Differing Administration Time-Dependent Effects of Aspirin on Blood Pressure in Dipper and Non-Dipper Hypertensives

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1 Differing Administration Time-Dependent Effects of Aspirin on Blood Pressure in Dipper and Non-Dipper Hypertensives Ramón C. Hermida, Diana E. Ayala, Carlos Calvo, José E. López, Artemio Mojón, Marta Rodríguez, José R. Fernández Abstract Aspirin is a potent antioxidative agent that reduces vascular production of superoxide, prevents angiotensin II induced hypertension, and induces NO release. Low-dose aspirin administered at bedtime, but not on awakening, has also been shown to reduce blood pressure, possibly enhancing the nocturnal trough in NO production. Because endothelium-dependent vasodilation is blunted through a decrease in NO release in non-dipper compared with dipper patients, we compared the administration time-dependent influence of aspirin on ambulatory blood pressure in dipper and non-dipper hypertensive subjects. We studied 257 patients with mild hypertension (98 men and 159 women), years of age, randomly assigned to receive 100 mg per day of aspirin either on awakening or at bedtime. Ambulatory blood pressure was measured for 48 hours at baseline and after 3 months of intervention. Blood pressure was slightly elevated after aspirin on awakening (increase of 1.5/1.0 mm Hg in the 24-hour mean of systolic/diastolic blood pressure; P 0.028). A highly significant blood pressure reduction was observed in patients who received aspirin at bedtime (decrease of 7.2/4.9 mm Hg in systolic/diastolic blood pressure; P 0.001). The reduction in nocturnal blood pressure mean was double in non-dippers (11.0/7.1 mm Hg) compared with dippers (5.5/3.3 mm Hg; P 0.001). This prospective trial corroborates the significant administration time-dependent effect of low-dose aspirin on blood pressure, mainly in non-dipper hypertensive patients. The timed administration of low-dose aspirin could thus provide a valuable approach, beyond prevention of cardiovascular disease, in the blood pressure control of patients with mild hypertension. (Hypertension. 2005;46[part 2]: ) Key Words: blood pressure monitoring, ambulatory hypertension, mild nitric oxide circadian rhythm Acetylsalicylic acid (ASA; aspirin) is a nonsteroidal anti-inflammatory drug (NSAID) with demonstrated inhibitory effects on cyclooxygenases (COXs) responsible for arachidonic acid metabolism and prostaglandin production. 1 Previous studies have demonstrated that ASA is a potent antioxidative agent that markedly reduces vascular production of superoxide in normotensive and hypertensive rats. 2 In addition, ASA was found to prevent angiotensin II induced hypertension and cardiovascular hypertrophy, mainly through its antioxidative properties in preventing the generation of superoxide. 3 Moreover, recent results have demonstrated that ASA induces NO release from vascular endothelium. 4,5 This effect appears to be attributable to a direct acetylation of the endothelial NO synthase protein. No attention has been paid so far in these studies to potential administration time dependencies in the effects of ASA. However, a significant circadian variation has been demonstrated in several oxidative stress markers, including 8-hydroxydeoxyguanosine, malondialdehyde, and 8-isoprostane. 6 The peak concentrations of the 3 markers occurred early in the evening, with trough values obtained during nocturnal sleep. These peak and trough times are highly correlated with those of serum NO. 6,7 Moreover, among many other variables related to the regulation of blood pressure (BP), a predictable circadian variation has been demonstrated in plasma renin activity, angiotensin II, catecholamines, atrial natriuretic peptides, aldosterone, and angiotensin-converting enzyme. 8 Previous laboratory animal and clinical trial research demonstrates administration time-dependent effects of ASA. Thus, the effects of ASA on lipoperoxides - and -adrenergic receptors and BP in clinically healthy subjects depend on the circadian timing of ASA administration. 9 Moreover, ASA has also been shown to produce an administration time-dependent 30% inhibition of angiotensin II, associated to the documented effects of ASA on plasma renin activity. 