Ambulatory Blood Pressure Control With Bedtime Aspirin Administration in Subjects With Prehypertension

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1 articles nature publishing group Ambulatory Blood Pressure Control With Bedtime Aspirin Administration in Subjects With Prehypertension Ramón C. Hermida 1, Diana E. Ayala 1, Artemio Mojón 1 and José R. Fernández 1 Background Aspirin has been found to prevent angiotensin II induced hypertension and to induce nitric oxide (NO) release from vascular endothelium. Low-dose aspirin has also been shown to reduce blood pressure (BP) when administered at bedtime, as opposed to upon awakening, in untreated hypertensive patients and highrisk pregnant women. Accordingly, we investigated the effects on ambulatory BP of aspirin administered at different times of the day in prehypertension. Methods We studied 244 subjects with prehypertension, 43.0 ± 13.0 years of age, randomly divided in three groups: nonpharmacological hygienic-dietary recommendations; the same recommendations and aspirin (100 mg/day) on awakening; or the same recommendations and aspirin at bedtime. BP was measured for 48 consecutive hours before and after 3 months of intervention. According to the Seventh Report of the Joint National Committee, 1 prehypertension is a designation chosen to identify individuals at high risk of developing hypertension and suffering cardiovascular events. 2,3 In a recent study, Hansen et al. 4 found that progression from optimal or normal blood pressure (BP) to high-normal BP or hypertension carries nearly the same risk for cardiovascular events as sustained high- normal BP or hypertension. The Trial of Preventing Hypertension study 5 has suggested that treating prehypertension with an angiotensin-receptor blocker might be effective in slowing the rate of progression to hypertension. Similar conclusions have been recently reported for the angiotensinconverting enzyme inhibitor ramipril. 6 Several criticisms, however, have been raised regarding the design, results, and conclusions derived from the Trial of Preventing Hypertension and its recommendation for pharmacologic treatment of prehypertension. 7,8 Moreover, current guidelines 1,9 indicate 1 Bioengineering and Chronobiology Laboratories, University of Vigo, Vigo, Spain. Correspondence: Ramón C. Hermida (rhermida@uvigo.es) Received 20 February 2009; first decision 21 March 2009; accepted 5 April 2009; advance online publication 30 April doi: /ajh American Journal of Hypertension, Ltd. Results Ambulatory BP was unchanged in subjects randomized to either nonpharmacological intervention or aspirin on awakening. A significant ambulatory BP reduction was, however, observed in the subjects who received aspirin at bedtime (decrease of 6/3 mm Hg in the 24-h mean of systolic (SBP)/diastolic BP (DBP), respectively; P < 01), without changes in heart rate (HR) from baseline. BP was homogenously controlled along the 24 h after bedtime aspirin administration (6/4 mm Hg reduction in activity mean of SBP/DBP; 6/3 mm Hg reduction in sleep-time mean, respectively). Conclusions This prospective trial documents a significant effect on BP of low dose aspirin only when ingested at bedtime by prehypertensive subjects. The timed administration of low-dose aspirin could thus provide a valuable and cost-effective approach for BP control in subjects at elevated risk of developing hypertension. Am J Hypertens 2009; 22: American Journal of Hypertension, Ltd. that individuals who are prehypertensive are not candidates for drug therapy on the basis of their level of BP and they should be advised to practice lifestyle modification in order to reduce their risk of developing hypertension in the future. Because subjects at low or moderate cardiovascular risk show poor compliance to lifestyle modification, 10 other low-cost and effective ways of controlling BP in prehypertension may be clinically relevant. Acetylsalicylic acid (aspirin, ASA) is a nonsteroidal antiinflammatory drug with demonstrated inhibitory effects on cyclooxygenases, responsible for arachidonic acid metabolism and prostaglandin production. 