Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension - study protocol for a randomized controlled trial.

BACKGROUND: Resistant hypertension is characterized when the blood pressure (BP) remains above the recommended goal after taking three antihypertensive drugs with synergistic actions at their maximum recommended tolerated doses, preferably including a diuretic. Identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether acting on the control of intravascular volume or sodium balance, or acting on the effects of the renin-angiotensin-aldosterone system (RAAS) on the kidney. METHODS/DESIGN: This is a randomized, open-label, clinical trial is designed to compare sequential nephron blockade and its contribution to the intravascular volume component with dual blockade of the RAAS plus bisoprolol and the importance of serum renin in maintaining BP levels. The trial has two arms: sequential nephron blockade versus dual blockade of the RAAS (with an angiotensin converting enzyme (ACE) inhibitor plus a beta-blocker) both added-on to a thiazide diuretic, a calcium-channel blocker and an angiotensin receptor-1 blocker (ARB). Sequential nephron blockade consists in a progressive increase in sodium depletion using a thiazide diuretic, an aldosterone-receptor blocker, furosemide and, finally, amiloride. On the other hand, the dual blockade of the RAAS consists of the progressive addition of an ACE inhibitor until the maximum dose and then the administration of a beta-blocker until the maximum dose. The primary outcomes will be reductions in the systolic BP, diastolic BP, mean BP and pulse pressure (PP) after 20 weeks of treatment. The secondary outcomes will evaluate treatment safety and tolerability, biochemical changes, evaluation of renal function and recognition of hypotension (ambulatory BP monitoring (ABPM)). The sample size was calculated assuming an alpha error of 5% to reject the null hypothesis with a statistical power of 80% giving a total of 40 individuals per group. DISCUSSION: In recent years, the cost of resistant hypertension (RH) treatment has increased. Thus, identifying the contribution of intravascular volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of intravascular volume or sodium balance, or by acting on the effects of the RAAS on the kidney. TRIAL REGISTRATION: Sequential Nephron Blockade vs. Dual Blockade Renin-angiotensin System + Bisoprolol in Resistant Arterial Hypertension (ResHypOT). ClinicalTrials.gov, ID: NCT02832973 . Registered on 14 July 2016. First received: 12 June 2016. Last updated: 18 July 2016.

Insuficiência cardíaca - fisiopatologia atual e implicações terapêuticas / Heart failure - current pathophysiology and terapeutic implications

Conhecer a fisiopatologia da insuficiência cardíaca propiciou uma evolução terapêutica em seu manejo, que se traduziu em melhora de desfechos clínicos relevantes, incluindo redução da mortalidade. O conceito do remodelamento ventricular, associado à ativação neuro-humoral descrita inicialmente, via ativação do sistema renina-angiotensina-aldosterona, e posteriormente via ativação simpática, levou ao uso de inibidores da ECA e de betabloqueadores, respectivamente, que mudaram o curso da história da insuficiência cardíaca. Ainda na categoria farmacológica, mais recentemente a modulação da rota da neprilisina, através do uso do composto sacubitril/valsartan, trouxe impacto adicional de redução de mortalidade em pacientes com insuficiência cardíaca. Por fim, dispositivos que também interfiram no processo de remodelamento ventricular, como marcapassos de ressincronização biventricular, demonstraram benefícios clínicos significativos. Novos alvos moleculares, microRNAs ou moléculas de sinalização intracelular, devem crescer como potenciais áreas de investigação na progressão da doença e, potencialmente, se transformarem em alvos terapêuticos

Knowledge of the pathophysiology of heart failure has led to a therapeutic evolution in its management that has resulted in improved clinical outcomes, including a reduction in mortality. The concept of ventricular remodeling associated with neurohumoral activation, initially described via activation of the renin-angiotensin-aldosterone system and later, via sympathetic activation, led to the use of ACE inhibitors and beta blockers, respectively, altering the course of history of heart failure. Also in the pharmacological category, more recently, modulation of the neprilysin route, through the use of the compound sacubitril/valsartan, brought additional impacts in reducing mortality in patients with heart failure. Finally, devices that also interfere in the process of ventricular remodeling, such as biventricular resynchronization pacemakers, have demonstrated significant clinical benefits. New molecular targets, microRNAs, or intracellular signaling molecules should increase as potential areas of research on disease progression, and could potentially become therapeutic targets

Effect of Combining Ivabradine and ß-Blockers: Focus on the Use of Carvedilol in the SHIFT Population.