10 Most important, the administration time-dependent influence of ASA on BP was demonstrated previously in a randomized trial on healthy women 9 and other independent double-blind, randomized, placebo-controlled clinical trials conducted: first on clinically healthy subjects, 11 a second on normotensive and hypertensive subjects, 12 a third on pregnant women at high risk for preeclampsia, 13 and a fourth in untreated patients with mild hypertension. 14 The findings of Received April 27, 2005; first decision May 12, 2005; revision accepted May 24, From the Bioengineering and Chronobiology Laboratories (R.C.H., D.E.A., A.M., J.R.F.), University of Vigo, Campus Universitario, Spain; and Hypertension and Vascular Risk Unit (C.C., J.E.L., M.R.), Hospital Clínico Universitario, Santiago de Compostela, Spain. Correspondence to Prof Ramón C. Hermida, PhD, Director, Bioengineering and Chronobiology Laboratories, E.T.S.I. Telecomunicación, Campus Universitario, Vigo (Pontevedra) 36200, Spain. rhermida@tsc.uvigo.es 2005 American Heart Association, Inc. Hypertension is available at DOI: /01.HYP c 1060

2 Hermida et al Chronopharmacology of ASA 1061 these BP studies, all of which used ambulatory BP monitoring (ABPM) to derive primary outcome variables, are consistent; BP-lowering effect of low-dose ASA is achieved when administered at bedtime but not on awakening. On the other hand, some specific features of the 24-hour BP pattern are linked to the progressive injury of target tissues and the triggering of cardiac and cerebrovascular events. 15 Many studies show the extent of the nocturnal BP decline is deterministic of cardiovascular injury and risk. Absence of the normal 10% to 20% sleep-time BP decline (dipper pattern) is associated with elevated risk of end-organ injury, particularly to the heart (left ventricular hypertrophy and myocardial infarct), brain (stoke), and kidney (albuminuria and progression to end-stage renal failure) Previous studies have found that non-dippers may be characterized by enhanced oxidative stress. 19 Moreover, recent results have suggested that endothelium-dependent vasodilation is blunted through a decrease in NO release in non-dippers compared with patients who have dipper hypertension. 20 The antioxidative properties of ASA and its documented beneficial effects on NO production could result in a further effect on BP in non-dippers compared with dippers. In keeping with the chronopharmacological effects of ASA, this prospective randomized study investigated the comparative influence of ASA on BP in dipper and nondipper subjects with mild hypertension who received lowdose ASA at different times of the day according to their rest activity cycle and who were evaluated by 48-hour ABPM before and after 3 months of pharmacological intervention. Methods Subjects The study was conducted at the Hypertension and Vascular Risk Unit, Hospital Clínico Universitario, Santiago de Compostela, Spain, between June 2003 and February Shift workers, heavy drinkers (alcohol intake 80 g per day), smokers ( 20 cigarettes per day), and heavy exercisers were excluded, as were individuals with contraindications to the use of ASA and those with either moderate or severe arterial hypertension (grade 2 or 3; ie, BP 160/ 100 mm Hg) or secondary arterial hypertension and cardiovascular disorders, including angina, heart failure, stroke, nephropathy, and retinopathy, or previous myocardial infarction or coronary revascularization, as revealed by thorough clinical evaluation according to the standardized protocol at the unit. Inclusion criteria required a diagnosis of previously untreated grade 1 (mild) essential hypertension based on conventional BP measurements (systolic BP [SBP] between 140 and 159 mm Hg or diastolic BP [DBP] between 90 and 99 mm Hg) 21 and corroboration by ABPM at the time of recruitment. A positive diagnosis of hypertension based on ABPM required that either the diurnal mean be 135/85 mm Hg, or the nocturnal mean be 120/70 mm Hg. 22,23 With these inclusion criteria, we identified and randomized 270 untreated volunteers. Among those, 257 volunteers (98 men and 159 women; years of age) completed the study and provided all required information. The use of antihypertensive and any other medication, apart from the provided dose of ASA, was forbidden during the trial. The demographic characteristics of the participants are included in Table 1. After providing informed consent to participate in this prospective, randomized, open-label, blinded end point (PROBE), parallelgroup trial, subjects were assigned randomly to receive ASA (100 mg per day) either on awakening or at bedtime. The dose of 100 mg used in this trial corresponds with the actual lower dose commercially available in Spain within the accepted range of low dose (75 to 150 mg 24 ). Compliance was measured on the basis of tablet count and a personal interview with each volunteer. Benefits of the PROBE design and its validity compared with double-blind, placebocontrolled trials in assessing antihypertensive efficacy based on blinded ABPM measurements have been documented previously. 