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

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

Ramón C. Hermida, Diana E. Ayala, Carlos Calvo, José E. López, José R. Fernández, Artemio Mojón,María J. Domínguez, Manuel Covelo

Abstract—Previous studies on the potential influence of aspirin on blood pressure have not taken into consideration thechronopharmacological effects of nonsteroidal anti-inflammatory drugs. This pilot study investigates the effects ofaspirin on blood pressure in untreated hypertensive patients who received aspirin at different times of the day accordingto 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 recom-mendations; the same recommendations and aspirin (100 mg/d) on awakening; or the same recommendations and aspirinbefore bedtime. Blood pressure was measured every 20 minutes during the day and every 30 minutes at night for 48consecutive hours before and after 3 months of intervention. The circadian pattern of blood pressure in each group wasestablished by population multiple-component analysis. After 3 months of nonpharmacological intervention, there wasa small, nonsignificant reduction of blood pressure (�1.1 mm Hg; P�0.341). There was no change in blood pressurewhen aspirin was given on awakening (P�0.229). A highly significant blood pressure reduction was, however, observedin 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-doseaspirin on blood pressure in untreated patients with mild hypertension. The influence of aspirin on blood pressuredemonstrated in this study indicates the need to quantify and control for aspirin effects in patients using this drug incombination with antihypertensive medication. (Hypertension. 2003;41:1259-1267.)

Key Words: antihypertensive agents � blood pressure monitoring, ambulatory � heart rate � hypertension, mild� drug therapy � circadian rhythm

There is an extensive literature on the effects of acetyl-salicylic acid (ASA, or aspirin), one of the most com-

monly consumed nonsteroidal anti-inflammatory drugs(NSAID), mainly in the prevention of cardiovascularevents.1–3 Although some of these studies reported averagevalues of office blood pressure (BP) measurements for thepatients before and after long-term administration of ASA orplacebo, the study of a possible effect from ASA on BP wasnot a primary objective. In fact, the effect of ASA on BP wasevaluated only in a few small studies.4–6 It has been reportedthat NSAID may increase BP both in normotensive andhypertensive subjects.4,7–9 The effects appear more marked inhypertensive subjects under treatment.4,7 The mechanismswhereby NSAID may increase BP are not fully understood,nor it is known whether the increase in BP is a long-termeffect. In any event, the dose of ASA regularly used to showanti-inflammatory effects is markedly larger than the doseused as anticoagulant10 and recommended for prevention ofcardiovascular events.1–3

ASA use in hypertensive patients is expected to increaseafter the publication of the results from the Hypertension

Optimal Treatment (HOT) study, which documented theefficacy of low-dose ASA in preventing major cardiovascularevents in hypertensive subjects.11 Recent studies have shownno influence of low-dose ASA on BP in hypertensive patientsunder pharmacological therapy,12,13 yet little if any attentionhas been paid thus far in clinical trials to potential circadianrhythm dependencies in effects.

Previous results suggest that effects of ASA on lipoperox-ides, �-adrenergic receptors, and BP in clinically healthysubjects depend on the circadian timing of ASA administra-tion.14 Moreover, the inhibition of collagen-induced plateletaggregation produced by ASA is circadian time–dependent.15

Another factor to be taken into consideration is the pharma-cokinetic observation that ASA has a faster rate of clearancewhen administered during the morning as compared with theevening.16 These results complement time-dependent changesthat have been described when the pharmacokinetics ofNSAID were investigated in humans.17,18

Along these lines, an effect of ASA on BP dependent bothon the dose as well as on the time of administration has been

Received December 23, 2002; first decision January 13, 2003; revision accepted April 8, 2003.From Bioengineering and Chronobiology Laboratories, University of Vigo (R.C.H., D.E.A., J.R.F., A.M.), Campus Universitario, Vigo, Spain; and the

Hypertension and Vascular Risk Unit, Hospital Clínico Universitario (C.C., J.E.L., M.J.D., M.C.), Santiago de Compostela, Spain.Correspondence to Prof Ramón C. Hermida, PhD, Bioengineering and Chronobiology Labs, E.T.S.I. Telecomunicación, Campus Universitario, VIGO

(Pontevedra) 36200, Spain. E-mail [email protected]© 2003 American Heart Association, Inc.

Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000072335.73748.0D

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documented in clinically healthy volunteers as well as in asmall group of patients with untreated mild hypertension.6 Inboth groups, results indicated a small but statistically signif-icant BP reduction when ASA (100 mg/d for 1 week) wasadministered in the evening and, to a larger extent, atbedtime, such effects could not be demonstrated when thesame dose of ASA was administered on awakening. A higherdose of ASA (500 mg/d), however, showed a pressor effect,even when administered before bedtime,6 although results aresomehow limited by the lack of follow-up of the volunteersbeyond 1 week. Finally, results from a double-blind, random-ized, placebo-controlled trial on the influence of low-doseASA (100 mg/d from 12 to 16 weeks of gestation untildelivery) on BP in pregnant women at high risk for pre-eclampsia also showed a highly significant administrationtime–dependent effect on BP by ASA.19–21 In keeping withthese chronopharmacological effects and the previous find-ings suggesting that ASA at low doses may have a potentialbeneficial effect on BP, the current study investigated theinfluence of ASA on BP in previously untreated hypertensivepatients who received low-dose ASA at different times of theday according to their rest-activity cycle and who wereevaluated by 48-hour ambulatory BP monitoring (ABPM)before and after 3 months of pharmacological intervention.

MethodsSubjectsWe studied 100 untreated volunteers (34 men and 66 women),42.5�11.6 years of age (range, 23 to 79), with diagnosis of mild(grade 1) essential hypertension, according to the recent WorldHealth Organization–International Society of Hypertension classifi-cation,22 based on conventional BP measurements and corroboratedby the results of an ABPM profile at the time of recruitment. Allpatients received medical care at the Hypertension and Vascular RiskUnit, Hospital Clínico Universitario, Santiago de Compostela, Spain.Shift workers and patients with either moderate or severe arterialhypertension, according to the definitions provided by the VI JointNational Committee23 and the World Health Organization–Interna-tional Society of Hypertension,22 secondary arterial hypertension,cardiovascular disorders other than essential hypertension, obstruc-tive sleep apnea, or contraindications to the use of ASA wereexcluded from this trial. In all cases, a complete clinical evaluationwas performed following the standardized protocol at the unit,including blood sampling and 24-hour urine collection. Bloodsamples were obtained from an antecubital vein in the early morninghours (8:00 AM to 9:00 AM) after nocturnal fasting, on the same daybefore starting ABPM, both before and after 3 months of interven-tion (see below).

Patients were randomly assigned to 1 of 3 possible groups,keeping a priori a proportion of 2/1/1 among groups to increasepower for comparisons between treated and untreated patients: group1, nonpharmacological hygienic-dietary recommendations (HDR)according to the recent guidelines for the management of mildhypertension22; group 2, the same HDR and ASA (100 mg/d) onawakening; and group 3, the same HDR and ASA (100 mg/d) beforebedtime. The dose of 100 mg used in this trial corresponds with theactual lower dose commercially available in Spain within theaccepted range of low dosing (75 to 150 mg3). Compliance wasmeasured on the basis of tablet count and a personal interview witheach volunteer. HDR included sodium restriction, information on theDietary Approach to Stop Hypertension Diet, limit alcohol intake,and regular aerobic exercise. Results from blood and urine samplingwere further used to evaluate adherence with HDR. The demo-graphic characteristics of the patients participating in this trial areincluded in the Table.

All issues related to ABPM, including handling and preparation ofthe monitors, individualized explanation about their use to eachpatient, and processing of the data provided by any patient aftermonitoring, were always carried out by the same member of theresearch group in one room of the unit. Conventional clinicalexaminations, usually done on the same day just after finishingABPM, were carried out by other members of the research group indifferent rooms of the unit. Conventional office BP measurements (6at each study visit after the patients had been seated for at least 5minutes, on the same day just before starting ABPM) were alwaysobtained by the same investigator to avoid observer’s bias. Assign-ment of volunteers to each of the 3 groups was done by one memberof the research team, according to the order of recruitment, byfollowing an allocation table constructed with the use of a comput-erized random-number generator. The assignment of patients to eachintervention group was always blinded to the investigator obtainingthe BP measurements as well as to those who performed thestatistical analysis of the data. The minimum sample size for this trial(22 patients for each treatment group) was calculated to show assignificant at the 95% level with a power of 95% changes in the24-hour mean of BP �5 mm Hg, according to the estimation ofinterindividual variability provided by previous studies.6 The centerEthics Committee of Clinical Research approved the study. Allpatients provided informed consent before entering the study.