OBJECTIVES: We explored the prescription of ß-blockers with ivabradine in patients with systolic heart failure, focusing on the most frequently coprescribed ß-blocker, carvedilol. METHODS: We analyzed outcomes in SHIFT patients with systolic heart failure who were prescribed ß-blockers (carvedilol, bisoprolol, metoprolol, or nebivolol) with ivabradine or placebo. Analysis was by intention to treat in patients prescribed a ß-blocker at the time of the event. RESULTS: Data were available for 2,596 patients receiving carvedilol, 1,483 bisoprolol, 1,424 metoprolol, and 197 nebivolol. Mean treatment duration was 19 months. There was no difference in the effect of ivabradine on the primary composite endpoint of cardiovascular death or heart failure hospitalization between the various ß-blockers [hazard ratios (HR) for risk reduction, 0.75-0.89; p for interaction=0.86]. Patients prescribed carvedilol with ivabradine had lower rates of primary composite endpoint (HR 0.80, 95% CI: 0.68-0.94), heart failure hospitalization (HR 0.73, 95% CI: 0.61-0.88), and cardiovascular hospitalization (HR 0.80, 95% CI: 0.69-0.92) versus carvedilol with placebo. The dosage of carvedilol had no detectable effect and there were no unexpected safety issues. CONCLUSIONS: Whatever ß-blocker was coprescribed with ivabradine, there were improvements in cardiovascular outcomes in patients with systolic heart failure, especially with the most prescribed ß-blocker--carvedilol.

Comparación de la combinación hidroclorotiazida/bisoprolol con enalapril/amlodipina en el manejo de la hipertensión arterial no controlada / Comparison of the combination hydrochlorothiazide/bisoprolol with enalapril/amlodipine in the management of uncontrolled hypertension

La hipertensión arterial afecta aproximadamente 50 millones de individuos en Estados Unidos de América y un mil millones de individuos en el resto del mundo, afectando de un 15 por ciento a 30 por ciento de la población mundial, y es uno de los factores predictivos de enfermedad cardiovascular más importantes, por lo tanto su control es indispensable. Este estudio comparó la acción antihipertensiva de la combinación hidroclorotiazida/bisoprolol con la combinación enalapril/amlodipina en pacientes con diagnóstico de hipertensión arterial no controlada. Métodos: Se realizó un ensayo clínico controlado aleatorizado en pacientes hipertensos con edades comprendidas entre 30 y 65 años con diagnóstico de hipertensión arterial con o sin tratamiento. Fueron distribuidos en dos grupos de 10 pacientes; uno recibió tratamiento con hidroclorotiazida/bisoprolol y el otro con enalapril/amlodipina bajo un protocolo de ajuste de dosis según metas de PA para 4 semanas. Resultados: Ambas combinaciones redujeron significativamente los valores de presión arterial a las 4 semanas (P=< 0,0001). Sin embargo, el efecto antihipertensivo de la combinación hidroclorotiazida/Bisoprolol fue superior para la reducción de la presión diastólica (P= 0,025), y el alcance de la meta de 120/70 mmHg (90 por ciento vs. 50 por ciento). Conclusión: La utilización de la combinación hidroclorotiazida / bisoprolol tiene mayor número de beneficios que los observados con la combinación enalapril / amlodipina en el manejo de la hipertensión arterial no controlada

The High Blood Pressure affects around 50 millions people in the EE.UU of America and a thousand million people all around the world, affecting 15 percent to 30 percent of the world’s population, and is one of the most important predictive factors of cardiovascular disease; therefore its control is essential. This study compared the antihypertensive action of the combination Hydrochlorothiazide/Bisoprolol with the combination Enalapril/Amlodipine in patients with uncontrolled High Blood Pressure diagnosis. Methods: We performed a randomized, controlled, clinical essay, in patients with High Blood Pressure between 30 and 65 years old, with High Blood Pressure previous diagnosis under treatment or not. They were distributed into two groups of 10 patients each one; one group received Hydrochlorothiazide/Bisoprolol, and the other one, received Enalapril/Amlodipine under a standardized regimen of titration according to BP goals during 4 weeks. Results: Both combinations reduced significantly BP values at 4 weeks of treatment (P= <0.0001). However, the antihypertensive effect of the combination Hydrochlorothiazide/Bisoprolol was superior in the reduction of diastolic values of BP (P= 0,025), and the reach of the 120/70 mmHg goal (90 percent vs. 50 percent). Conclusions: the use of the combination Hydrochlorothiazide/Bisoprolol is related to a higher number of benefits than the use of the combination Enalapril/Amlodipine in the management of patients with uncontrolled High Blood Pressure diagnosis

Congestive heart failure and renal complications.

