presence of severe tricuspid regurgitation. The probability of survival was low in both groups. Thus, the median life in the de novo HF group was 2.1 years and in the acutely decompensated HF group, 3.5 years. There was a lower probability of long-term survival in the de novo HF group (p = 0.035). The variables associated with mortality were age (p <0.0001), ischemic heart disease (p <0.0001), hypertension (p = 0.009), obesity (p = 0.025), diabetes (p = 0.001), and N-terminal pro-brain natriuretic peptide at admission (p <0.0001). A higher glomerular filtration rate was associated with better survival (p = 0.033). De novo HF was associated with a higher mortality than chronic HF with acute decompensation (hazard ratio 1.53, 95% confidence interval 1.03 to 2.27, p = 0.036). In conclusion, the first admission for HF decompensation in patients with no previous diagnosis of HF identifies a subgroup of patients with higher long-term mortality.
Subject(s)
Heart Failure , Ventricular Dysfunction, Left , Humans , Stroke Volume , Prognosis , Ventricular Function, Left , HospitalsABSTRACT
BACKGROUND: The treatment of congestion in heart failure (HF) is a challenge despite the therapeutic arsenal available. The aim of this study was to analyze different combinations of diuretics used to resolve congestion in patients admitted for decompensated HF and to define clinical profiles according to these treatments. METHODS: Single-center study of 1,559 patients admitted for decompensated HF was done between 2016 and 2020. Patients were grouped according to the diuretic combination that led to clinical stabilization and discharge from the hospital: (1) Loop diuretic. (2) Loop diuretic + distal tubule (antialdosterone ± thiazides). (3) Loop diuretic + distal + proximal tubule (acetazolamide ± SGLT2 inhibitor). (4) Loop diuretic + distal tubule + collecting duct (tolvaptan). (5) Loop diuretic + distal + proximal + collecting duct. Based on these diuretic combinations, profiles with clinical, analytical, and echocardiographic differences were established. RESULTS: There were more previous hospitalizations in groups 4 and 5 (p = 0.001) with a predominance of pulmonary congestion in profiles 1 and 2 and systemic congestion in 3, 4, and 5. Creatinine and CA125 were higher in profiles 4 and 5 (p = 0.01 and p = 0.0001), with no differences in NT-proBNP. Profiles 4 and 5 had a higher proportion of dilatation and depression of right ventricular (p = 0.0001) and left ventricular (p = 0.003) function. Diuretic therapy-defined groups showed difference in clinical characteristics. CONCLUSIONS: The diuretic treatment used identifies five clinical profiles according to the degree of congestion, renal function, CA125, and right ventricular functionality. These profiles would guide the best diuretic treatment on admission.
Subject(s)
Diuretics , Heart Failure , Humans , Diuretics/therapeutic use , Sodium Potassium Chloride Symporter Inhibitors/therapeutic use , Treatment Outcome , Heart Failure/drug therapy , PhenotypeSubject(s)
Humans , Male , Female , Aged , Ultrafiltration , Cardio-Renal Syndrome/drug therapy , Heart Diseases , Retrospective Studies , CardiologyABSTRACT
AIM: Patients with advanced heart failure (AHF) who are not candidates to advanced therapies have poor prognosis. Some trials have shown that intermittent levosimendan can reduce HF hospitalizations in AHF in the short term. In this real-life registry, we describe the patterns of use, safety and factors related to the response to intermittent levosimendan infusions in AHF patients not candidates to advanced therapies. METHODS AND RESULTS: Multicentre retrospective study of patients diagnosed with advanced heart failure, not HT or LVAD candidates. Patients needed to be on the optimal medical therapy according to their treating physician. Patients with de novo heart failure or who underwent any procedure that could improve prognosis were not included in the registry. Four hundred three patients were included; 77.9% needed at least one admission the year before levosimendan was first administered because of heart failure. Death rate at 1 year was 26.8% and median survival was 24.7 [95% CI: 20.4-26.9] months, and 43.7% of patients fulfilled the criteria for being considered a responder lo levosimendan (no death, heart failure admission or unplanned HF visit at 1 year after first levosimendan administration). Compared with the year before there was a significant reduction in HF admissions (38.7% vs. 77.9%; P < 0.0001), unplanned HF visits (22.7% vs. 43.7%; P < 0.0001) or the combined event including deaths (56.3% vs. 81.4%; P < 0.0001) during the year after. We created a score that helps predicting the responder status at 1 year after levosimendan, resulting in a score summatory of five variables: TEER (+2), treatment with beta-blockers (+1.5), Haemoglobin >12 g/dL (+1.5), amiodarone use (-1.5) HF visit 1 year before levosimendan (-1.5) and heart rate >70 b.p.m. (-2). Patients with a score less than -1 had a very low probability of response (21.5% free of death or HF event at 1 year) meanwhile those with a score over 1.5 had the better chance of response (68.4% free of death or HF event at 1 year). LEVO-D score performed well in the ROC analysis. CONCLUSION: In this large real-life series of AHF patients treated with levosimendan as destination therapy, we show a significant decrease of heart failure events during the year after the first administration. The simple LEVO-D Score could be of help when deciding about futile therapy in this population.