11 Previous studies have demonstrated that ASA is a potent antioxidative agent that markedly reduces vascular production of superoxide in normotensive and hypertensive rats. 12 In addition, ASA was found to prevent angiotensin II induced hypertension and cardiovascular hypertrophy in rats, mainly through its antioxidative properties in preventing the generation of superoxide. 13 Moreover, recent results have demonstrated that ASA induces nitric oxide (NO) release from vascular endothelium. 14,15 This effect appears to be due to a direct acetylation of the endothelial NO synthase protein. Most relevant, previous clinical trials demonstrate effects of ASA that depend on the daily time of administration. Thus, the 896 AUGUST 2009 VOLUME 22 NUMBER AMERICAN JOURNAL OF HYPERTENSION

2 Low-Dose Aspirin in Prehypertension articles effects of ASA upon lipoperoxides, α- and β-adrenergic receptors, and BP in clinically healthy subjects depend on the circadian timing of ASA administration. 16 ASA has also been shown to produce a >30% inhibition of angiotensin II only when administered at bedtime, associated to the documented administration-time-dependent effects of ASA on plasma renin activity. 17 Moreover, an administration-time-dependent influence of ASA on ambulatory BP was previously demonstrated in a double-blind placebo- controlled trial on pregnant women at high-risk for preeclampsia 18 and a prospective trial on patients with untreated mild hypertension. 10 The findings of these studies are consistent; BP-lowering effect of lowdose ASA is achieved when administered at bedtime but not upon awakening. In keeping with these collective findings suggesting that low-dose ASA may have a beneficial effect on BP regulation, this prospective, randomized study investigated the influence of ASA on ambulatory BP in subjects with prehypertension (thus with lower baseline BP compared to patients in all previous studies summarized above), who received ASA at different times of the day according to their rest activity cycle and who were evaluated by 48-h ambulatory BP monitoring (ABPM) before and after 3 months of pharmacologic intervention. Methods Inclusion and exclusion criteria. Inclusion criteria were age 18 years, diagnosis of prehypertension according to the Seventh Report of the Joint National Committee guidelines, 1 as determined by repeated clinic BP measurements for at least the previous 3 months (systolic BP (SBP) mm Hg and/or diastolic BP (DBP) mm Hg), and lack of previous diagnosis of hypertension or use of BP-lowering medication. Pregnant women, shift-workers, heavy drinkers (alcohol intake >80 g/day), heavy smokers (>20 cigarette/day), and heavy exercisers were excluded, as were individuals with contraindications to the use of ASA, treated or untreated essential hypertension, type 1 diabetes, or cardiovascular disorders, including concomitant unstable angina pectoris, heart failure, stroke, life threatening arrhythmia, nephropathy, retinopathy, or prior (within the last year) myocardial infarction or coronary revascularization. Study design. This was a single-center prospective, randomized, open-label, parallel-group, blinded endpoint (PROBE) trial conducted at the Hospital Clínico Universitario, Santiago de Compostela, Spain. Benefits of the PROBE design and its validity as compared to double-blind, placebo-controlled trials, in assessing antihypertensive efficacy based on blinded ABPM measurements have been previously documented. 19 During the inclusion period ( ), we recruited 249 subjects (all adhering to a routine of daytime activity alternating with nocturnal rest) who met the inclusion/exclusion criteria. Among these, 244 (97 men and 138 women), 43.0 ± 13.0 years of age, completed the study and provided all required information for this trial. Subjects were recruited among those sent for evaluation and possible diagnosis of hypertension by ABPM to the hospital by their primary care physicians. The Ethics Committee of Clinical Research approved the study, one of the chronotherapy trials performed within a larger prospective morbidity study ( code NCT ) (ref. 20). All subjects gave written informed consent. Subjects were randomly assigned to one of three possible groups, keeping a priori a proportion of among groups (Table 1) to increase power for comparisons between controls and treated subjects. 