High-dose versus low-dose angiotensin converting enzyme inhibitors in heart failure: systematic review and meta-analysis.

OBJECTIVE: To systematically review evidence comparing the effect of low-dose versus high-dose ACE inhibitors (ACEIs) on all-cause and cardiovascular mortality and hospitalisation, functional capacity and side effects in patients with heart failure (HF). METHODS: We searched PubMed, Embase, Cochrane CENTRAL and LILACS up to January 2019. We included randomised controlled trials (RCTs) comparing low-dose versus high-dose ACEIs in adults with HF with reduced left ventricular ejection fraction (HFrEF). Study selection and data extraction were performed by two independent reviewers. Risk of bias was assessed with RoB 2.0, and quality of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). We conducted random effects meta-analysis and trial sequential analysis. RESULTS: We included eight RCTs (5829 patients with HF). In comparison with low-dose ACEIs, high-dose ACEIs showed a non-significant effect on all-cause mortality (8 RCTs, n=5828, relative risk (RR) 0.95, 95% CI 0.88 to 1.02; moderate quality of evidence), cardiovascular mortality (6 RCTs, n=4048, RR 0.93, 95% CI 0.85 to 1.01; moderate quality of evidence), all-cause hospitalisation (5 RCTs, n=5394, RR 0.95, 95% CI 0.82 to 1.10; moderate quality of evidence) and cardiovascular hospitalisation (4 RCTs, n=5242, RR 0.98, 95% CI 0.83 to 1.17; low quality of evidence). High-dose ACEI increased functional capacity (4 studies, n=555, standardised mean difference 0.38, 95% CI 0.20 to 0.55; low quality of evidence) and the risk of hypotension (4 RCTs, n=3783, RR 1.64, 95% CI 1.30 to 2.05; moderate quality of evidence). High-dose ACEI had no effect on dizziness (3 RCTs, n=4994, RR 1.37, 95% CI 0.97 to 1.93; low quality of evidence), but decreased the risk of cough (4 RCTs, n=5146, RR 0.85, 95% CI 0.73 to 0.98; moderate quality of evidence). CONCLUSIONS: The magnitude of benefit of using high dose versus low to intermediate doses of ACEIs might be less than traditionally suggested in clinical guidelines. These findings might help clinicians address the complex task of HF management in a more rational and timely fashion, saving efforts to implement strategies with the greatest net clinical benefit.

Recently Approved and Under Investigation Drugs for Treating Patients with Heart Failure.

Heart Failure (HF) represents a leading cause of morbidity and mortality worldwide. Despite the recent advances in the treatment of this condition, patients´ prognosis remains unfavorable in most cases. Sacubitril/valsartan and ivabradine have been recently approved to improve clinical outcomes in patients with HF with reduced ejection fraction. Drugs under investigation for treating patients with HF encompass many novel mechanisms including vasoactive peptides, blocking inflammatory- mediators, natriuretic peptides, selective non-steroidal mineralocorticoid-receptor antagonists, myocardial ß3 adrenoreceptor agonists, inhibiting the cytochrome C/cardiolipin peroxidase complex, neuregulin-1/ErbB signaling and inhibiting late inward sodium current. The aim of this manuscript is to review the main drugs under investigation for the treatment of patients with HF and give perspectives for their implementation into clinical practice.

Evaluación hemodinámica no invasiva a largo plazo de la terapia de resincronización cardíaca endocárdica izquierda / Long-term Non-invasive Hemodynamic Evaluation of Left Endocardial Cardiac Resynchronization Therapy

