Monitoring The Entry of New Platelets Into The Circulation After Ingestion of Aspirin

Clinical Trials
Time-Dependent Effects of Aspirin on Blood Pressure and

Morning Platelet Reactivity
A Randomized Cross-Over Trial
Tobias N. Bonten, Jaapjan D. Snoep, Willem J.J. Assendelft, Jaap Jan Zwaginga,
Jeroen Eikenboom, Menno V. Huisman, Frits R. Rosendaal, Johanna G. van der Bom
AbstractAspirin is used for cardiovascular disease (CVD) prevention by millions of patients on a daily basis. Previous
studies suggested that aspirin intake at bedtime reduces blood pressure compared with intake on awakening. This has never
been studied in patients with CVD. Moreover, platelet reactivity and CVD incidence is highest during morning hours.
Bedtime aspirin intake may attenuate morning platelet reactivity. This clinical trial examined the effect of bedtime aspirin
intake compared with intake on awakening on 24-hour ambulatory blood pressure measurement and morning platelet
reactivity in patients using aspirin for CVD prevention. In this randomized open-label crossover trial, 290 patients were
randomized to take 100 mg aspirin on awakening or at bedtime during 2 periods of 3 months. At the end of each period,
24-hour blood pressure and morning platelet reactivity were measured. The primary analysis population comprised 263
(blood pressure) and 133 (platelet reactivity) patients. Aspirin intake at bedtime did not reduce blood pressure compared
with intake on awakening (difference systolic/diastolic: 0.1 [95% confidence interval, 1.0, 0.9]/0.6 [95% confidence
interval, 1.2, 0.0] mmHg). Platelet reactivity during morning hours was reduced with bedtime aspirin intake (difference:
22 aspirin reaction units [95% confidence interval, 35, 9]). The intake of low-dose aspirin at bedtime compared
with intake on awakening did not reduce blood pressure of patients with CVD. However, bedtime aspirin reduced
morning platelet reactivity. Future studies are needed to assess the effect of this promising simple intervention on the
excess of cardiovascular events during the high risk morning hours.(Hypertension. 2015;65:743-750. DOI: 10.1161/
HYPERTENSIONAHA.114.04980.) Online Data Supplement
Key Words: aspirin
blood pressure
ardiovascular disease (CVD) is still a leading cause of mortality and morbidity worldwide.1,2 One of the most important modifiable risk factors for CVD is blood pressure. Even
small reductions of blood pressure significantly decrease the risk
of myocardial infarction and stroke.3 However, almost half of the
patients with hypertension remain uncontrolled, despite blood
pressure lowering medication.4 Thus, simple interventions to
improve blood pressure control are needed. Aspirin traditionally
was assumed to have no effect on blood pressure,5 but in recent
studies, aspirin intake at bedtime compared with intake on awakening considerably reduced blood pressure.611 Additionally, we
previously found that aspirin intake at bedtime compared with
on awakening reduced plasma renin activity and cortisol, dopamine and norepinephrine excretions over 24 hours.12 However,
all previous studies included healthy subjects, pregnant women,
or patients with mild hypertension.611,13 If the effect of bedtime
aspirin intake on blood pressure also holds for patients who
chronotherapy
platelet activation
already use aspirin for CVD prevention, simply changing the

time of intake from awakening to bedtime could substantially
reduce their risk for recurrent cardiovascular events.
Furthermore, platelet aggregation peaks during morning
hours, which is thought to contribute to the observed peak of
CVD from 6 to 12 AM.14,15 Because of its short half-life, aspirin
only inhibits the platelets that are present at the time of intake,
whereas new platelets are released at a rate of 10% per day in
healthy subjects.16,17 Thus, just before each aspirin intake, these
newly released platelets are uninhibited and can induce platelet aggregation.18,19 However, it is desirable to achieve optimal
platelet aggregation inhibition particularly during those high risk
morning hours. As already suggested by previous authors, intake
of aspirin at bedtime might attenuate the morning peak of platelet reactivity, but this was never evaluated in a clinical trial.20,21
To assess whether aspirin intake at bedtime compared with
intake on awakening reduces blood pressure and morning
Received November 25, 2014; first decision December 11, 2014; revision accepted January 25, 2015.
From the Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands (T.N.B., J.D.S., F.R.R., J.G.v.d.B.);
Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, the Netherlands (W.J.J.A.); Department of Public Health
and Primary Care, Leiden University Medical Center, Leiden, the Netherlands (W.J.J.A.); JJ van Rood Center for Clinical Transfusion Research, Sanquin
Research, Leiden, the Netherlands (J.J.Z., J.G.v.d.B.); and Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the
Netherlands (J.E., M.V.H.).
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.
114.04980/-/DC1
Correspondence to T.N. Bonten, Leiden University Medical Center, Department of Clinical Epidemiology, C7-P, PO Box9600, 2300 RC Leiden, the
Netherlands. E-mail t.n.bonten@lumc.nl
2015 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.114.04980
Downloaded from http://hyper.ahajournals.org/