25 The review board on human studies at our institution approved the protocol. Blood samples were obtained in the clinic from the antecubital vein after nocturnal fasting between 8 AM and 9 AM on the same days when 48-hour ABPM was initiated, immediately before and after 3 months of timed treatment. Clinic BP measurements (6 per study visit after being seated for 5 minutes, on the same day just before starting ABPM) were always obtained by the same investigator with a validated automatic oscillometric device (HEM-737; Omron Health Care Inc.). 26 The sample size for this trial was calculated as follows. Assuming an SD of 8 mm Hg for ABPM, 14 with 41 subjects per arm, the study could have 80% power to show as significant at the 95% level changes of 5 mm Hg in ABPM between treatment groups. Assuming with the provided inclusion criteria a prevalence of non-dippers about one third of the total sample, 14,27 a minimum of 123 patients per arm would be needed. The distribution of patients who completed the study was as follows (Table 1): 80 dipper and 46 non-dipper patients received ASA on awakening; 83 dipper and 48 non-dipper patients received ASA at bedtime. ABPM Assessment The SBP, DBP, and heart rate (HR) of each participant were automatically measured every 20 minutes from 7 AM to 11 PM and every 30 minutes during the night for 48 consecutive hours with a properly calibrated SpaceLabs device (SpaceLabs Inc.). Subjects were studied by ABPM under baseline conditions, when subjects were free of medication, and again after 3 months of timed intervention with ASA. They were assessed while adhering to their usual diurnal activity (8 AM to 11 PM for most) and nocturnal sleep routine. Participants were instructed to go about their usual activities with minimal restrictions but to follow a similar schedule during the 2 days of ABPM and to avoid daytime napping. No one was hospitalized during monitoring. ABPM always began between 10 AM and 12 PM. BP series were not considered valid for analysis if 30% of the measurements were lacking, if they had missing data for 2-hour spans, or if they were collected from subjects while they were experiencing an irregular rest activity schedule or a nighttime sleep span of 6 hours or 12 hours during monitoring. Protocolcorrect data series were collected from 257 subjects. Baseline BP profiles of 13 additional subjects (7 assigned to morning treatment with ASA and 6 to bedtime treatment) could not be used for analysis because the patients failed to return for the second ABPM at the end of intervention. Actigraphy During 48-hour ABPM, each participant wore a Mini-Motion- Logger actigraph (Ambulatory Monitoring Inc.) on the dominant wrist to monitor physical activity every minute. This compact (about half the size of a wrist watch) device functions as an accelerometer. The internal clocks of the actigraph and the ABPM devices were synchronized through their respective interfaces by the same computer. The actigraphy data were used to determine the onset and offset times of diurnal activity and nocturnal sleep to accurately determine the diurnal and nocturnal BP means of each subject. The mean activity for the 5 minutes before each BP reading was then calculated for further statistical analysis on circadian variability of activity, according to previous studies on this area. 27,28 Statistical Methods Each individual s clock hour BP and HR values were first rereferenced from clock time to hours after awakening from nocturnal sleep according to the information obtained from wrist actigraphy. This transformation avoided the introduction of bias caused by differences among subjects in their sleep/activity routine. 27 BP and HR time