BP AssessmentThe systolic BP (SBP), mean arterial BP (MAP), diastolic BP (DBP),and heart rate (HR) of each patient were automatically measuredevery 20 minutes during the day (7:00 AM to 11:00 PM) and every 30minutes during the night for 48 consecutive hours with a validatedSpaceLabs 90207 (SpaceLabs Inc) device before and after 3 monthsof intervention with either ASA or HDR alone. To keep a possible“white-coat” effect to a minimum, only the first BP measurementwas performed at the medical setting to validate the proper function-ing of the ABPM device and to check accuracy by comparison of BPreadings with those obtained conventionally. Patients were assessedwhile adhering to their usual diurnal activity (8:00 AM to 11:00 PM

for most)–nocturnal sleep routine. They were instructed to go abouttheir usual activities with minimal restrictions but to follow a similarschedule during the 2 days of ABPM. No person was hospitalizedduring monitoring. BP series were eliminated from analysis whenthey did not contain at least 70% of valid measurements and whenthe subjects showed an irregular rest-activity schedule during the 2days of sampling, an odd sampling with spans of �3 hours withoutBP measurement or a night resting span �6 hours or �12 hours.Apart from the 100 patients provided all required information, 4subjects were eliminated from the trial because of invalid ABPMmeasurement.

The clinical evaluation of this oscillometric monitor according tothe standards published by the Association for Advancement ofMedical Instrumentation and the British Hypertension Society hasbeen previously established.24 The BP cuff was worn on thenondominant arm, with cuff size determined by upper arm circum-ference at each study visit. The monitor was always set to theso-called “blind function.” Accordingly, the display never shows theactual BP readings after measurement, keeping the information blindto the patient. To ensure accuracy of BP measurement for the whole48 hours, we used nickel metal hydride rechargeable batteries. Sincethey have no memory effect, the batteries always can be recharged totheir maximum capacity. The SpaceLabs 90207 can run up to 21consecutive days with these batteries. ABPM always began between10:00 AM and noon. During monitoring, each subject maintained adiary listing the times they went to bed at night, woke in the morning,and ate meals; exercise and unusual physical activity; and events andmood/emotional states that might affect BP.

ActigraphyThe patients wore a MiniMotionLogger actigraph (AmbulatoryMonitoring Inc) on the dominant wrist to monitor physical activityevery minute at the time of ABPM. This compact device (about halfthe size of a wristwatch) functions as an accelerometer. The clock

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time of the actigraph and the ABPM device were always synchro-nized through their respective interfaces with the same computer.The mean activity for the 5 minutes before each BP reading was thencalculated for analysis, according to previous studies on this ar-ea.25,26 This information was used to determine diurnal and nocturnalmeans of BP for each patient according to individual resting time.

Statistical MethodsEach individual’s clock hour BP and HR values were first rerefer-enced from clock time to hours after awakening from nocturnalsleep, according to the information obtained from wrist actigraphy.This transformation avoided the introduction of bias caused bydifferences among subjects in their sleep/activity routine.27 BP and

HR time series were then edited according to conventional criteria toremove measurement errors and outliers.28 The circadian rhythm ofBP and HR before and after 3 months of intervention was objectivelyassessed by population multiple-component analysis,29 a methodapplicable to nonsinusoidal-shaped hybrid time series data (timeseries of data collected from a group of subjects) consisting of valuesdistributed at equal or unequal intervals. Circadian parametersobtained for each group of patients before and after intervention werecompared with a paired parametric test developed to assess differ-ences in parameters derived from population multiple-componentsanalysis.29 Additionally, the demographic and clinical characteristicsin the Table were compared among groups by ANOVA and beforeand after 3 months of intervention within each group by paired t test.