by guest on May 3, 2016
743
744Hypertension April 2015

platelet reactivity, we conducted a randomized crossover trial
in patients using low-dose aspirin for prevention of CVD.
Methods
Design Overview
An overview of the study design is depicted in Figure1. A prospective, randomized, open-label, blinded end point (PROBE), 2-period
crossover study was conducted at a single center in the Netherlands
and registered at www.clinicaltrials.gov/ct2/show/NCT01379079.
Benefits of the PROBE design and its validity for studies measuring
ambulatory blood pressure have been previously documented.22 The
study was conducted in accordance with the Declaration of Helsinki,
approved by the Leiden University Medical Center (LUMC) Ethics
Committee, and all subjects gave written informed consent.
Setting and Participants

Patients between 18 and 75 years of age using low-dose (80100 mg)
aspirin for secondary prevention of CVD were recruited from general
practitioner practices around Leiden, the Netherlands. Exclusion criteria
were baseline blood pressure (BP) <120/70 or >160/100 mmHg, use
of other antiplatelet or anticoagulant drugs, change of antihypertensive
medication in the 3 months before baseline, use of nonsteroidal antiinflammatory drugs, employment as shift worker, evidence of secondary
arterial hypertension (eg, pheochromocytoma), and pregnancy.
Randomization and Interventions

Randomization was performed with a computer-generated randomization code by an independent person at the Department of Clinical
Epidemiology of the LUMC and was inaccessible to the investigators. Eligible subjects were randomized (1:1 ratio) to take aspirin
on awakening followed by aspirin at bedtime or the opposite order
during 2 intervention periods of 3 months (Figure1). The 2 intervention periods were not separated by a wash-out period because
withholding aspirin to the included patients was considered unethical. The duration of each intervention period was analogous to previous studies.911 All subjects received 100 mg effervescent aspirin
(Carbasalate Calcium, Vemeda Manufacturing, the Netherlands). At
the end of each intervention period, subjects visited the research site
for 2 consecutive days. At day 1, 24-hour ambulatory blood pressure
measurement (ABPM) was started between 8 to 12 AM, and subjects
took aspirin at the same time as in the preceding 3 months. At day
2, subjects refrained from taking aspirin in the morning, ABPM was
ended, and blood was drawn. The time of ABPM start at day 1 and
blood draw at day 2 was similar for each participant at each visit.
Outcomes
Blood Pressure
Baseline BP was measured by an automatic device (Mobil-O-Graph

NG device; IEM GmbH, Germany) every 2 minutes in seated position after 10 minutes of rest. The average of 6 readings was used
to determine baseline blood pressure. As the primary end point,

ABPM was performed during participants normal daily routine with
a validated and calibrated Mobil-O-Graph NG device (IEM GmbH,
Germany). Measurements started between 8 and 12 AM, and the
same device was used at each visit. The BP cuff was adjusted to arm
circumference and worn on the nondominant arm. Systolic and diastolic BP were automatically measured every 20 minutes during day
and every 30 minutes during night for 24 consecutive hours, with the
screen turned off to blind subjects for BP readings. Bed and awakening times were recorded in a diary. ABPM was considered valid
if 70% of measurements were valid, sleep time during ABPM was
between 6 and 12 hours, and data were not missing for >2 hours.
Platelet Reactivity
As a secondary end point, platelet reactivity was measured during

morning hours (between 8 and 12 AM). At the morning of blood
sampling, subjects refrained from taking aspirin. Blood was sampled
without stasis from the antecubital vein, and platelet reactivity was
measured with the VerifyNow Aspirin Assay (Accumetrics, San
Diego, USA) and reported in Aspirin Reaction Units (ARU).23
Questionnaires, Compliance, and Patient Preference
Subjects completed a questionnaire to assess eligibility criteria, medical