Subject(s)
Cardiovascular Agents , Heart Failure , Humans , Simendan , Cardiotonic Agents/therapeutic use , Retrospective Studies , Treatment Outcome , Heart Failure/diagnosis , RegistriesABSTRACT
BACKGROUND: Tricuspid regurgitation (TR) after heart transplant (HT) can be an important complication depending on its etiology and severity. This study aims to analyze the prevalence of TR, the causes, and its evolution over time after HT. METHODS: We performed a retrospective study of transplants performed between 2000 and 2019 in 2 centers (1009 patients). TR was grouped according to etiology: primary graft dysfunction (PGD), acute rejection, cardiac allograft vasculopathy (CAV), pulmonary hypertension, prolapse, endomyocardial biopsy complication (EMB), pacemaker (PM), and unclear etiology (TR not related to any process and for which no justification was found). RESULTS: The prevalence of TR after HT was 19.8% (moderate: 13.2%, severe: 6.6%). Significant TR was more prevalent in the first months (month 1: 51%, month 3: 40%, month 6: 29%, 1 year: 24%). These results were related to the etiologies. Thus, in the first month, TR due to PGD is frequent and it is the only time when TR due to pulmonary hypertension appears. During the first 6 months, TR of unclear cause gains relevance, which tends to decrease over time. After 1 year, TR due to rejection predominates. After 5 years, TR is less frequent (< 10%) and related to long-term complications of HT, such as CAV, EMB, and those associated with PM. CONCLUSIONS: The prevalence of TR after HT is 19.8%. Prevalence and etiology change over time. Initially it is usually related to PGD, in the medium-term to rejection and in the long-term to CAV and procedures such as EMB and PM.
Subject(s)
Heart Transplantation , Hypertension, Pulmonary , Tricuspid Valve Insufficiency , Humans , Tricuspid Valve Insufficiency/epidemiology , Tricuspid Valve Insufficiency/etiology , Retrospective Studies , Prevalence , Follow-Up Studies , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/complications , Myocardium/pathology , Heart Transplantation/adverse effects , Heart Transplantation/methodsABSTRACT
BACKGROUND: The age of heart transplant (HTx) donors and recipients is progressively increasing. The combination of donor-recipient ages has been shown to have prognostic implications. The objective of this study is to analyze survival in the first year and in the long-term based on the difference in age between donor and recipient of HTx. METHODS: We performed a retrospective analysis of all consecutive HTxs performed in 1 center from 1987 to December 2021. Patients younger than 16 years, retransplants, and combined transplants were excluded. Three groups were considered according to the age of the donor and recipient: group 1: recipient and donor of the same age ± 10 years; group 2: donor >10 years older than recipient; and group 3: donor >10 years younger than recipient. RESULTS: A total of 841 HTxs were included (81% men, 31% urgent HTxs, donor mean (standard deviation) age 38.5 [12.3] years and recipient age 51.2 [12]). The most frequent group was group 3 with 476 patients (56%) followed by group 1 with 305 patients (36%). Figure 1 shows that long-term survival is similar in groups 1 and 2, being worse in group 3, P = .026. Mortality at the end of follow-up is 38.7% in group 1, 34.9% in group 2, and 71.9% in group 3 (P < .0001). These differences occurred in the long-term without finding significant differences the first year after HTx. No differences were found in early graft failure between the 3 groups. CONCLUSIONS: Using donors of a different age from the recipient does not seem to have an impact on long-term survival, except when donors are used who are more than 10 years younger than the recipient, where survival is lower. This consolidates the concept that the use of elderly donors does not affect survival, allowing the pool of donors to be expanded.
Subject(s)
Graft Survival , Heart Transplantation , Male , Humans , Aged , Adult , Middle Aged , Child , Female , Retrospective Studies , Time Factors , Tissue Donors , Heart Transplantation/adverse effects , Age FactorsABSTRACT
BACKGROUND: In advanced heart failure (HF), each hospitalization for decompensation is a vulnerable moment, and it requires optimizing pharmacologic treatment. This study aimed to analyze changes in the pharmacologic treatment of HF before admission (P), during hospitalization (H), and at discharge (D) of patients with decompensated advanced HF. METHODS: We performed an ambispective, cross-sectional, noninterventional study conducted from January 2020 to June 2020. There were 252 consecutive patients admitted for decompensated advanced HF. The following were excluded: de novo HF cases, deceased patients, and scheduled admissions. Finally, 134 patients were analyzed, compared in 3 subgroups: pulmonary congestion (n = 90), systemic congestion (n = 31), and low output (n = 13). RESULTS: In the global analysis, an increase was detected in angiotensin receptor and neprilysin inhibitors (P: 9.7%, H: 16.4, D: 22.4%; P < .02), beta blockers (P: 67.2%, H: 77.6%, D: 84.3%; P < .004), mineralocorticoid receptor antagonists (P: 29.9%, H: 44.4%, D: 46.3%; P < .01), loop diuretics (P: 70.1%, H: 99.3%, D: 95.5%; P < .001), and nitrates (P: 6.0%, H: 22.4%, D: 9.7%; P < .001). Pulmonary congestion was predominant with a significant increase in beta blockers (P: 61.1%, H: 77.8%, D: 88.9%; P < .001) and loop diuretics (P: 64.4%, H: 100%, D: 100%; P < .001); diuretics were increased in the systemic congestion group (P: 80.6%, H: 100%, D: 100%; P < .002), and 22.6% required 3% hypertonic saline solution. In patients with low output, beta blockers and diuretics were withdrawn (P: 84.6%, H: 76.9%, D: 46.1%; P < .08 and P: 84.6%, H: 92.3%, D: 61.5%; P < .1 respectively), without variation in the other pharmacologic groups. CONCLUSIONS: In daily clinical practice, HF drugs are increased and optimized in decompensated HF with a pulmonary or systemic congestion profile. When the profile is low output, beta blockers and diuretics are reduced.