Demographic and Analytical Characteristics of Subjects Investigated

Variable HDR ASA-1 ASA-2P for GroupComparison

Patients, n 50 24 26

Age, y 43.7�12.4 40.0�6.3 45.2�12.7 0.172

Height, cm 163.1�10.1 164.1�10.9 160.2�11.6 0.394

Before intervention

Weight, kg 74.2�14.7 76.1�14.9 74.4�14.2 0.866

BMI, kg/m2 27.9�5.1 28.2�4.9 28.9�5.2 0.677

Waist, cm 88.8�12.4 91.0�13.5 91.3�11.9 0.630

Hip, cm 104.4�9.1 105.6�9.9 105.8�10.4 0.788

SBP, mm Hg* 143.1�14.0 144.2�11.9 146.6�10.1 0.442

DBP, mm Hg* 84.2�8.5 86.0�8.0 85.5�6.3 0.388

Hemoglobin, g/dL 14.4�1.3 14.4�1.5 14.3�1.2 0.909

Glucose, mg/dL 93.6�10.7 100.6�28.8 99.3�13.6 0.268

Creatinine, mg/dL 0.86�0.13 0.82�0.10 0.85�0.14 0.448

Cholesterol, mg/dL 217.6�47.3 202.6�44.8 224.91�46.3 0.289

Triglycerides, mg/dL 114.2�80.9 98.15�57.8 103.0�52.8 0.659

Sodium (serum), mmol/L 139.6�0.2 139.9 �0.4 139.7�0.4 0.233

Potassium (serum), mmol/L 4.41�0.03 4.40�0.06 4.39�0.07 0.757

Sodium (urine), mEq/L 106.7�5.8 119.7�20.4 98.3�18.7 0.265

Potassium (urine), mEq/L 55.2�3.4 60.3�7.4 48.1�8.6 0.252

After intervention (P value from comparisonwith values before intervention)

Weight, kg 73.6�14.4 (0.283) 76.0�15.2 (0.679) 74.4�14.5 (0.962) 0.801

BMI, kg/m2 27.6�4.8 (0.181) 28.2�5.0 (0.672) 29.0�5.7 (0.863) 0.534

Waist, cm 87.0�13.2 (0.104) 91.0�14.2 (0.964) 91.9�12.0 (0.481) 0.232

Hip, cm 103.8�8.0 (0.308) 106.0�10.3 (0.613) 105.4�10.4 (0.514) 0.585

SBP, mm Hg* 141.4�12.6 (0.143) 142.3�10.8 (0.357) 141.7�11.7 (0.008) 0.620

DBP, mm Hg* 81.9�8.0 (0.125) 83.8�6.6 (0.144) 82.0�6.9 (0.007) 0.583

Hemoglobin, g/dL 14.4�1.3 (0.872) 14.2�1.7 (0.229) 14.0�1.1 (0.447) 0.582

Glucose, mg/dL 93.5�9.0 (0.296) 100.7�27.3 (0.423) 102.7�13.6 (0.648) 0.247

Creatinine, mg/dL 0.87�0.13 (0.494) 0.85�0.11 (0.321) 0.87�0.16 (0.833) 0.852

Cholesterol, mg/dL 214.5�40.0 (0.508) 198.3�36.0 (0.382) 197.3�29.0 (0.027) 0.179

Triglycerides, mg/dL 112.8�69.5 (0.724) 97.1�57.9 (0.377) 100.0�66.0 (0.881) 0.654

Sodium (serum), mmol/L 139.2�0.3 (0.338) 139.3�0.5 (0.282) 139.4�0.4 (0.501) 0.237

Potassium (serum), mmol/L 4.39�0.03 (0.573) 4.35�0.07 (0.268) 4.36�0.05 (0.629) 0.435

Sodium (urine), mEq/L 90.5�8.4 (0.104) 106.0�26.8 (0.740) 89.5�21.2 (0.632) 0.622

Potassium (urine), mEq/L 51.3�3.4 (0.319) 54.0�8.2 (0.220) 44.8�7.3 (0.187) 0.472

All values are mean�SD. HDR indicates hygienic-dietary recommendations; ASA-1, aspirin (100 mg/day) on awakening; ASA-2,aspirin (100 mg/day) before bedtime.

*Values provided correspond to the average of 6 conventional BP measurements obtained for each patient before starting ABPM.

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ResultsDemographic Characteristics and Serum ParametersThe baseline characteristics of the 3 groups of previouslyuntreated hypertensive patients investigated in this trial weresimilar in age, height, weight, body mass index (BMI), andwaist and hip perimeters, as well as in the average of 6conventional measurements of SBP and DBP obtained on thesame morning just before starting ABPM (Table). Resultsfurther indicated the lack of statistically significant changesafter 3 months of intervention in weight, BMI, or waist andhip perimeters in any of the 3 groups of hypertensive patients.Conventional BP measurements were unchanged after 3months of intervention with either HDR alone or in combi-nation with ASA given on awakening. There was, however, astatistically significant reduction of 4.9 and 3.5 mm Hg inoffice values of SBP and DBP, respectively, after 3 months ofASA given before bedtime (P�0.008 and 0.007 for SBP andDBP, respectively). Serum values of glucose, cholesterol, andtriglycerides remained unchanged after HDR or ASA onawakening. Cholesterol was slightly reduced after ASAbefore bedtime, although the difference would not be statis-tically significant if corrected for multiple testing. Only 38%of the patients in this group showed a reduction in cholesterolafter intervention. Moreover, the average values of cholester-ol at baseline and after intervention were not different amonggroups of patients. The use of the low-dose of 100 mg/d ofASA did not modify the baseline values of hemoglobin at anytime of administration here tested (Table). Sodium andpotassium (both serum and 24-hour urine samples) were notsignificantly modified in any group, although they show aslight tendency to decrease after 3 months of intervention.