10 Group 1: nonpharmacological lifestyle modification, including recommendations for weight loss, sodium restriction, information on the Dietary Approach to Stop Hypertension diet, limit alcohol intake, quit cigarette smoking, and regular aerobic exercise. Group 2: the same recommendations and ASA (100 mg/day) on awakening. Group 3: the same recommendations and ASA (100 mg/day) at bedtime. The dose of 100 mg used in this trial corresponds with the actual lowest dose commercially available in Spain within the accepted range of low-dose ( mg; ref. 21). Compliance and safety were evaluated on the basis of interviews and pill count at the final study visit. No patient ingested any other medication during the study. One member of the research team assigned patients to treatment groups by order of recruitment, using an allocation table produced by a computerized random-number generator. Assignment of patients to the respective treatment groups was blinded from the research team member conducting the clinic BP measurements and from those performing the statistical analysis of the data. At each of the two visits to the hospital, before and after 3 months of intervention, respectively, six clinic BP measurements (Table 1) were obtained, after the patient had rested in a seated position for at least 10 min, using a validated automatic oscillometric device (HEM-705IT; Omron Health Care, Vernon Hills, IL). Blood samples were obtained during both clinic visits from the antecubital vein between 8 am and 9 am after nocturnal fasting. Blood was analyzed for the variables described in Table 1 using routine automatic techniques at the hospital laboratory. ABPM assessment. The SBP, DBP, and heart rate (HR) of each participant were automatically measured every 20 min from 7 am to 11 pm and every 30 min during the night for 48 consecutive hours, before and after intervention, with a properly calibrated SpaceLabs device (SpaceLabs, Issaquah, WA). Participants were instructed to go about their usual activities with minimal restrictions but to follow a similar schedule during the two days of ABPM and to avoid daytime napping. BP series were not considered valid for analysis, and thus repeated within the same week (six profiles), if >30% of the measurements were missing, if data were missing for an interval of >2 h, if data were obtained while subjects had an irregular rest activity schedule, or if the nighttime sleep period was <6 h or >12 h during ABPM. Protocol-correct data series were collected from 244 subjects and therefore included in this efficacy study. Baseline BP profiles of AMERICAN JOURNAL OF HYPERTENSION VOLUME 22 NUMBER 8 AUGUST

3 articles Low-Dose Aspirin in Prehypertension five additional subjects (two originally assigned to lifestyle modification, one assigned to ASA on awakening and two assigned to ASA at bedtime) were not used for analysis because those subjects failed to return for the second ABPM at the end of intervention. No subject withdrew from the study due to adverse effects. Actigraphy. All participants wore an actigraph (Mini- Motion-Logger; Ambulatory Monitoring, Ardsley, NY) on the dominant wrist to monitor physical activity every minute during both ABPM sessions. This compact (about half the size of a wristwatch) device works as an accelerometer. We synchronized the internal clocks of the actigraph and the ABPM device through their respective interfaces using the same computer. The actigraphy data were used to corroborate absence of daytime napping, and to determine the beginning and the end of daytime activity and nocturnal sleep so that the awake and asleep BP means for each patient could be determined with accuracy. Table 1 Demographic characteristics of subjects investigated Variable Statistical methods. Assuming a standard deviation of 7.5 mm Hg for ABPM, 10 with 60 subjects per arm the study could have 90% power to show as significant at the 95% level changes of 4.5 mm Hg in ABPM between treatment groups. As explained above, we decided a priori to duplicate the required number of control subjects (to obtain a total equal number of treated and untreated subjects). Each individual s clock hour BP and HR values were first referenced to hours after awakening from nocturnal sleep, based on data obtained by wrist actigraphy. This transformation avoided the introduction of bias due to differences among subjects in their sleep/activity routine. To correct for measurement errors and outliers, BP and HR were edited according to conventional criteria. 