history, medication use, and chronobiological rhythm at baseline. Missing
information was completed with general practitioner or pharmacy
records. At each follow-up visit, side effects and change of medication
was registered by questionnaires. Subjects were instructed to take aspirin
within 1 hour after awakening or 1 hour before bedtime. Compliance was
assessed and optimized with electronic pill boxes (Evalan, Amsterdam,
the Netherlands), which registered time of intake and sent an SMS text
message if subjects were noncompliant. Additionally, pill count was performed at each visit. Participants and general physicians were instructed
not to change or start new medication during the study, which was
checked with questionnaires at each follow-up visit.
Statistical Analysis
To detect an interindividual difference of 3 mmHg in blood pressure with 80% power at a 5% significance level, we calculated a
required sample size of 250 patients. We assumed an intraindividual standard deviation of 12.9 mmHg, as derived from a previous
study.12 Estimating a drop-out of 10% and invalid ABPM of 5%, we
randomized 290 subjects. As planned on beforehand, platelet reactivity was measured in the first consecutive 160 patients, yielding
a power of 90% to detect a difference of 17 ARU at a 5% significance level. For this calculation, we used an intraindividual standard
deviation of 46.85 ARU.24 Continuous characteristics are described as
meanstandard deviation (SD) if normally distributed or as median
(interquartile range [IQR]) if not normally distributed. Categorical
variables are expressed as numbers (percentages). ABPM values were
edited according to conventional criteria to remove measurement
errors and outliers. Because sampling frequency was denser during
the day (3/hour) than during the night (2/hour), we calculated a
weighted overall mean BP, as suggested previously25:
(mean day BP nr day measurements) + (mean night BP nr night measurements)
ments
nr day measurements + nr night measurem
Mean day and night BP was calculated as
Figure 1. Study design. Visit 1, Screening for inclusive and

exclusion criteria. Visit 2 and 3, Ambulatory blood pressure
measurement (ABPM) measurement, blood draw during morning
hours, questionnaire.
sum day or night measurements

nr day or night measurements
The start of day- and nighttimes was obtained from diaries. The primary end point was assessed in a primary and secondary analysis population. The primary analysis population included all subjects who were
randomized and completed measurements of end points. The secondary
analysis population excluded subjects with 1 invalid ABPM, change of
antihypertensive medication, or compliance <90%. Paired t-tests were
performed to analyze day, night, and overall mean BP after intake of
aspirin on awakening and at bedtime. Additionally, linear mixed models
were used to assess treatment effects and period or carry-over effects.
Subgroup analyses were prespecified for users of -blockers, inhibitors of the reninangiotensin system (users versus nonusers), users of
no- versus 1 blood pressure lowering drugs, and subjects with baseline
systolic BP of >140 versus 140 mmHg.
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Bonten et al Blood Pressure and Bedtime Aspirin 745

The secondary end point platelet reactivity was analyzed with a
paired t-test and linear mixed models. Subjects who forgot to take
aspirin on the day before platelet reactivity measurements (n=3) were
excluded from analysis. Subgroup analyses were prespecified for
diabetic subjects, current smokers (yes versus no), and mean platelet
volume values (divided into quartiles). Although not prespecified, an
additional subgroup analysis for body mass index was performed because obesity, as a marker for metabolic syndrome, may be associated
with platelet reactivity.26 Side effects and patient preferences were
analyzed descriptively and using McNemars test. All analyses were
performed in SPSS 20.0 (IBM corp., USA) and were 2-sided, with a
level of significance of 0.05.
Results
Study Population and Compliance
Between June 2011 and March 2013, 3479 subjects were
screened at 30 general practitioner practices, of whom 1704 did
not meet inclusion criteria, primarily because of age >75 years
(n=1080) and use of other platelet inhibiting drugs (n=386;
Figure2). A total of 290 subjects were randomized, and baseline characteristics were similar between groups (Table1).
Study follow-up was discontinued by 26 subjects, primarily
because study participation was too aggravating (18/26; 70%).
Primary and secondary analysis populations comprised 263
and 150 subjects, respectively, for assessment of the primary
end point. Measurements for the secondary end point platelet reactivity were complete for 136 subjects. Compliance as
measured by electronic pill boxes and pill count was high and
similar with aspirin intake on awakening (99% [97%100%]
and 100% [100%100%], respectively) and intake at bedtime
(98% [94%100%] and 100% [100%100%]).
Study start: September 2011
Blood Pressure
The circadian 24-hour ABPM profile after 3 months aspirin intake on awakening and 3 months intake at bedtime is
depicted in Figure3. The mean (SD) 24-hour systolic and diastolic blood pressures were 127 (12) and 79 (9) mmHg with
aspirin intake on awakening, whereas these were 127 (12) and
78 (8) with aspirin at bedtime. This resulted in differences of
0.1 mmHg (95% confidence interval, 1.0 to 0.9) and 0.6
mmHg (95% confidence interval, 1.2 to 0.0). Furthermore,
systolic and diastolic blood pressures during day- and nighttime did not differ by the timing of aspirin intake (Table2).
Mixed model analysis showed the same results and no evidence for carry-over or period effects (data not shown).
Additionally, findings among subgroups of subjects using or
not using -blockers, angiotensin inhibitors, blood pressure
lowering drugs in general, or subjects with baseline office BP
>140 or 140 mmHg were similar to the overall results (Table
S1 in the online-only Data Supplement). Finally, in the secondary analysis, comprising only patients with valid ABPM at
both visits who did not change their antihypertensive medication between visit 2 and 3 and were 90% compliant as registered with electronic pill boxes, aspirin intake at bedtime was
not associated with a reduction of mean 24-hour blood pressure or day- and nighttime blood pressure (Table S2).
Platelet Reactivity
Three subjects forgot to take aspirin on the day before platelet
reactivity measurements and were excluded from this analysis. In the remaining 133 subjects, aspirin intake at bedtime
reduced morning platelet reactivity (mean difference 22 ARU
Assessed for eligibility (n=3479)
Study completion: September 2013
Randomized (n=290)
Allocated to evening intake (n=145)