Hygienic-Dietary RecommendationsThe circadian rhythm of SBP, MAP, DBP, and HR, inuntreated mild hypertensive patients measured by 48-hourABPM before and after 3 months of nonpharmacologicalHDR, is depicted in Figure 1. Hours of nocturnal rest(average across all patients) are indicated by the dark bar onthe lower horizontal axis of each graph. Results indicate asmall and not statistically significant reduction in BP and HRafter 3 months of nonpharmacological intervention. Most ofthe apparent reduction in BP was found in the few hours ofdaily activity soon after starting ABPM. This difference couldthus just be explained by the significant pressor effect thatcharacterizes mostly the first but in a much lower degreesuccessive profiles of ABPM in hypertensive patients (therecently described “ABPM effect”30,31).

ASA on AwakeningThere was no statistically significantly change in the 24-hour,daily, or nocturnal means of BP and HR after 3 months of 100mg/d of ASA given on awakening (Figure 2). The smallincrease in BP, mainly during nocturnal resting hours, wasvery small and not statistically significant (P�0.279).

ASA Before BedtimeFigure 3 shows the BP changes after 3 months of ASA givenbefore bedtime. The administration of low-dose ASA at thiscircadian time resulted in a significant reduction of 6.2 and

4.1 mm Hg in the 24-hour mean of SBP and DBP, respec-tively (P�0.001). A reduction in BP was observed in 85% ofthe patients in this group. Despite the significant effect on BP,HR remained unchanged after 3 months of intervention(Figure 3). BP reduction was slightly higher during daytimeactivity as compared with nocturnal resting hours. The BPreduction, however, was statistically significant for both thediurnal as well as for the nocturnal means of BP (P�0.01 inall cases).

Comparison Among GroupsThe comparison of results provided in Figures 1 through 3indicates the lack of statistically significant differences in BPat baseline among the 3 intervention groups (P�0.393 forcomparison of 24-hour mean of SBP among groups; P�0.283for DBP). The 24-hour mean of HR was also equivalent atbaseline among groups (P�0.335). After intervention, resultsindicate a highly significant reduction in the 24-hour mean ofBP after ASA given before bedtime in comparison to theother 2 groups (P�0.001 for SBP; P�0.002 for DBP). Figure4 provides further information on the comparison amonggroups of the changes in diurnal, nocturnal, and 24-hourmean BP values after 3 months of intervention. Results, as acomplement to those shown in Figures 1 through 3, indicatehighly significant differences when comparing the BPchanges among the 3 groups of patients.

DiscussionThe major result of this study is that ASA selectivelydecreases BP as a function of the timing of its administrationin relation to the rest-activity cycle of each individual subject.The administration time–dependent effects of ASA on BPshown in Figure 3 are fully in agreement with conclusionsfound earlier in clinically healthy normotensive subjectsusing the same low dose of ASA but for the much shortertime of 1 week.6 Similar conclusions regarding the time-dependent influence of ASA on BP was also corroborated inpregnant women who used 100 mg/d of ASA for most of theduration of their pregnancy.19–21 In the current study, low-dose ASA given before bedtime not only significantly re-duced the mean BP from ABPM but also the average ofconventional BP measurements. Further results from theTable indicate the poor compliance of HDR among all 3groups of patients, inasmuch as there was no significantchange in weight, waist and hip perimeters, serum glucose,cholesterol, or triglycerides after 3 months of intervention.Although there was a tendency to lower values of sodium inurine after intervention, the change was not statisticallysignificant. Hemoglobin levels also remained unchanged afterASA administration.