22 Thus, readings of 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. Hourly BP means obtained before and after intervention were compared within each treatment-group by paired t-test corrected for multiple Hygienic-dietary recommendations ASA on awakening ASA at bedtime P between groups Patients, n Sex, % men Age, years 43.0 ± ± ± Height, cm ± ± ± Before intervention Weight, kg 75.5 ± ± ± BMI, kg/m ± ± ± Waist, cm 90.5 ± ± ± Hip, cm ± ± ± SBP, mm Hg a 132 ± ± ± DBP, mm Hg a 78 ± 7 78 ± 6 79 ± HR, beats/min a 75 ± ± ± Hemoglobin, g/dl 13.9 ± ± ± Smokers, % Alcohol use 3 times/week, % After intervention Weight, kg 75.8 ± ± ± BMI, kg/m ± ± ± Waist, cm 91.1 ± ± ± Hip, cm ± ± ± SBP, mm Hg a 135 ± ± ± 10* 03 DBP, mm Hg a 81 ± 8 78 ± 8 77 ± 7* 30 HR, beats/min a 74 ± ± ± Hemoglobin, g/dl 13.9 ± ± ± Smokers, % Alcohol use 3 times/week, % Values are shown as mean ± s.d. ABPM, ambulatory BP monitoring; ASA, acetylsalicylic acid; BMI, body mass index; BP, blood pressure; DBP, diastolic BP; HR, heart rate; SBP, systolic BP. a Values provided correspond to the average of six conventional BP measurements obtained for each subjects at the clinic before commencing ABPM. *P < 5 from baseline. 898 AUGUST 2009 VOLUME 22 NUMBER 8 AMERICAN JOURNAL OF HYPERTENSION

4 Low-Dose Aspirin in Prehypertension articles testing. In so doing, the level of significance was established at P 02, after dividing the usual level of 5 by the number of tests (24, one for each hourly mean) done on the same variable. Both the absolute and the relative changes from baseline in awake, asleep, and 24-h BP means were compared by analysis of variance between groups. The demographic and clinical characteristics in Table 1 were compared between groups by analysis of variance (quantitative variables) or nonparametric χ 2 -test. Within-group comparisons of clinical characteristics before and after intervention were performed using a paired t-test. Results Demographic and analytic characteristics The demographic characteristics of the three groups were comparable at baseline, and they remained unchanged after treatment (Table 1). Clinical BP measurements, comparable at baseline between the three treatment-groups, were slightly but significantly reduced (4 and 2 mm Hg in SBP and DBP; P < 01 and P = 42, respectively) only in the group receiving ASA at bedtime. The serum values of glucose, creatinine, uric acid, cholesterol, triglycerides (not shown), and other laboratory chemistry variables of the three treatment-groups were comparable at baseline and were unchanged after 3 months of intervention. The use of 100 mg/day ASA for 3 months did not modify the baseline values of hemoglobin at any time of administration here tested (Table 1). ABPM characteristics The circadian variation of SBP and DBP in subjects with prehypertension measured by 48-h ABPM before and after 3 months of nonpharmacologic lifestyle modification is depicted in Figure 1. Results indicate no significant change in BP after nonpharmacological intervention (P > 0.54). HR also remained unchanged (increase of 0.4 beats/min in SBP (mm Hg) Before intervention 2 After intervention 24-h mean, P = 0.58; not shown). Using 3 mm Hg as a cutoff arbitrary threshold for the 24-h BP mean, 31% of the subjects in this group showed decreased BP after intervention, while BP increased in 30% of the subjects, and it was unchanged in the remaining 39%. There was no statistically significantly change (P > 0.40) in ambulatory BP after 3 months of 100 mg/day ASA ingested upon awakening (Figure 2). The circadian pattern of HR was similar before and after intervention in this group (increase of 0.7 beats/min in 24-h mean, P = 0.67). A reduction of 3 mm Hg in the 24-h SBP mean was observed in 24% of the subjects in this