Manuel Covelo

Administration Time-Dependent Effects of Valsartan on Ambulatory Blood Pressure in Hypertensive Subjects

Abstract—This study investigated the administration time–dependent antihypertensive efficacy of valsartan, an angiotensin II receptor blocker. We studied 90 subjects (30 men and 60 women), 49.0±14.3 (mean±SD) years of age with stage 1 to 2 essential hypertension; they were randomly assigned to receive valsartan (160 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured by ambulatory monitoring every 20 minutes during the day and every 30 minutes at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of blood pressure on a per-subject basis. The highly significant blood pressure reduction after 3 months of treatment with valsartan (P <0.001) was similar for both treatment times (17.0 and 11.3 mm Hg reduction in the 24-hour mean of systolic and diastolic blood pressure with morning administration and 14.6 and 11.4 mm Hg reduction with bedtime administration; P >0.174 for treatment time effect). Valsartan administration at bedtime as opposed to on wakening resulted in a highly significant average increase by 6% (P <0.001) in the diurnal-nocturnal ratio of blood pressure; this corresponded to a 73% relative reduction in the number of nondipper patients. The findings confirm that valsartan efficiently reduces blood pressure throughout the entire 24 hours, independent of treatment time. They also suggest that time of treatment can be chosen according to the dipper status of a patient to optimize the effect of antihypertensive therapy, an issue that deserves further investigation.

Treatment of non-dipper hypertension with bedtime administration of valsartan.

Background Previous results have indicated that valsartan administration at bedtime, as opposed to upon wakening, may improve the diurnal: nocturnal ratio of blood pressure without loss in 24-h coverage and efficacy. Objectives To investigate the administration time-dependent antihypertensive efficacy of valsartan in non-dipper patients. Methods We studied 148 non-dipper patients with grade 1–2 essential hypertension, aged 53.0 ± 12.6 years, who were randomly assigned to receive valsartan (160 mg/day) as a monotherapy either on awakening or at bedtime. Blood pressure was measured every 20 min during the day and every 30 min at night for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of blood pressure on a per subject basis. Results The significant blood pressure reduction after 3 months of valsartan (P < 0.001) was similar for both treatment times (13.1 and 8.5 mmHg reduction in the 24-h mean of systolic and diastolic blood pressure with morning administration; 14.7 and 10.3 mmHg with bedtime administration; P > 0.126 for treatment-time effect). The diurnal: nocturnal ratio of blood pressure was significantly increased only when valsartan was administered before bedtime, which resulted in 75% of the patients in this group reverting to dippers, a significant increase in the percentage of patients with controlled blood pressure over 24 h, and a reduction in urinary albumin excretion. Conclusions In non-dipper hypertensive patients, dosing time with valsartan should be chosen at bedtime, for improved efficacy during the nocturnal resting hours, as well as the potential associated reduction in cardiovascular risk.

Administration-Time-Dependent Effects of Doxazosin GITS on Ambulatory Blood Pressure of Hypertensive Subjects

Previous studies have shown that a single nighttime dose of standard doxazosin, an α-adrenergic antagonist, reduces blood pressure (BP) throughout the 24 h. We investigated the administration-time-dependent effects of the new doxazosin gastrointestinal therapeutic system (GITS) formulation. We studied 91 subjects (49 men and 42 women), 56.7 ± 11.2 (mean ± SD) yrs of age with grade 1–2 essential hypertension; 39 patients had been previously untreated, and the remaining 52 had been treated with two antihypertensive medications with inadequate control of their hypertension. The subjects of the two groups, the monotherapy and polytherapy groups, respectively, were randomly assigned to receive the single daily dose of doxazosin GITS (4 mg/day) either upon awakening or at bedtime. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours just before and after 3 months of treatment. After 3 months of doxazosin GITS therapy upon awakening, there was a small and nonstatistically significant reduction in BP (1.8 and 3.2 mm Hg in the 24 h mean of systolic and diastolic BP in monotherapy; 2.2 and 1.9 mm Hg in polytherapy), mainly because of absence of any effect on nocturnal BP. The 24 h mean BP reduction was larger and statistically significant (6.9 and 5.9 mm for systolic and diastolic BP, respectively, in monotherapy; 5.3 and 4.5 mm Hg in polytherapy) when doxazosin GITS was scheduled at bedtime. This BP-lowering effect was similar during both the day and nighttime hours. Doxazosin GITS ingested daily on awakening failed to provide full 24 h therapeutic coverage. Bedtime dosing with doxazosin GITS, however, significantly reduced BP throughout the 24 h both when used as a monotherapy and when used in combination with other antihypertensive pharmacotherapy. Knowledge of the chronopharmacology of doxazosin GITS is key to optimizing the efficiency of its BP-lowering effect, and this must be taken into consideration when prescribing this medication to patients.

