Jose E. Lopez

Effects of Time of Day of Treatment on Ambulatory Blood Pressure Pattern of Patients With Resistant Hypertension

Patients with resistant hypertension present high prevalence of a non-dipper blood pressure pattern. Recent results indicate that non-dipping is related partly to the absence of 24-hour therapeutic coverage in patients treated with single morning doses. Accordingly, we investigated the impact of treatment time on the blood pressure pattern in 700 patients with resistant hypertension on the basis of clinic measurements who were studied by 48-hour ambulatory monitoring. Among them, 299 patients received all their medication on awakening, and 401 were taking ≥1 antihypertensive drug at bedtime. The percentage of patients with controlled ambulatory blood pressure was double in patients taking 1 drug at bedtime (P=0.008). Among the 578 patients with true resistant hypertension, subjects receiving 1 drug at bedtime showed a significant reduction in the 24-hour mean of systolic and diastolic blood pressure (3.1 and 1.6 mm Hg, respectively; P<0.011). This reduction was much more prominent during nighttime (5.1 and 3.0 mm Hg; P<0.001). Accordingly, the diurnal/nocturnal blood pressure ratio was significantly increased by 2.7 and the prevalence on non-dipping reduced (56.9 versus 81.9%; P<0.001) in patients taking 1 drug at bedtime. Compared with patients receiving all drugs on awakening, subjects with 1 drug at bedtime also showed significant reductions in the average values of glucose, cholesterol, fibrinogen, and urinary albumin excretion (P<0.011). In patients with resistant hypertension, pharmacological therapy should take into account when to treat with respect to the rest–activity cycle of each patient to improve control and to avoid the non-dipper pattern associated to higher cardiovascular risk.

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.

Decrease in Urinary Albumin Excretion Associated With the Normalization of Nocturnal Blood Pressure in Hypertensive Subjects

Previous results have indicated that valsartan administration at bedtime as opposed to on wakening improves the diurnal/nocturnal ratio of blood pressure without loss in efficacy and therapeutic coverage. We hypothesized that increasing this ratio could reduce microalbuminuria. We conducted a prospective, randomized, open-label, blinded endpoint trial on 200 previously untreated nonproteinuric patients with grade 1 to 2 essential hypertension, assigned to receive valsartan (160 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured by ambulatory monitoring 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 significant blood pressure reduction after 3 months of therapy was similar for both treatment times. The diurnal/nocturnal blood pressure ratio was unchanged after valsartan on awakening, but significantly increased from 7.5 to 12.2 (P<0.001) when valsartan was administered at bedtime. Urinary albumin excretion was significantly reduced by 41% after bedtime treatment. This reduction was independent of the 24-hour blood pressure decrease but highly correlated with the decrease in nocturnal blood pressure and mainly with the increase in diurnal/nocturnal ratio (P<0.001). Bedtime valsartan administration improves the diurnal/nocturnal blood pressure ratio to a more dipper profile. This normalization of the circadian blood pressure pattern is associated with a significant decrease in urinary albumin excretion and plasma fibrinogen, and could thus reduce the increased cardiovascular risk in nondipper hypertensive patients.

Evaluation of the extent and duration of the “ABPM effect” in hypertensive patients☆

OBJECTIVESnThe goal of this study was to test and quantify the extent and duration over time of a possible pressor effect due to ambulatory monitoring.nnnBACKGROUNDnThe use of ambulatory blood pressure monitoring has provided a method of blood pressure (BP) assessment that compensates for some of the limitations of office values. While a white-coat pressor effect on conventional measurements has been defined and frequently used for the improved evaluation of hypertensive patients, there has not been clear indication that the ambulatory technique could also influence BP.nnnMETHODSnWe studied 538 mild-to-moderate hypertensive patients (233 men), 54.2 +/- 14.2 (mean +/- SD) years of age. Blood pressure and heart rate were measured at 20-min intervals during the day and at 30-min intervals at night for 48 consecutive hours, and physical activity was simultaneously evaluated at 1-min intervals with a wrist actigraph. One-third of the patients were evaluated twice or more times.nnnRESULTSnIn both treated and untreated hypertensive patients evaluated for the first time, results indicate a statistically significant (p < 0.001) reduction during the second day of monitoring as compared with the first in the diurnal mean of systolic and diastolic BP, but not in heart rate or physical activity. This pressor effect remains statistically significant for the first 6 h to 8 h of monitoring independently of gender, days of the week of monitoring or number of antihypertensive drugs used by the treated patients. The nocturnal mean of BP was, however, similar between both days of sampling. This ambulatory monitoring effect was not observed when the patients were evaluated after the same sampling scheme for the second or successive times three months apart.nnnCONCLUSIONSnAmbulatory monitoring for 48 consecutive hours reveals a statistically significant pressor response that could reflect a novelty effect in the use of the monitoring device for the first time. This effect has marked implications in both research and clinical daily practice for a proper diagnosis of hypertension and evaluation of treatment efficacy by the use of ambulatory monitoring.