Congestive heart failure is the leading cause of hospital admission among patients over the age of 65 years. It affects population within the United States, including Puerto Rico, presenting itself as the leading cause of heart related deaths worldwide. Its management can include pharmacologic agents which will affect neuroendocrine axis mainly but also include novel non-pharmacologic approaches such as ultrafiltration. The coexistence of heart failure and renal dysfunctions are very common within our medical community, especially within the western hemisphere, causing greater concerns amongst the medical field with increased research and investigation activity. This clinical review article will address the theme of congestive heart failure, highlighting the edema formation concept, volume homeostasis, cardio-renal syndrome and neuroendocrine pathways. The management of acute decompensated heart failure is discussed, primarily focusing with available novel non-pharmacologic approaches.

Effects of bisoprolol on cardiac function and exercise in patients with heart failure.

OBJECTIVE: To assess the effects of bisoprolol on exercise capacity and ventricular function in patients with heart failure. METHODS: Clinical and hemodynamic variables, ventricular function and remodeling, and ergospirometry of patients with heart failure of different etiologies were evaluated before and after the administration of bisoprolol. RESULTS: Twenty-two patients were analyzed; one patient did not tolerate medication and 14 patients reached the study goal. The group consisted of 9 men and 5 women, the mean age was 52 (36-64) years, and patients were followed during 551 days (238-1109). We observed an improvement in NYHA functional class, reduction in resting heart rate (78.8+/-8.7 vs 63+/-6.4 bpm, p <0.001), increase in left ventricular ejection fraction (31.3+/-8.5% vs 39+/-14.7%. p=0.043), and a tendency towards improved quality of life scores (31+/-20.6 vs 17.8+/-14.8. p=0.058). The maximum heart rate dropped during exercise (138.1+/-20.2 vs 116.7+/-27.1. p=0.01), as did peak oxygen consumption (20.9+/-6.8 vs 15.1+/-3.5. p<0.001); no change was observed on the EV/VCO2 slope. The effects were observed for all etiologies, including Chagas disease. CONCLUSION: Bisoprolol was safe and well tolerated in patients with heart failure. Bisoprolol therapy improved the symptoms, hemodynamic variables, as well as the cardiac function for all etiologies; however, it did not result in improved exercise capacity.

Efeito do bisoprolol sobre a função cardíaca e o exercício em pacientes com insuficiência cardíaca / Effects of bisoprolol on cardiac function and exercise in patients with heart failure

OBJETIVO: Avaliar o efeito do bisoprolol sobre a capacidade de exercício e a função ventricular em pacientes com insuficiência cardíaca. MÉTODOS: Foi feita a análise das variáveis clínicas e hemodinâmicas, da função e do remodelamento ventricular, e da ergoespirometria de pacientes com insuficiência cardíaca com diferentes etiologias, antes e após administração de bisoprolol. RESULTADOS: Foram analisados 22 pacientes, dos quais 1 paciente não tolerou a medicação e 14 pacientes alcançaram a meta do estudo. A média das idades foi de 52 anos (36 a 64 anos), 9 pacientes eram do sexo masculino e 5 eram do sexo feminino, com tempo médio de seguimento de 551 dias (238 a 1.109 dias). Foram observados melhora da classe funcional, redução da freqüência cardíaca de repouso (78,8 + 8,7 bpm vs. 63 + 6,4 bpm; p < 0,001), aumento da fração de ejeção do ventrículo esquerdo (31,3 + 8,5 por cento vs. 39 + 14,7 por cento; p = 0,043) e tendência a melhora do escore de qualidade de vida (31 + 20,6 vs. 17,8 + 14,8; p = 0,058). Ocorreu queda da freqüência cardíaca máxima no exercício (138,1 + 20,2 vs. 116,7 + 27,1; p = 0,01) e do consumo máximo de oxigênio (20,9 + 6,8 vs. 15,1 + 3,5; p < 0,001). Não houve modificação do slope VE/VCO2. Os efeitos ocorreram em todas as etiologias, inclusive na doença de Chagas. CONCLUSÃO: O bisoprolol produziu melhora clínica e hemodinâmica e de função cardíaca nas diferentes etiologias, sem, entretanto, apresentar efeitos de melhora na capacidade de exercício.