Seasonal Variation of Fibrinogen in Dipper and Nondipper Hypertensive Patients

Background—A seasonal variation with higher values in winter has been previously reported in plasma fibrinogen, a recognized marker of the potential risk of myocardial infarction and stroke. The lack of nocturnal decline in blood pressure has also been associated with an increase in cardiovascular events. Accordingly, we have compared the yearly variation of plasma fibrinogen in dipper and nondipper hypertensive patients. Methods and Results—We studied 1006 stage 1 to 2 hypertensive patients (482 men and 524 women, 53.0±13.4 years of age). Blood pressure was measured every 20 minutes during the day and every 30 minutes at night for 48 consecutive hours. Physical activity was simultaneously evaluated at 1-minute intervals with a wrist actigraph. A blood sample was collected on the same day before starting blood pressure monitoring. The circannual variation of fibrinogen was established for all patients as well as for subgroups of dippers and nondippers (n=513; nocturnal blood pressure decline <10%) by multiple-component analysis. For the whole group of patients, fibrinogen was characterized by a highly significant seasonal variation (P <0.001) with a mean value of 318 mg/dL, double circannual amplitude (extent of predictable change along the year) of 40 mg/dL, and time of peak value in February. Throughout the year, the nondippers showed higher plasma fibrinogen levels than did the dippers (P <0.001). Conclusions—The elevated plasma fibrinogen levels in nondipper patients appear to be directly related to their increased risk in vascular events, which are more prominent during the late winter months.

Administration Time–Dependent Effects of Aspirin on Blood Pressure in Untreated Hypertensive Patients

Abstract— Previous studies on the potential influence of aspirin on blood pressure have not taken into consideration the chronopharmacological effects of nonsteroidal anti‐inflammatory drugs. This pilot study investigates the effects of aspirin on blood pressure in untreated hypertensive patients who received aspirin at different times of the day according to their rest‐activity cycle. We studied 100 untreated patients with mild hypertension (34 men and 66 women), 42.5±11.6 (mean±SD) years of age, randomly divided into 3 groups: nonpharmacological hygienic‐dietary recommendations; the same recommendations and aspirin (100 mg/d) on awakening; or the same recommendations and aspirin before bedtime. Blood pressure was measured every 20 minutes during the day and every 30 minutes at night for 48 consecutive hours before and after 3 months of intervention. The circadian pattern of blood pressure in each group was established by population multiple‐component analysis. After 3 months of nonpharmacological intervention, there was a small, nonsignificant reduction of blood pressure (<1.1 mm Hg;P >0.341). There was no change in blood pressure when aspirin was given on awakening (P =0.229). A highly significant blood pressure reduction was, however, observed in the patients who received aspirin before bedtime (decrease of 6 and 4 mm Hg in systolic and diastolic blood pressure, respectively;P <0.001). Results indicate a statistically significant administration time–dependent effect of low‐dose aspirin on blood pressure in untreated patients with mild hypertension. The influence of aspirin on blood pressure demonstrated in this study indicates the need to quantify and control for aspirin effects in patients using this drug in combination with antihypertensive medication.

Efectos de la administración temporalizada de fármacos antihipertensivos en pacientes con hipertensión arterial resistente