RESUMEN Introducción: La terapia de resincronización cardíaca presenta una tasa de un 25%-30% de pacientes "no respondedores". La resincronización endocárdica, en la que el catéter del ventrículo izquierdo se implanta en el endocardio, sería una alternativa para estos pacientes, aunque su evolución a largo plazo no ha sido investigada. Objetivos: Evaluación hemodinámica no invasiva a largo plazo de la resincronización endocárdica en respondedores clínicos. Métodos: Se incluyeron pacientes implantados según los criterios para resincronización, usando la técnica Jurdham, con más de 6 meses desde el implante. Todos eran respondedores clínicos. La respuesta hemodinámica se evaluó con un analizador de la función cardíaca, que mide los intervalos sistólicos (períodos preeyectivo y eyectivo) del ventrículo izquierdo y calcula automáticamente un índice de función sistólica y estimar la fracción de eyección (Systocor mod ÍS100). Para determinar la eficacia mecánica de la TRCe se comparó la función cardíaca durante el modo biventricular con el bloqueo completo de la rama izquierda, espontáneo o por estimulación única del ventrículo derecho; los pacientes fueron sus propios controles. Se promediaron al menos 20 latidos en cada modo de estimulación y se consideraron solo los cambios >1% con valor p < 0,01 como clínicamente relevantes y estadísticamente significativos. Resultados: Se incluyeron 17 pacientes, con mediana de seguimiento de 43 meses, rango 9 a 78 meses. La resincronización endocárdica, en comparación con la activación ventricular con BCRI, demostró que todos los pacientes acortaron el período preeyectivo en un promedio de 31 ms (15%), indicativo de disminución de la disincronía interventricular causada por el BCRI. En todos aumentó el índice de función sistólica en 0,3 (23%) y la FE en el 8,3%. En 12/17 (71%) aumentó el período eyectivo en promedio 8,7 mseg (2,9%), lo que sugiere un aumento del volumen sistólico. En todos los cambios el valor de p fue menor de 0,01. Conclusiones: La TRCe ofrece mejoría hemodinámica significativa a largo plazo, detectada por intervalos sistólicos.

ABSTRACT Background: Cardiac resynchronization therapy has 25% to 30% rate of "non-responder" patients. Endocardial cardiac resynchronization therapy (eCRT), in which the left ventricular catheter is implanted in the endocardium, would be an alternative for these patients; however, its long-term outcome has not been investigated. Objectives: The aim of this study was the long-term non-invasive hemodynamic evaluation of eCRT in clinical responders. Methods: Patients implanted according to the criteria for resynchronization, using the Jurdham technique, with more than 6 months after the implant, were included in the study. All were clinical responders. The hemodynamic response was evaluated with a cardiac function analyzer, which measures the left ventricular systolic intervals (preejection and ejection periods) and automatically calculates an index of systolic function and estimates the ejection fraction (Systocor mod ÍS100). To assess the mechanical efficacy of eCRT, the cardiac function during biventricular mode was compared with left bundle branch block (LBBB), either spontaneous or by single stimulation of the right ventricle, with patients as their own controls. At least 20 beats were averaged in each stimulation mode and only changes >1% with p <0.01 were considered as clinically relevant and statistically significant. Results: Seventeen patients were included, with a median follow-up of 43 months, (9 to 78 months). Endocardial resynchronization, compared with LBBB ventricular activation, showed that all patients shortened the preejection period by an average of 31 ms (15%), indicative of decreased interventricular dyssynchrony caused by LBBB. In all patients, systolic function index increased by 0.3 (23%) and the EF by 8.3%. In 12/17 of cases (71%) the ejective period increased on average 8.7 ms (2.9%), suggesting an increase in systolic volume. In all changes p was <0.01. Conclusions: Endocardial resynchronization therapy offers significant long-term hemodynamic improvement, detected by systolic intervals.

Gaps and Resemblances in Current Heart Failure Guidelines: A Clinical Perspective.

The newly available clinical guidelines in heart failure (HF) from Europe (2012), the United States (2010 and 2013), and Canada (2015) were compared, focusing on the systems for grading the evidence and classifying the recommendations, HF definitions, pharmacologic treatment, and devices used in HF. Some gaps were evident in the methodology for assessing evidence or in HF definitions. Pharmacologic treatments and recommendations for cardiac resynchronization therapy and implantable cardioverter-defibrillators are similar but some differences need to be considered by the practicing clinician. Guideline recommendations regarding new emergent treatments are becoming available.