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.

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

Previous results have indicated that valsartan administration at bed‐time, as opposed to upon wakening, improves the diurnal/nocturnal ratio of blood pressure (BP) toward a normal dipping pattern, without loss of 24 h efficacy. This ratio is characterized by a progressive decrease with aging. Accordingly, we investigated the administration time‐dependent antihypertensive efficacy of valsartan, an angiotensin blocking agent, in elderly hypertensive patients. We studied 100 elderly patients with grade 1–2 essential hypertension (34 men and 66 women), 68.2±4.9 years of age, randomly assigned to receive valsartan (160 mg/d) as a monotherapy either upon awakening or at bed‐time. BP was measured for 48 h by ambulatory monitoring, at 20 min intervals between 07∶00 to 23∶00 h and at 30 min intervals at night, before and after 3 months of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately determine the duration of sleep and wake spans to enable the accurate calculation of the diurnal and nocturnal means of BP for each subject. There was a highly significant BP reduction after 3 months of valsartan treatment (p<0.001). The reduction was slightly larger with bed‐time dosing (15.3 and 9.2 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively) than with morning dosing (12.3 and 6.3 mm Hg reduction in the 24 h mean of systolic and diastolic BP, respectively). The diurnal/nocturnal ratio, measured as the nocturnal decline of BP relative to the diurnal mean, was unchanged in the group ingesting valsartan upon awakening (−1.0 and −0.3 for systolic and diastolic BP; p>0.195). This ratio was significantly increased (6.6 and 5.4 for systolic and diastolic BP; p<0.001) when valsartan was ingested at bed‐time. The reduction of the nocturnal mean was doubled in the group ingesting valsartan at bed‐time, as compared to the group ingesting it in the morning (p<0.001). In elderly hypertensive patients, mainly characterized by a diminished nocturnal decline in BP, bed‐time valsartan dosing is better than morning dosing since it improves efficacy during the nighttime sleep span, with the potential reduction in cardiovascular risk that has been associated with a normalized diurnal/nocturnal BP ratio.

DOSE- AND ADMINISTRATION TIME-DEPENDENT EFFECTS OF NIFEDIPINE GITS ON AMBULATORY BLOOD PRESSURE IN HYPERTENSIVE SUBJECTS

Previous chronotherapy studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium channel blockers (CCB), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the antihypertensive efficacy and safety profile of the slow‐release, once‐a‐day nifedipine gastrointestinal therapeutic system (GITS) formulation administered at different times with reference to the rest‐activity cycle of each participant. We studied 80 diurnally active subjects (36 men and 44 women), 52.1±10.7 yrs of age, with grade 1–2 essential hypertension, who were randomly assigned to receive nifedipine GITS (30 mg/day) as a monotherapy for eight weeks, either upon awakening in the morning or at bedtime at night. Patients with uncontrolled BP were up‐titrated to a higher dose, 60 mg/day nifedipine GITS, for an additional eight weeks. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after therapy with either dose. The BP reduction after eight weeks of therapy with the lower dose of 30 mg/day was slightly, but not significantly, larger with bedtime dosing. The efficacy of 60 mg/day nifedipine GITS in non‐responders to the initial 30 mg/day dose was twice as great with bedtime as compared to morning dosing. Moreover, bedtime administration of nifedipine GITS reduced the incidence of edema as an adverse event by 91%, and the total number of all adverse events by 74% as compared to morning dosing (p=0.026). Independent of the time of day of administration, a single daily dose of 30 mg/day of nifedipine GITS provides full 24 h therapeutic coverage. The dose‐dependent increased efficacy and the markedly improved safety profile of bedtime as compared to morning administration of nifedipine GITS should be taken into account when prescribing this CCB in the treatment of essential hypertension.

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.