group, while BP increased above 3 mm Hg in 31% of the subjects. Figure 3 shows the significant reduction compared to baseline of 6 and 3 mm Hg in the 24-h mean of SBP and DBP, respectively (P < 01) after 3 months of 100 mg/day ASA ingested at bedtime. BP was homogeneously reduced during the hours of diurnal activity and nocturnal rest. Figure 3 further indicates that the mean reduction in BP was statistically significant at most of the hourly intervals during the 24-h dosing interval, mainly for SBP (P always <5 after correcting for multiple testing). A reduction of 3 mm Hg in the 24-h SBP mean was observed in 71% of the individuals in this group, while 6% showed increased BP after treatment. Despite the significant effect on BP, HR remained unchanged after 3 months of intervention with ASA at bedtime (decrease of 0.7 beats/min, P = 0.59). The comparison of results provided in Figures 1 3 indicates the lack of statistically significant differences in BP at baseline among the three treatment-groups (Table 2). Results indicate a highly significant reduction (both in absolute values as well as in percent changes from baseline) in the 24-h BP mean after ASA ingested at bedtime in comparison to the other two treatment-groups (P < 01 for SBP and DBP; Table 2). DBP (mm Hg) Figure 1 Lack of changes in SBP (left) and DBP (right) after hygienic-dietary intervention in subjects with prehypertension studied by 48-h ABPM. Each graph shows hourly means and standard errors of data collected before (continuous line) and after (dashed line) 3 months of nonpharmacological intervention. Dark shading along the lower horizontal axis of the graphs represents average hours of nocturnal sleep across the subjects. ABPM, ambulatory blood pressure monitoring; DBP, diastolic blood pressure; SBP, systolic blood pressure. AMERICAN JOURNAL OF HYPERTENSION VOLUME 22 NUMBER 8 AUGUST

5 articles Low-Dose Aspirin in Prehypertension Before intervention 2 After intervention SBP (mm Hg) DBP (mm Hg) Table 2 Ambulatory blood pressure characteristics of subjects investigated Variable Hygienic-dietary recommendations ASA on awakening ASA at bedtime P between groups Patients, n Before intervention Nocturnal rest, h 8.7 ± ± ± Awake SBP, mm Hg 126 ± ± ± Asleep SBP, mm Hg 111 ± ± ± h SBP, mm Hg 121 ± ± ± Awake DBP, mm Hg 82 ± 7 83 ± 4 82 ± Asleep DBP, mm Hg 67 ± 6 66 ± 6 67 ± h DBP, mm Hg 77 ± 6 78 ± 4 77 ± After intervention Nocturnal rest, h 8.6 ± ± ± Awake SBP, mm Hg 126 ± ± ± 7* <01 Asleep SBP, mm Hg 111 ± ± ± 7* <01 24-h SBP, mm Hg 121 ± ± ± 6* <01 Awake DBP, mm Hg 82 ± 7 84 ± 5 78 ± 7* <01 Asleep DBP, mm Hg 67 ± 7 67 ± 5 64 ± 7* h DBP, mm Hg 77 ± 7 79 ± 4 74 ± 7* <01 Average percent reduction from baseline Awake SBP, % 0.4 ± ± ± 4.3* <01 Asleep SBP, % 0.1 ± ± ± 5.8* <01 24-h SBP, % 0.3 ± ± ± 4.0* <01 Awake DBP, % 0.1 ± ± ± 5.2* <01 Asleep DBP, % 0.1 ± ± ± 7.6* <01 24-h DBP, % 0.2 ± ± ± 4.8* <01 All values are shown as mean ± s.d. ASA, acetylsalicylic acid; DBP, diastolic blood pressure; SBP, systolic blood pressure. *P < 01 from comparison with values before treatment by paired t-test Figure 2 Lack of changes in SBP (left) and DBP (right) after ASA (100 mg/day) administered on awakening in subjects with prehypertension studied by 48-h ABPM. Each graph shows hourly means and standard errors of data collected before (continuous line) and after (dashed line) 3 months of ASA administration. Dark shading along the lower horizontal axis of the graphs represents average hours of nocturnal sleep across the subjects. ABPM, ambulatory blood pressure monitoring; ASA, acetylsalicylic acid; DBP, diastolic blood pressure; SBP, systolic blood pressure. 900 AUGUST 2009 VOLUME 22 NUMBER 8 AMERICAN JOURNAL OF HYPERTENSION

