Efficacy of omecamtiv mecarbil in heart failure with reduced ejection fraction according to N-terminal pro-B-type natriuretic peptide level: insights from the GALACTIC-HF trial.

AIM: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT-proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC-HF). METHODS AND RESULTS: The primary outcome was the composite of a worsening heart failure event (urgent clinic visit, emergency department visit, or hospitalization) or cardiovascular death. We prespecified analysis of the effect of treatment according to baseline NT-proBNP (≤ median, > median), excluding individuals with atrial fibrillation/flutter (AF/AFL). Of the 8232 patients analysed, 8206 had an available baseline NT-proBNP measurement. Among the 5971 patients not in AF/AFL, the median (Q1-Q3) NT-proBNP level was 1675 (812-3579) pg/ml. Hazard ratios (HR) for the effect of omecamtiv mecarbil, compared with placebo, for the primary endpoint in patients without AF/AFL were: ≤ median 0.94 (95% confidence interval [CI] 0.80-1.09), > median 0.81 (0.73-0.90) (p-interaction = 0.095); for the overall population (including patients with AF/AFL) the HRs were ≤ median 1.01 (0.90-1.15) and > median 0.88 (0.80-0.96) (p-interaction = 0.035). There was an interaction between treatment and NT-proBNP, examined as a continuous variable, with greater effect of omecamtiv mecarbil on the primary outcome in patients with a higher baseline NT-proBNP (p-interaction = 0.086). CONCLUSIONS: In GALACTIC-HF, the benefit of omecamtiv mecarbil appeared to be larger in patients with higher baseline NT-proBNP levels, especially in patients without AF/AFL. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02929329; EudraCT number, 2016-002299-28.

Registro colombiano de falla cardiaca (RECOLFACA): resultados / Colombian registry of heart failure (RECOLFACA): results

Resumen Introducción: La falla cardiaca (FC) es un problema de salud pública mundial. En Latinoamérica, la incidencia es de 199/100.000 personas-año y la prevalencia de ≈1%. En Colombia, pocos estudios han descrito el comportamiento sociodemográfico y clínico de los pacientes con FC agudamente descompensada (FCAD) y FC crónica (FCC). Método: Se implementó un registro multicéntrico para identificar características que puedan ayudar en la planeación y desarrollo de estrategias de prevención secundaria y tratamiento de esta población. Resultados: Se incluyeron 2528 pacientes. 57.59% hombres, edad promedio 69 años. La principal comorbilidad fue hipertensión arterial (72.04%). Las principales causas de descompensación de la FC fueron la progresión de la enfermedad (35.00%) y el tratamiento insuficiente (19.09%). La etiología más frecuente fue isquémica (43.99%). Al momento del ingreso, 86.95% de pacientes recibían betabloqueador, 67.25% recibían diuréticos, 55.66% recibían ARM, 42.41% recibían ARA-II, 33.66% recibían IECA y 9.73% recibían ARNI. Conclusiones: Los pacientes con FC en Colombia son similares a los descritos por otros registros de FC en el mundo occidental, destacando el uso de terapias basadas en la evidencia. Se documentó una proporción menor de fibrilación auricular, con mayor frecuencia de disfunción sistólica moderada-grave y un aparente uso subóptimo de dispositivos implantables.

Abstract Introduction: Heart failure (HF) is a public health problem worldwide. In Latin America, incidence is 199 / 100,000 person-year and prevalence is ≈1%. In Colombia, few studies have described the sociodemographic and clinical behavior of patients with acutely decompensated HF (ADHF) and chronic HF (CHF). Method: A multicenter registry was implemented to identify characteristics that can help in the planning and development of secondary prevention and treatment strategies for this population. Results: 2528 patients were included. 57.59% men, average age 69 years. The main comorbidity was arterial hypertension (72.04%). The main causes of HF decompensation were disease progression (35.00%) and insufficient treatment (19.09%). The most frequent etiology was ischemic (43.99%). At the time of admission, 86.95% of patients received beta-blocker, 67.25% received diuretics, 55.66% received MRA, 42.41% received ARB-II, 33.66% received ACEI, and 9.73% received ARNI. Conclusions: Patients with HF in Colombia are similar to those described by other HF registries in the western world, highlighting the use of evidence-based therapies. A lower proportion of atrial fibrillation was documented, with a higher frequency of moderate-severe systolic dysfunction and an apparent suboptimal use of implantable devices.