Visit 2 (3 months)
Withdrawal of consent (n=6)
Participation too aggravating (n=4)
Dyspepsia (n=2)
Allocation
Follow-up
Not included (n=3189)

Did not meet inclusion criteria (n=1704)
Declined to participate (n=655)
Did not respond to invitation (n=527)
Excluded for other reasons* (n=303)
Allocated to evening intake (n=145)

Visit 2 (3 months)
Stopped aspirin use (n=2)
Crossed over to evening intake (n=139)
Crossed over to morning intake (n=136)
Visit 3 (6 months)
Visit 3 (6 months)
Completed 6 month study period (n=134)
Completed 6 month study period (n=130)
Primary analysis population

Primary endpoint: ABPM (n=134)
Secondary endpoint: Platelet reactivity (n=71)
Secondary analysis population (n=73)
Excluded (n=61)
Invalid ABPM visit 1 and/or visit 2 (n=30)
Change of blood pressure lowering drugs (n=8)
Compliance during whole study < 90% (n=23)
Analysis populations
Primary analysis population

Primary endpoint: ABPM (n=129)
Secondary endpoint: Platelet reactivity (n=65)
Secondary analysis population (n=77)
Excluded (n=52)
Invalid ABPM visit 1 and/or visit 2 (n=27)
Change of blood pressure lowering drugs (n=6)
Compliance during whole study < 90% (n=19)
Figure 2. Patient flow. ABPM indicates ambulatory blood pressure measurement. *Other reasons: stopped aspirin use before inclusion,
not able to participate in clinical trial as judged by general practitioner, changed address, not speaking Dutch language. One subject
refused ABPM at the last follow-up visit.

Table 1. Baseline Clinical Characteristics of Randomized
Study Participants (n=290)*
Variable
AwakeningBedtime
Group (n=145)
BedtimeAwakening
Group (n=145)
Sex (M/F)
106/39
106/39
647
647
Age, y
Current smokers
21 (15)
28 (19)
Body mass index, kg/m2
28.44.7
2814.6
Systolic blood pressure,

mmHg
13710
13710
Diastolic blood pressure,

mmHg
888
888
Diabetics
17 (12)
14 (10)
Myocardial infarction
53 (37)
59 (41)
Stable angina pectoris
59 (41)
61 (42)
Stroke/transient
ischemic attack
28 (19)
23 (16)
Atrial fibrillation
14 (10)
13 (9)
Peripheral artery
disease
12 (8)
9 (6)
3 (2)
1 (1)
106 (73)
100 (69)
Aspirin use at baseline