6 Low-Dose Aspirin in Prehypertension articles Before intervention 2 After intervention *P < 5 for hourly differences from t-test adjusted for multiple testing SBP (mm Hg) DBP (mm Hg) ** ************ * ****** ***** ** * **** Figure 3 Reduction in SBP (left) and DBP (right) after ASA (100 mg/day) administered at bedtime in subjects with prehypertension studied by 48-h ABPM. Each graph shows hourly means and standard errors of data collected before (continuous line) and after (dashed line) 3 months of ASA administration. Dark shading along the lower horizontal axis of the graphs represents average hours of nocturnal sleep across the subjects. ABPM, ambulatory blood pressure monitoring; ASA, acetylsalicylic acid; DBP, diastolic blood pressure; SBP, systolic blood pressure. Discussion The major result from this study is that, within the rage of high-normal BP, ASA selectively has an effect on BP as a function of the timing of its administration in relation to the rest activity cycle of each individual subject. The administration-time- dependent effects of ASA on ambulatory BP demonstrated here in subjects with prehypertension are in agreement with conclusions found earlier in untreated patients with grade-1 essential hypertension, 10 using also the same lowdose of 100 mg/day ASA. In all other trials reporting BP values before and after ASA, as reviewed elsewhere, 10 patients were not randomized by time of treatment and ASA was consistently ingested in the morning. Similar conclusions regarding the influence of ASA on ambulatory BP when administered at bedtime but not upon awakening were also obtained from a double-blind, placebo-controlled trial in pregnant women who ingested 100 mg/day of ASA for most of their pregnancy. 18 Another double-blind, placebo-controlled study on both normotensive and untreated hypertensive subjects indicated that a higher dose of ASA (500 mg/day), however, showed a pressor effect, even when administered at bedtime. 23 Indeed, it has been reported that nonsteroidal anti-inflammatory drugs (including ASA at anti-inflammatory dose) may increase BP both in normotensive and hypertensive subjects. 24 Results from this study thus indicate that, in those subjects with prehypertension currently advised by their physicians to take lowdose aspirin, administration-time might be preferred to be at bedtime, to gain additional BP-control benefit. Further results from Tables 1 and 2 indicate the poor compliance with recommendations for lifestyle modification, inasmuch as there was no significant change in weight, waist and hip perimeters, serum glucose, cholesterol, triglycerides, clinical or ambulatory BP after 3 months of nonpharmacologic intervention. Moreover, the percentage of subjects who either smoke and/or were frequent alcohol drinkers (arbitrarily defined as 64.5 alcohol use 3 times/week) was not significantly reduced after 3 months of intervention, independently of treatment-group (Table 1). A poor compliance with hygienic-dietary recommendations was also noted before in relatively young subjects with mild essential hypertension and no target organ damage. 10 With respect to the potential mechanism(s) involved in the responsiveness of BP to low-dose ASA administered at different times according to the rest activity cycle of each subject, the effects of ASA upon α- and β-adrenergic receptors depend markedly on the circadian timing of ASA administration. 16 α-adrenoceptor blockade reduces peripheral resistance more effectively in the early morning hours than at other times of the day. 25 Along these lines, a recent study exploring the administration-time-dependent effects of the gastrointestinal therapeutic system formulation of the α-blocker doxazosin 26 concluded that daily ingestion of the medication at bedtime resulted in a statistically significant doubling of the amount of 24-h BP mean reduction as compared to 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. 17 Moreover, ASA is known to acetylate a variety of proteins, including cyclooxygenase-2. Cyclooxygenase-2 inhibition has also been shown to decrease renin content and to lower BP in a model of renovascular hypertension. 27 These results may be relevant inasmuch as ASA given at the end of the activity cycle, but not upon awakening, could thus target the nocturnal peak of plasma renin activity, 28 while enhancing the nocturnal trough in the production of NO. 29 This hypothesis gains relevancy given the significantly enhanced effect of ASA in reducing the asleep mean of BP in hypertensive patients with a nondipper BP profile, as previously documented. 30 Patients with an altered nondipper BP pattern are characterized by a decrease in NO release as compared to dipper patients. 31 Thus, the enhanced reduction in plasma renin activity, beneficial impact AMERICAN JOURNAL OF HYPERTENSION VOLUME 22 NUMBER 8 AUGUST