OBJECTIVE: To assess the effects of bisoprolol on exercise capacity and ventricular function in patients with heart failure. METHODS: Clinical and hemodynamic variables, ventricular function and remodeling, and ergospirometry of patients with heart failure of different etiologies were evaluated before and after the administration of bisoprolol. RESULTS: Twenty-two patients were analyzed; one patient did not tolerate medication and 14 patients reached the study goal. The group consisted of 9 men and 5 women, the mean age was 52 (36-64) years, and patients were followed during 551 days (238-1109). We observed an improvement in NYHA functional class, reduction in resting heart rate (78.8±8.7 vs 63±6.4 bpm, p <0.001), increase in left ventricular ejection fraction (31.3±8.5 percent vs 39±14.7 percent. p=0.043), and a tendency towards improved quality of life scores (31±20.6 vs 17.8±14.8. p=0.058). The maximum heart rate dropped during exercise (138.1±20.2 vs 116.7±27.1. p=0.01), as did peak oxygen consumption (20.9±6.8 vs 15.1±3.5. p<0.001); no change was observed on the EV/VCO2 slope. The effects were observed for all etiologies, including Chagas' disease. CONCLUSION: Bisoprolol was safe and well tolerated in patients with heart failure. Bisoprolol therapy improved the symptoms, hemodynamic variables, as well as the cardiac function for all etiologies; however, it did not result in improved exercise capacity.

Estudio comparativo entre bisoprolol y metoprolol, asociados a hidroclorotiazida, como terapia antihipertensiva / Comparative study between bisoprolol and metoprolol/hydrochlorothiazide in anti-hypertensive therapy

El objetivo de este estudio fue el de comparar la eficacia y seguridad del bisoprolol (B), un nuevo betabloqueador cardioselectivo (desprovisto de actividad simpaticomimético intrínseca) y del metoprolol (M) asociados a hidroclorotiazida (HCTZ) en el tratamiento de la hipertensión arterial (HTA) leve a moderada. En un estudio doble ciego, aleatorizado, controlado con placebo fueron evaluados 62 pacientes (47 mujeres y 15 hombres), con edades entre 20 y 70 años (media 52.5 ñ 10.4). Después de un periodo de lavado y una fase de placebo de 2 semanas cada uno, los enfermos fueron asignados recibir B (10 mg) más 6.25 mg de HCTZ o M (100 mg) más 6.25 mg de HCTZ, durante 4 semanas. Al término de este periodo, aquellos enfermos en los cuales no se había reducido la presión arterial diastólica (PAD) por abajo de 90 mmHg la dosis del betabloqueador fue duplicada. Después de ocho semanas de tratamiento, la disminución promedio en la presión arterial sistólica (PAS) y PAD en relación a los valores basales fueron: 31.8 mmHg/21.2 mmHg y 28.0 mmHg/20.6 mmHg para B/HCTZ y M/HCTZ, respectivamente (p < 0.0001). No se encontraron modificaciones significativas en los parámetros de laboratorio, al concluir el estudio en ninguno de los dos grupos. La disminución de la presión arterial (PA) con B/HCTZ se encuentra relacionada con un perfil de eventos adversos y cambios metabólicos semejante a los observados con otras drogas.

[Comparative study between bisoprolol and metoprolol, combined with hydrochlorothiazide, as antihypertensive therapy]. / Estudio comparativo entre bisoprolol y metoprolol, asociados a hidroclorotiazida, como terapia antihipertensiva.