Fundamento y objetivo: Los pacientes con hipertension arterial resistente son un problema en la practica clinica habitual por su mal control terapeutico, la elevada incidencia de lesion organica y el consiguiente incremento del riesgo cardiovascular. Las estrategias de tratamiento en este tipo de pacientes incluyen un cambio secuencial de farmacos o la combinacion sinergica de nuevos antihipertensivos. La mayoria de los pacientes, sin embargo, reciben toda su medicacion antihipertensiva en dosis unica matutina. En este estudio hemos evaluado, en pacientes con hipertension resistente, el impacto en el perfil circadiano de la presion arterial (PA) del cambio de la hora de administracion del tratamiento, sin modificar la dosis ni el numero de farmacos. Pacientes y metodo: Participaron 123 pacientes con hipertension resistente (73 varones y 50 mujeres) con una media (desviacion estandar) de edad de 59,9 (11,9) anos, que recibian 3 farmacos todos ellos antihipertensivos administrados en dosis unica matutina. Se asigno a los pacientes de un modo aleatorio a 2 grupos, de acuerdo con la modificacion de su esquema terapeutico: a) cambiar un farmaco por otro, manteniendo los 3 medicamentos en regimen de administracion matutina, y b) el mismo cambio de un farmaco por otro, pero administrando 2 a la hora de levantarse y 1 farmaco a la hora de acostarse. Se realizo la monitorizacion ambulatoria de la PA cada 20 min entre las 07.00 y las 23.00 h y cada 30 min por la noche durante 48 h consecutivas antes y despues de 3 meses de tratamiento con el nuevo esquema terapeutico. Resultados: Cuando se administro los 3 farmacos en dosis matutina, se produjo una leve y no significativa reduccion de la PA (p > 0,374). En el seguimiento basal, solo un 22% de los pacientes en este grupo era dipper, y este porcentaje se redujo todavia mas (15%) despues de 3 meses de tratamiento con 3 farmacos en la manana. La reduccion de la PA fue mucho mayor y estadisticamente significativa (8,6 y 5,9 mmHg en la media de 24 h de la PA sistolica y la PA diastolica; p < 0,001) cuando uno de los farmacos paso a ser administrado por la noche. Esta reduccion fue superior en la media nocturna que en la media diurna de la PA. Asi, mientras que solo un 13% de los pacientes de este grupo era dipper en el perfil basal, un 53% lo fue en el perfil postintervencion (p < 0,001). Conclusiones: Los resultados de este estudio indican que, en pacientes con hipertension arterial resistente, la hora de administracion del tratamiento antihipertensivo puede ser mas importante en el control del paciente y en el modelado adecuado del perfil circadiano de la PA que el cambio de farmacos en el esquema terapeutico combinado.

Efecto de la administración temporalizada de ácido acetilsalicílico a dosis bajas sobre la presión arterial en pacientes hipertensos

Fundamento y objetivos Los estudios previos sobre el posible efecto del acido acetilsalicilico(AAS) sobre la presion arterial no han tenido en cuenta los cambios en la farmacocinetica de lamedicacion antiinflamatoria no esteroidea en funcion de la hora de administracion del farmaco.El objetivo de este estudio piloto ha sido investigar los efectos del AAS sobre la presion arterialen pacientes con hipertension arterial esencial ligera, sin tratamiento antihipertensivo y que recibieronAAS a distintas horas del dia, en funcion de su ciclo de actividad y descanso. Pacientes y metodo Estudiamos a 64 pacientes con hipertension arterial esencial (24 varones),con una edad media (DE) de 43,5 (12,0) anos, que fueron aleatorizados a tres grupos de tratamiento:grupo 1, con recomendaciones higienicodieteticas sin intervencion farmacologica; grupo2, con recomendaciones higienicodieteticas y AAS (100 mg/dia) a la hora de levantarse, ygrupo 3, con recomendaciones higienicodieteticas y AAS (100 mg/dia) en el momento de acostarse.La presion arterial se monitorizo en cada paciente durante 48 h consecutivas antes ydespues de tres meses de intervencion. El patron circadiano de variacion de la presion arterialpara cada grupo de pacientes se establecio mediante analisis poblacional de componentesmultiples. Los parametros circadianos calculados para cada grupo antes y despues de la intervencionse compararon con una prueba no parametrica pareada. Resultados Despues de los tres meses de tratamiento, en el grupo 1 se produjo una leve y nosignificativa reduccion de la presion arterial ( Conclusiones Los resultados indican que la administracion de AAS en pacientes con hipertensionesencial tiene un significativo efecto hipotensor, que es claramente dependiente de lahora de administracion del farmaco. Este efecto del AAS sobre la presion arterial implica la necesidadde tenerlo en cuenta cuando se utilice AAS en los pacientes hipertensos que, ademas,reciben medicacion antihipertensiva.