The mechanism(s) involved in the responsiveness of BP toASA administered at different times according to the rest-activity cycle is still unknown and awaits further investiga-tion. The hypothesis that a time-dependent effect of ASA onthromboxane production could also be at least partly respon-sible for the time-dependent effects of ASA on BP gainssome relevancy given the lack of any effect of ASA on HR(Figure 3). Taking into account the administration time–dependent BP lowering by ASA, relevant studies have also

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shown statistically significant circadian rhythms inthromboxane and prostacyclin production,32 circulating plate-lets,33 platelet aggregation,32,34,35 clotting and fibrinolyticinhibitors,32 and in the inhibition of platelet aggregationproduced by ASA.15 On the other hand, ASA has also been

shown not only to restore vascular refractoriness to angioten-sin II36 but also to produce a dose-dependent BP reductionand �30% inhibition of angiotensin II.37 Along these lines,previous results have demonstrated a predictable circadianvariation in plasma renin activity, angiotensin II, catechol-

Figure 1. Changes in circadian pattern of BP and HR after 3 months of HDR in patients with mild hypertension sampled by 48-hourambulatory monitoring. Each graph shows 2-hourly means and standard errors of data collected before (continuous line) and after(dashed line) 3 months of nonpharmacological intervention. Nonsinusoidal-shaped curves correspond to the best-fitted waveformmodel determined by population–multiple component analysis. Arrows descending from upper horizontal axis point to circadianorthophase (rhythm crest time).

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amines, atrial natriuretic peptides, aldosterone, and angioten-sin-converting enzyme.38–43 These results may be relevantinasmuch as ASA given at the end of the activity cycle couldthus target the nocturnal peak of plasma renin activity while

enhancing the nocturnal through in the production of nitricoxide,44,45 hypotheses that deserve further investigation.

From the clinical point of view, the effects of ASA on BPdemonstrated in this study indicate the need to identify

Figure 2. Changes in circadian pattern of BP and HR after aspirin (100 mg/d) administered on awakening in patients with mild hyper-tension sampled by 48-hour ambulatory monitoring. Each graph shows 2-hourly means and standard errors of data collected before(continuous line) and after (dashed line) 3 months of aspirin administration. Nonsinusoidal-shaped curves correspond to the best-fittedwaveform model determined by population–multiple component analysis. Arrows descending from upper horizontal axis point to circa-dian orthophase (rhythm crest time).

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patients using both ASA and antihypertensive medication, aswell as the time of ingestion of ASA, due to the possibleconfounding effects of ASA on BP that could result from itsuse in conjunction with other drugs. Whether or not ASA

enhances the effects of antihypertensive medication or if sucha possible influence is circadian time–dependent are furtherissues of clinical interest that should be addressed in futureresearch.

Figure 3. Changes in circadian pattern of BP and HR after aspirin (100 mg/d) administered before bedtime in patients with mild hypertension sam-pled by 48-hour ambulatory monitoring. Each graph shows 2-hourly means and standard errors of data collected before (continuous line) and after(dashed line) 3 months of aspirin administration. Nonsinusoidal-shaped curves correspond to the best-fitted waveform model determined by popu-lation–multiple component analysis. Arrows descending from upper horizontal axis point to circadian orthophase (rhythm crest time).

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Apart from these limitations, one could also discuss thepotential risks of ASA administered at different times of theday. Compliance is not different between morning and nightdose because those two times are mainly equally rememberedby the patient, as previously demonstrated.6,19,20 With respectto tolerability and potential side effects, a previous endo-scopic trial on volunteers who took high-dose ASA (1300mg) at different times on separate study days have shown thatthe evening dose, in comparison to the morning, produced37% fewer gastric hemorrhagic lesions.46 Although low-doseASA would be generally associated to lower potential risks ascompared with higher doses, a conclusion has been made thatnighttime administration of ASA is better tolerated thanmorning administration.47

PerspectivesThe results from this trial in untreated patients with mildhypertension corroborate earlier findings on the administra-tion time–dependent influence of low-dose ASA on BP.Results indicate that the timed administration of low-doseASA with respect to the rest-activity cycle of each individualpatient could provide a valuable approach not just for thesecondary prevention of cardiovascular disease but also in theadded BP control of patients with mild essential hypertensionand poor compliance with hygienic and/or dietaryrecommendations.

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Hermida et al ASA Effects on Blood Pressure 1267

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Mojón, María J. Domínguez and Manuel CoveloRamón C. Hermida, Diana E. Ayala, Carlos Calvo, José E. López, José R. Fernández, Artemio

Hypertensive PatientsDependent Effects of Aspirin on Blood Pressure in Untreated−Administration Time

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