The main objective of this research was to compare the efficacy and security of bisoprolol (B), a new cardioselective beta-blocker, that does not have intrinsic sympathomimetic activity, and metoprolol associated to hydrochlorothiazide (HCTZ), in the treatment of patients with mild to moderate hypertension. Sixty-two hypertensive patients (47 females and 15 males) aged 20 to 70 years (mean 52.5 +/- 10.4) were included in a double-blind, placebo controlled and randomized clinical trial. After a two-weeks wash out period and a similar placebo phase, patients were randomly assigned to receive either a once-daily dosing of B (10 mg) with 6.25 mg of HCTZ, or M (100 mg) plus 6.25 mg of HCTZ during four-weeks. If there was no reduction below 90 mmHg at the end of this period, the dosing of either beta-blocker was doubled. After eight weeks of treatment, the mean decreases in systolic/diastolic blood pressures from baseline were 31.8/21.2 and 28.0/20.6 mmHg for B/HCTZ and M/HCTZ, respectively (p < 0.0001). There were no clinically significant changes from baseline in laboratory parameters in either group. Reduction in blood pressure with B/HCTZ is associated with adverse events and metabolic changes similar to those observed with other antihypertensive drugs.

Eficácia e tolerabilidade da associaçäo bisoprolol hidroclorotiazida na hipertensäo arterial / Efficacy and tolerability of the bisoprolol/hydrochlorothiazide combination in the treatment of arterial hypertension

Objetivo - Estudo multicêntrico, aberto e não comparativo, para avaliar a eficácia e a tolerabilidade de dois agentes anti-hipertensivos combinados em doses baixas: o beta-bloqueador cardiosseletivo bisoprolol (2,5 e 5,0mg) com 6,25mg de hidrocloratizada. Métodos - Cento e seis pacientes com hipertensão arterial nos estágios I e II (leve a moderada) receberam a combinação bisoprolol/hidrocloratizada, em uma única dose diária, e foram submetidos a uma avaliação da pressão arterial sistólica (PAS) e pressão arterial diastólica (PAD), durante 8 semanas. Resultados - A combinação bisoprolol/hidrocloratiazida reduziu significativamente os valores médios iniciais da PAS (157,4mmHg para 1373,3mmHg) e da PAD (98,8mmHg para 87,4mmHg). Ao final do estudo, 61 por cento haviam normalizado a PA (<90mmHg) e 22,9 por cento deles foram responsivos ao tratamento, resultando em elevada taxa de resposta terapêutica (normalizados + responsivos) - total de 83,9 por cento dos casos. Eventos adversos foram descritos em 18,9 por cento dos pacientes, sendo os mais freqüentes: tontura e cefaléia. Não se observaram alterações clinicamente significativas nos níveis plasmáticos de glicose, potássio, ácido útico e perfil lipídico. Conclusão - A combinação bisoprolol/hidroclorotiazida em baixas doses pode ser considerada uma alternativa racional, eficaz e bem tolerada para o tratamento inicial da hipertensão arterial leve ou moderada.

[Efficacy and tolerance of the bisoprolol/hydrochlorothiazide combination in arterial hypertension]. / Eficácia e tolerabilidade da associação bisoprolol/ hidroclorotiazida na hipertensão arterial.

PURPOSE: Multicenter, open and non-controlled study to evaluated the efficacy and the tolerability of a low-dose combination of two anti-hypertensive agents: a cardioselective beta-blocker, bisoprolol (2.5 and 5.0 mg) with 6.25 mg of hydrochlorothiazide. METHODS: One hundred and six patients in the stage I and stage II of the systemic hypertension (mild to moderate) were given the bisoprolol/hydrochlorothiazide combination once daily and the diastolic and systolic blood pressures were monitored during the 8-week trial. RESULTS: The bisoprolol/hydrochlorothiazide combination reduced the initial mean values of systolic and diastolic blood pressures, respectively, from the 157.4 mmHg and 98.8 mmHg to 137.3 mmHg and 87.4 mmHg. At the end of the treatment period, 61% of the patients normalized blood pressure values (< 90 mmHg) and 22.9% of them had responded to the treatment, resulting in a total response rate (normalized + responsive) of 83.9% of cases. Adverse events were described only in 18.9% of the patients and dizziness and headache were the most common. There were no clinically significant changes on plasma levels of potassium, uric acid, glucose, or in the lipid profile. CONCLUSION: The combination of low dosages of bisoprolol and hydrochlorothiazide may be considered an effective, well tolerated and rational alternative for the initial treatment of the patients with mild to moderate hypertension.