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC-HF baseline characteristics and comparison with contemporary clinical trials.

AIMS: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials. METHODS AND RESULTS: Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594). CONCLUSIONS: GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation.

Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial.

BACKGROUND: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. METHODS AND RESULTS: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), ß-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. CONCLUSIONS: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Síndrome de encefalopatía posterior reversible secundaria a tacrolimus / Tacrolimus-associated posterior reversible encephalopathy syndrome

Los inhibidores de la calcineurina, la ciclosporina y el tacrolimus han jugado un papel preponderante en la prevención de los episodios de rechazo y de la enfermedad de injerto contra el huésped en pacientes tratados mediante el trasplante de órgano sólido y de la médula ósea. No obstante, el tacrolimus presenta efectos adversos relacionados con la neurotoxicidad, siendo el síndrome de encefalopatía posterior reversible la consecuencia más severa de dicha neurotoxicidad. El reporte de nuestro caso es de una mujer de 30 años de edad, con 2 días de evolución de cefalea intensa en la frente, náuseas, emesis, hiporexia y epigastralgia, afebril. Antecedente de un trasplante cardiaco 45 días antes, en tratamiento inmunosupresor con tacrolimus y micofenolato mofetilo. Se documentan niveles de tacrolimus adecuados (12,1 ng/ml), los estudios imagenológicos normales y los resultados de laboratorio negativos para infección, lo que permite descartar las causas vasculares e infecciosas y la neurotoxicidad por el tacrolimus. Sin embargo, ante el desarrollo de alteraciones neuropsiquiátricas, y a pesar de niveles de tacrolimus < 5,5 ng/ml, se realiza nueva resonancia nuclear magnética cerebral con hallazgos que indican síndrome de leucoencefalopatía posterior reversible. Se suspende el tacrolimus y se inicia tratamiento con everolimus, lográndose remisión total. Este sería el primer caso reportado en el cual las alteraciones imagenológicas asociadas al síndrome de encefalopatía posterior reversible se desarrollaron en una paciente intervenida de trasplante cardiaco con niveles de tacrolimus < 10 ng/ml. El reporte de este caso permitirá a los grupos médicos tratantes considerar este diagnóstico a pesar de niveles de tacrolimus en rango terapéutico, de manera que se realice un reconocimiento y tratamiento oportuno, evitando así el desarrollo de complicaciones o secuelas neurológicas.

Calcineurin inhibitors, cyclosporine and tacrolimus, have played a major role in preventing graft rejection and graft-versus-host disease in patients undergoing bone marrow and solid organ transplantation. However, tacrolimus has adverse effects related with neurotoxicity, being the posterior reversible encephalopathy syndrome the most severe consequence of this neurotoxicity. We report the case of a 30 year-old woman with 2-day history of severe frontal headache, náusea, emesis, hiporexia and epigastric pain, without fever. History of heart transplant 45 days ago, immunosuppressive therapy with tacrolimus and mycophenolatemofetil. Appropriate levels of tacrolimus (12.1 ng/ml), normal imaging and lab results were documented, excluding vascular and infectious causes as well as tacrolimus neurotoxicity. Nevertheless, due to the development of neuropsychiatric disorders and despite tacrolimus levels being < 5.5 ng/ml, a new brain MRI was performed showing a reversible posterior leukoencephalopathy syndrome. Tacrolimus was switched to everolimus achieving complete remission. This is the first reported case in which the imaging alterations associated with posterior reversible encephalopathy syndrome were developed in a patient undergoing heart transplantation with tacrolimus levels < 10 ng/ml. The report of this case will allow the treating physician groups to consider this diagnosis regardless oftacrolimus levels within therapeutic range, allowing therefore an early recognition and treatment, thus avoiding the development of complications and/or neurological sequels.