3 1062 Hypertension October 2005 Part II TABLE 1. Demographic and Analytical Characteristics of Subjects Investigated Variable* Aspirin on Awakening Aspirin at Bedtime P for Group Comparison Patients, n Sex, % men Age, years Height, cm Before treatment Weight, kg BMI, kg/m Waist, cm Hip, cm Clinic SBP, mm Hg Clinic DBP, mm Hg Clinic pulse pressure, mm Hg Clinic HR, bpm Non-dipper, % Hemoglobin, g/dl Glucose, mg/dl Creatinine, mg/dl Uric acid, mg/dl Cholesterol, mg/dl Triglycerides, mg/dl After treatment (in parentheses; P value from comparison with values before treatment) Weight, kg (0.481) (0.146) BMI, kg/m (0.414) (0.205) Waist, cm (0.589) (0.983) Hip, cm (0.236) (0.647) Clinic SBP, mm Hg (0.205) ( 0.001) Clinic DBP, mm Hg (0.107) ( 0.001) Clinic pulse pressure, mm Hg (0.698) ( 0.001) Clinic HR, bpm (0.102) (0.047) Non-dipper, % 35.7 (0.896) 26.7 (0.084) Hemoglobin, g/dl (0.871) (0.272) Glucose, mg/dl (0.841) (0.243) Creatinine, mg/dl (0.505) (0.082) Uric acid, mg/dl (0.945) (0.140) Cholesterol, mg/dl (0.101) (0.009) Triglycerides, mg/dl (0.644) (0.006) *All values given in mean SD. Non-dipper: 10% decline in nocturnal mean relative to the diurnal mean of BP using data sampled by ABPM for 48 consecutive hours. Values provided correspond to the average of 6 conventional BP measurements obtained for each subject at the clinic before starting ABPM. series were then edited according to conventional criteria to remove measurement errors and outliers. 29 Thus, readings with SBP 250 or 70 mm Hg, DBP 150 or 40 mm Hg, and pulse pressure (difference between SBP and DBP) 150 or 20 mm Hg were automatically discarded. For descriptive purposes, the circadian rhythm of BP, HR, and wrist activity before and after 3 months of intervention was assessed objectively by population multiplecomponent analysis. 30 The circadian rhythm parameters of midline estimating statistic of rhythm (average value of the rhythmic function fitted to the data), overall amplitude (one half the difference between the maximum and the minimum values of the best fitted curve), and orthophase (peak time, expressed as a lag from the time of awakening from nocturnal sleep) obtained for each group of patients before and after intervention were compared with a paired nonparametric test developed to assess differences in parameters derived from population multiple-components analysis. 31 Hourly BP means obtained before and after intervention were compared by t test corrected for multiple testing with the Holm procedure. 32 The daily (24-hour), diurnal, and nocturnal means of BP were further compared among groups by ANOVA. The demographic and clinical characteristics in Table 1 were compared among groups by ANOVA (quantitative variables) or nonparametric 2 test.

4 Hermida et al Chronopharmacology of ASA 1063 Results Demographic and Analytic Characteristics The baseline characteristics of the 2 groups of subjects (Table 1) were similar in age, height, weight, body mass index (BMI), waist and hip perimeters, and clinic SBP and DBP (average of the 6 morning measurements obtained just before ABPM). Moreover, there were no statistically significant changes in weight, BMI, and the waist and hip perimeters in either group after 3 months of intervention. Clinic BP measurements were reduced significantly from baseline ones (5.2 and 2.4 mm Hg in SBP and DBP; P 0.001) only in the group receiving ASA at bedtime. The serum values of glucose, creatinine, uric acid, cholesterol, triglycerides (Table 1), and other laboratory chemistry variables were comparable between the 2 treatment groups at baseline and after 3 months of intervention. Use of the low dose of 100 mg per day of ASA did not modify the baseline values of hemoglobin at any time of administration tested here (Table 1). Plasma lipids were reduced slightly after ASA at bedtime (Table 1), although the reduction would not be statistically significant if corrected for multiple testing. ABPM Characteristics The circadian variation of SBP (top) and DBP (bottom) in untreated mild hypertensive patients (irrespective of their baseline dipping status) measured by 48-hour ABPM before and after 3 months of ASA on awakening is depicted in Figure 1 (left panels). There was no statistically significantly change in the diurnal means of BP after 3 months of 100 mg per day of ASA ingested on awakening. BP slightly increased during nocturnal resting hours (Table 2). The graphs on the right in Figure 1 show the significant reduction compared with baseline of 7.2 and 4.9 mm Hg in the 24-hour mean of SBP and DBP, respectively (P 0.001), after 3 months of 100 mg per day of ASA