7 articles Low-Dose Aspirin in Prehypertension on endothelial function and blocking of α- and β-adrenergic receptors associated to bedtime administration of low-dose ASA could explain the impact of this intervention on BP here documented in subjects with high-normal BP. While considering the potential benefits of a cost-effective use of low-dose ASA for BP control in subjects with prehypertension, one could also discuss the potential risks of ASA administered at different times of the day. Compliance was not different in this trial between awakening and bedtime dose, and both >94% of the prescribed medication. The number of patients who concluded the study was similar at both treatment times, while no patient abandoned the trial due to side effects. With respect to tolerability and potential adverse effects, a previous endoscopic trial on volunteers who took high-dose ASA (1,300 mg) at different times on separate study days have shown that the evening, in comparison to the morning dose, produced 37% fewer gastric hemorrhagic lesions. 32 Although low-dose ASA would be generally associated with lower potential risks as compared to higher doses, nighttime administration of ASA is better tolerated than morning administration. 32 In keeping with many other trials comparing the antihypertensive efficacy of several antihypertensive agents, this study relied on a PROBE design. As previously described, 19,33 this design offers certain benefits, including a closer similarity between study design and daily clinical practice. Potential investigator bias is minimized because the primary endpoint data (that is, ABPM) were analyzed in a blinded manner. On the other hand, knowledge of both patients and clinical personnel of the treatment assignment can be considered a limitation of the design. However, a recent meta-analysis has demonstrated the validity of the PROBE design, as compared to double-blind, placebo-controlled trials, in assessing antihypertensive efficacy based on blinded ABPM measurements. 19 Finally, the use of a double-blind design in chronotherapy trials had the added limitation of reduced compliance, as the subjects would always be required to take two pills, one in the morning upon awakening (either active treatment or placebo) and a different one at bedtime. 34 In conclusion, the results from this prospective trial in subjects with prehypertension corroborate earlier findings on the administration-time-dependent influence of low-dose ASA on ambulatory BP. Apart from the documented benefits of ASA in the prevention of cardiovascular disease, results indicate that the timed administration of low-dose ASA with respect to the rest activity cycle of each individual could provide a valuable approach for BP control of subjects with prehypertension and poor compliance with hygienic and/or dietary recommendations. 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 normotensive pregnant women. 18 Whether or not low-dose ASA administered at the end of the activity cycle is also able to provide added cardiovascular protection deserves prospective investigation. Acknowledgments: This independent investigator-promoted research was supported in part by grants from Dirección General de Investigación, Ministerio de Educación y Ciencia (SAF FEDER); Consellería de Presidencia, Relacións Institucionais e Administración Pública, Secretaría Xeral de Investigación e Desenvolvemento, Xunta de Galicia (PGIDIT03-PXIB PR); Consellería de Educación e Ordenación Universitaria, Dirección Xeral de Promoción Científica e Tecnolóxica do Sistema Universitario de Galicia, Xunta de Galicia (R.C.H.); Consellería de Innovación e Industria, Dirección Xeral de Investigación, Desenvolvemento e Innovación, Xunta de Galicia (INCITE07-PXI ES & INCITE08-E1R ES); and Vicerrectorado de Investigación, University of Vigo. Clinical trial registration information: code NCT Disclosure: The authors declared no conflict of interest. 1. 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