Variación estacional del fibrinógeno plasmático en pacientes dippers y no dippers con hipertensión arterial esencial ligera-moderada

Fundamento y objetivo El incremento de las concentraciones plasmaticas de fibrinogeno se consideraun factor de riesgo de enfermedad arteriosclerotica, fundamentalmente cardiopatia coronaria y accidentecerebrovascular. En estudios previos se ha descrito una variacion estacional en el fibrinogeno,con valores mas altos en los meses mas frios. Por otra parte, la ausencia de descenso nocturno en lapresion arterial se ha asociado tambien a un aumento de acontecimientos cardiovasculares. En consecuencia,hemos cuantificado la variacion estacional del fibrinogeno en pacientes hipertensos esenciales,clasificados en funcion del descenso nocturno de la presion arterial. Pacientes y metodo Estudiamos a 577 pacientes con hipertension arterial esencial ligera-moderada(254 varones), con una edad media (DE) de 53,8 (13,8) anos, reclutados a lo largo de dos anos. Lapresion arterial se monitorizo cada 20 min de dia y cada 30 min por la noche, durante 48 h consecutivas.La actividad fisica se monitorizo simultaneamente cada minuto con un actigrafo de muneca. Elfibrinogeno se determino a partir de un analisis de sangre realizado el mismo dia de inicio de la monitorizacion.La variacion estacional del fibrinogeno plasmatico se determino para todos los sujetos asicomo para los subgrupos de dippers (n = 287) y no dippers (n = 290; pacientes con un descenso nocturnoinferior al 10% con respecto a la media diurna de la presion sistolica) mediante analisis decomponentes multiples longitudinal. Resultados Para el total de pacientes hipertensos estudiados, el fibrinogeno presenta una variacion estacionalaltamente significativa (p Conclusiones La elevacion de la concentracion de fibrinogeno en pacientes no dipper podria apoyarlos resultados que asocian la ausencia de descenso nocturno en la presion arterial a un aumento deacontecimientos cardiovasculares, de acuerdo con la correlacion existente entre la variacion circanualdel fibrinogeno y la variacion estacional comunicada para acontecimientos coronarios.

P-209: Effects of valsartan monotherapy on the circadian blood pressure profile of patients with grade 1–2 essential hypertension

tigated the administration time-dependent antihypertensive efficacy of valsartan in elderly hypertensive patients. We studied 50 elderly patients with grade 1–2 essential hypertension (20 men), 67.0 0.8 years of age, randomly assigned to receive single daily valsartan monotherapy (160 mg/day) either on awakening or before bedtime. BP was measured by ambulatory monitoring at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 hours before and after 3 months of therapeutic intervention. Physical activity was also monitored every minute by wrist actigraphy, and the information used to determine diurnal and nocturnal means of BP for each patient according to individual resting time. There was a highly significant BP reduction after 3 months of valsartan (P 0.001), similar for both treatment times (14.1 and 7.7 mm Hg reduction in the 24-hour mean of systolic and diastolic BP after valsartan on awakening; 14.7 and 8.2 mm Hg when valsartan was administered before bedtime). The day/night ratio measured as the nocturnal decline of BP relative to the diurnal mean was unchanged after valsartan on awakening ( 2.1 and 0.6 for systolic and diastolic BP; P 0.184). This ratio was highly significantly increased (6.1 and 6.3 for systolic and diastolic BP, P 0.001) when valsartan was administered before bedtime. The reduction of nocturnal mean was, therefore, significantly larger after valsartan before bedtime (P 0.032). Results indicate that, at either the time of administration, 160 mg/day valsartan efficiently reduce BP for the whole 24 hours. In elderly hypertensive patients, characterized by a diminished nocturnal decline in BP, dosing time with valsartan might be chosen at bedtime, for improved efficacy during the nocturnal resting hours, and the potential reduction in cardiovascular risk associated to the normalized day/ night ratio.

P-20: Effects of hygienic-dietary recommendations on ambulatory blood pressure in untreated patients with grade 1 hypertension

calculated from the original series and those obtained from shorter series up to data obtained at 2-hour intervals. Sensitivity, however, was reduced by 9%, and specificity by a very high 44%, when diagnosis was based on data sampled at 20–30 min intervals for the first 24 hours. This prospective study demonstrates that sampling for just 24 hours is insufficient for a proper diagnosis of hypertension based on the highly reproducible tolerance-hyperbaric test. Moreover, sampling rate can be greatly reduced, for increased patient compliance, by expanding the monitoring span for at least 2 consecutive days. Results also corroborate that the proper estimation of any parameter derived from a BP series (such as the HBI) is markedly dependent on duration of sampling, but not on sampling rate.