taken at bedtime. BP was reduced homogeneously during the hours of diurnal activity and nocturnal rest. Figure 1 further indicates that the mean reduction in BP at each hourly average during the 24-hour dosing interval was statistically significant (P always 0.05 after correcting for multiple testing). A reduction in BP was observed in 94% of the patients in this group. Only 2 patients experienced a significant BP elevation after treatment. Despite the significant effect on BP, HR remained unchanged after 3 months of treatment (decrease in the 24-hour mean of 1.3 bpm; P 0.218). The circadian pattern of wrist activity was also similar before and after 3 months of therapy (P for comparison of 24-hour mean activity). Average duration of nocturnal rest determined by actigraphy was not statistically different (P 0.698) for the profiles obtained before and after intervention (Table 2). The comparison of results provided in Figure 1 indicates the lack of statistically significant differences in BP at baseline among the 2 treatment groups. After intervention, results indicate a highly significant absolute and relative reduction in BP only after ASA ingested at bedtime but not on awakening (P for SBP and DBP; Table 2). ASA Effects According to Dipping Status Figure 2 provides information on the comparison between the treatment groups of the changes in the diurnal, nocturnal, and 24-hour mean BP values after 3 months of therapy, with patients in each group divided according to their baseline dipping status. Results indicate the lack of significant effects of SBP (top) and DBP (bottom) of ASA administered on awakening in dipper (patients with 10% decline in the nocturnal relative to the diurnal BP mean using all data sampled for 48 hours) and non-dipper hypertensive patients. There was no difference in BP changes between dipper and non-dipper patients after morning dosing of ASA. Results from Figure 2 further indicate the statistically significant reduction in the 24-hour mean of SBP and DBP after ASA at bedtime. This reduction was comparable for dipper and non-dipper patients (P and for comparison of 24-hour mean reduction in SBP and DBP, respectively, between groups). The BP reduction during diurnal active hours was slightly although not significantly larger in dippers compared with non-dippers. However, the reduction in nocturnal BP mean was double in non-dippers (11.0 and 7.1 mm Hg in SBP and DBP, respectively) compared with dippers (5.5 and 3.3 mm Hg; P 0.001). Accordingly, there was a significant decrease in the nocturnal decline relative to the diurnal mean of BP (diurnal/nocturnal BP ratio) in non-dipper patients after bedtime dosing with ASA (4.0 and 4.4 for SBP and DBP; P 0.001). Among these patients, 58.3% reverted to a dipper BP pattern after treatment. Discussion Corroborating previous findings, 14 the major result from this study is that ASA selectively decreases BP as a function of the timing of its administration in relation to the rest activity cycle of each individual subject. The administration timedependent effects of ASA on BP demonstrated here are fully in agreement with conclusions found previously in clinically healthy normotensive subjects as well as in hypertensive patients using the same low dose of 100 mg per day ASA but for the much shorter time of just 1 week. 11,12 However, a higher dose of ASA (500 mg per day) showed a pressor effect even when administered before bedtime. 12 Indeed, it has been reported that NSAID may increase BP in normotensive and hypertensive subjects. 33,34 In any event, the dose of ASA regularly used to show anti-inflammatory effects is markedly larger than the dose used as anticoagulant and recommended for prevention of cardiovascular events. 35 Similar results regarding the time-dependent influence of low-dose ASA on BP were also shown in pregnant women who used 100 mg per day of ASA for most of their pregnancy, 13 as well as in a previous independent trial in patients with mild hypertension. 14 In the present study, low-dose ASA administered at bedtime not only significantly reduced the mean BP from ABPM but also conventional BP measurements. With respect to the potential mechanism(s) involved in the responsiveness of BP to ASA administered at different times according to the rest activity cycle, the effects of ASA on and -adrenergic receptors depend markedly on the circadian timing of ASA administration. 9 -Adrenoceptor blockade more effectively reduces peripheral resistance in the early morning hours than at other times of the day. 36 Moreover, a recent study exploring the administration time-dependent

5 1064 Hypertension October 2005 Part II Figure 1. Changes in the circadian pattern of SBP (top) and DBP (bottom) after aspirin (100 mg per day) administered on awakening (left) or at bedtime (right) in patients with mild hypertension sampled by 48-hour ABPM. Each graph shows the hourly means and SEs of data collected before (continuous line) and after (dashed line) 3 months of aspirin administration. Dark shading along the lower horizontal axis of the graphs represents average hours of nocturnal sleep across the patients. Nonsinusoidal-shaped curves represented around means and SEs correspond to the best-fitted waveform model determined by population multiple-component analysis. Arrows descending from upper horizontal axis point to the circadian orthophase (rhythm crest time). effects of the new gastrointestinal therapeutic system formulation of the -blocker doxazosin 37 concluded that daily ingestion of the medication at bedtime resulted in a statistically significant doubling of the amount of 24-hour mean BP reduction compared with morning dosing. Most important, ASA has been shown to provide a significant inhibition of angiotensin II dependent on the dose and circadian time of ASA administration. 10 Moreover, ASA is known to acetylate a variety of proteins, including COX-2. COX-2 inhibition has also been shown to decrease renin content and to lower BP in

6 Hermida et al Chronopharmacology of ASA 1065 TABLE 2. ABPM Characteristics of Subjects Investigated Variable* Aspirin on Awakening Aspirin at Bedtime Patients, n Before treatment P for Group Comparison Nocturnal rest, hours Diurnal mean of SBP, mm Hg Nocturnal mean of SBP, mm Hg hour mean of SBP, mm Hg Diurnal/nocturnal ratio of SBP, % Diurnal mean of DBP, mm Hg Nocturnal mean of DBP, mm Hg hour mean of DBP, mm Hg Diurnal/nocturnal ratio of DBP, % After treatment (in parentheses; P value from comparison with values before treatment) Nocturnal rest, hours (0.109) (0.698) Diurnal mean of SBP, mm Hg (0.139) ( 0.001) Nocturnal mean of SBP, mm Hg (0.101) ( 0.001) hour mean of SBP, mm Hg (0.054) ( 0.001) Diurnal/nocturnal ratio of SBP, % (0.485) (0.028) Diurnal mean of DBP, mm Hg (0.362) ( 0.001) Nocturnal mean of DBP, mm Hg (0.054) ( 0.001) hour mean of DBP, mm Hg (0.092) ( 0.001) Diurnal/nocturnal ratio of DBP, % (0.109) (0.261) Average percent reduction from baseline Diurnal mean of SBP Nocturnal mean of SBP hour mean of SBP Diurnal mean of DBP Nocturnal mean of DBP hour mean of DBP *All values given in mean SD. The diurnal/nocturnal ratio, an index of the BP dipping, is defined as the percent decline in BP during hours of nocturnal rest relative to the mean BP obtained during the hours of diurnal activity. a model of renovascular hypertension. 38 These results may be relevant inasmuch as ASA given at the end of the activity cycle could thus target the nocturnal peak of plasma renin activity while enhancing the nocturnal trough in the production of NO. 7 This hypothesis gains relevancy given the significantly enhanced effect of ASA in reducing the nocturnal mean of BP in non-dipper hypertensive patients (Figure 2), who are characterized by a decrease in NO release compared with dipper patients. 20 The potential added impact on NO or plasma renin activity attributable to the timed administration of low-dose ASA deserves further investigation. The mechanisms underlying the loss of the nocturnal decline in BP are still unclear. Nonetheless, the extent of the nocturnal decline in BP in hypertension seems to be of clinical importance. Verdecchia et al 16 showed that after an average follow-up period of 3.2 years, non-dipper hypertensive patients experienced nearly 3 as many adverse cardiovascular events as dippers. More recently, Staessen et al, 17 summarizing results from the Syst-Eur trial, in which nitrendipine was dosed at bedtime, reported that non-dippers experienced a greater incidence of stroke and myocardial infarction than the group of persons who had a normal dipping pattern after treatment. Results of this trial also suggested that nighttime BP was the best predictor of risk. A recent evaluation of the data from the Ohasama Study indicated that after an average follow-up of 9.2 years, a 5% decrease in the decline of nocturnal SBP in hypertensive patients was associated with a 31% increased risk of cardiovascular mortality. 18 The potential reduction in cardiovascular risk associated with the normalization of the circadian variability of BP (converting a non-dipper to dipper pattern) has not yet been clearly established. Apart from the Syst-Eur trial mentioned above, results from the Heart Outcomes Prevention Evaluation (HOPE) substudy, in which patients were evaluated by ABPM, indicated a significant BP reduction, mainly during hours of nighttime sleep. 39 The authors suggested that the

7 1066 Hypertension October 2005 Part II Figure 2. Changes in diurnal, nocturnal, and 24-hour means of SBP (top) and DBP (bottom) after aspirin (100 mg per day) administered on awakening or at bedtime in dipper and non-dipper patients with mild hypertension studied by 48-hour ABPM. P values are shown for comparison between groups of patients by ANOVA. beneficial effects on cardiovascular morbidity and mortality in the HOPE study may be related to the 8% increase in the diurnal/nocturnal ratio of BP seen after ramipril was administered at bedtime. The potential advantages in terms of cardiovascular risk reduction from bedtime administration of ASA, mainly in non-dipper patients, deserve further prospective investigation. Results from this prospective trial refer exclusively to untreated patients with newly diagnosed mild hypertension. Other studies have shown no influence of low-dose ASA on BP in hypertensive patients under pharmacological therapy, 40,41 yet the time of ingestion of ASA (presumably morning 27 ) has not been reported. Whether or not ASA enhances the effects of antihypertensive medication or if such a possible influence is circadian time dependent are further issues of clinical interest that should be addressed in future research. Regarding other relevant issues related to ASA administered at different times of the day, compliance was not different in this trial between awakening and bedtime dose.

8 Hermida et al Chronopharmacology of ASA 1067 The number of patients who concluded the study was similar at both treatment times, and no patients abandoned the trial because of secondary effects. With respect to tolerability and potential side effects, a previous endoscopic trial on volunteers who took high-dose ASA (1300 mg) at different times on separate study days has shown that the evening dose compared with the morning dose produced 37% fewer gastric hemorrhagic lesions. 42 Although low-dose ASA would be associated generally with lower potential risks compared with higher doses, previous studies have concluded that nighttime administration of ASA is better tolerated than morning administration. 42 Perspectives The results from this prospective trial in untreated patients with mild hypertension corroborate previous findings on the administration time-dependent influence of low-dose ASA on BP. These beneficial effects are significantly larger in nondipper compared with dipper patients, mainly in the control of nocturnal BP, a result that may be related to the documented increase in NO release from vascular endothelium attributable to ASA. Apart from the documented benefits of ASA in the secondary prevention of cardiovascular disease, results indicate that the timed administration of low-dose ASA with respect to the rest activity cycle of each individual patient could provide a valuable approach for BP control of patients with mild essential hypertension. Apart from the BP-lowering effect, low-dose ASA administered at bedtime, but not on awakening, has also been shown to be protective against preeclampsia, gestational hypertension, intrauterine growth retardation, and preterm delivery in high-risk pregnant women. 13 Whether or not low-dose ASA administered at the end of the activity cycle is able to provide further cardiovascular protection in hypertensive patients beyond documented findings deserves prospective investigation. Acknowledgments This research was supported in part by grants from Xunta de Galicia (PGIDIT03-PXIB-32201PR), Química Farmacéutica Bayer, and Vicerrectorado de Investigación, University of Vigo. References 1. Patrono C, Ciabattoni G, Patrignani P, Pugliese F, Filabozzi P, Catella F, Dave G, Forni L. Clinical pharmacology of platelet cyclo-oxygenase inhibition. Circulation. 1985;72: Wu R, Lamontagne D, de Champlain J. 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