On awakening
Duration, y
6 (311)
6 (414)
2 (12.5)
2 (13)
Medication use
Number of blood
pressure lowering
drugs
-Blockers
74 (51)
80 (55)
Ace-inhibitors
60 (41)
55 (38)
Angiotensin II
inhibitors
37 (26)
33 (23)
Calcium antagonists
29 (20)
27 (19)
Diuretics
37 (26)
46 (32)
116 (80)
123 (85)
Lipid lowering drugs
Discussion
In this large crossover trial among patients using low-dose
aspirin for CVD prevention, 24-hour blood pressure did not
differ between aspirin intake at bedtime and intake on awakening. However, aspirin intake at bedtime was associated with
lower morning platelet reactivity.
Comparison With Previous Studies
Cardiovascular history
Other
entry. A total of 32/264 (12%) switched from intake on awakening to intake at bedtime and 21/264 (8%) from at bedtime
to on awakening. So, no clear patient preference was present
for time of intake.
*Continuous values are presented as meansstandard deviation (SD) or

medians+interquartile range if not normally distributed. Categorical values are
presented as number (%).
Other cardiovascular disease: heart valve disease (n=3), myelodysplastic
syndrome (n=1).
Blood pressure lowering drugs: -blockers, -blockers, ace-inhibitors,
angiotensin-II inhibitors, calcium antagonists, thiazide and loop diuretics,
nitrates (daily use).
[95% confidence interval 35 to 9]; P=0.001; Figure4).

Subgroup analysis showed that, besides in subjects with diabetes mellitus, aspirin intake at bedtime reduced platelet reactivity in all subgroups (Table S3).
Side Effects and Patient Preference

Three subjects did not complete the study because of side
effects (Table S4). The frequency of well-known aspirin side
effects (dyspepsia, nausea, heartburn) was similar between
aspirin intake on awakening and at bedtime (Table S5).
After completion of the study, 53/264 (20%) preferred to
switch to another time of aspirin intake than before study
Multiple previous studies, mostly from a single source in this

field, reported a blood pressure lowering effect of bedtime
aspirin intake.611,13,27 Subsequently, our group found a biological plausible mechanism underlying this phenomenon:
compared with intake on awakening, bedtime aspirin intake
reduced plasma renin activity and cortisol, dopamine, and
norepinephrine excretions over 24 hours.12 So, the finding that aspirin intake at bedtime compared with intake on
awakening does not reduce blood pressure is in contrast with
these previous studies. This may be explained by differences
in study populations. First, previous studies included subjects who did not use blood pressure lowering drugs, such
as -blockers or inhibitors of the reninangiotensinaldosterone system. This is an important difference because the
mechanism behind the time-dependent effect of aspirin on
blood pressure was previously related to a reduction renin
angiotensinaldosterone system and catecholamine activity
over 24 hours.12 However, we did not find an effect in both
users and nonusers of -blockers or reninangiotensin
aldosterone system inhibitors. Even in the subgroup that
did not use any blood pressure lowering drugs, there was
no effect. Our findings corroborate those of an earlier study,
which also did not find a blood pressure lowering effect of
bedtime aspirin intake among treated hypertensive patients.28
Second, patients in all previous studies did not use aspirin
before study entry. In contrast, all patients in our study had
a medical indication for aspirin use and had used aspirin for
median 6 years. It is possible that the time-dependent effect
of aspirin on blood pressure weakens over time because of
increased arterial stiffening.29 However, a potential blood
pressure lowering effect of bedtime aspirin intake would only
be clinically relevant in patients already using aspirin for
CVD prevention, and we are the first in this field to include
this clinically relevant patient group. Given the absence of
a blood pressure lowering effect of bedtime aspirin in any
subgroup of our study, in our opinion, no further studies are
needed to assess the blood pressure lowering effect of bedtime aspirin in patients using aspirin for CVD prevention.
The circadian rhythm of platelet reactivity and its relation with the morning peak of cardiovascular events has been
thoroughly studied.15,30 Previous authors suggested that platelet inhibition during these high risk morning hours could be
optimized by aspirin intake at bedtime.20,21 Subsequent studies
clearly showed that the antiplatelet effect of aspirin declines
during the 24-hour dosing interval.18,19,31 In our study, we compared platelet function 12 hours after aspirin intake (bedtime
Figure 3. Effect of low-dose aspirin intake at bedtime compared with intake on awakening on 24-hour ambulatory blood pressure profile
in the primary analysis population (n=263). A, Systolic blood pressure. B, Diastolic blood pressure. Each graph shows hourly means and
standard errors of blood pressure measured at low-dose aspirin intake on awakening (continuous black line) and low-dose aspirin intake
at bedtime (dashed gray line). Hours on the x-axis refer to hours after awakening from nocturnal sleep. The shaded area represents the
average nocturnal period for all subjects.
intake) with 24 hours after intake (morning intake). So, a

decline in platelet activity during morning hours could have
been expected. Nevertheless, to the best of our knowledge,
this has never been evaluated in a clinical trial. Additionally,
reducing platelet reactivity during the high risk morning hours
could be clinically relevant for patients with CVD.
Previously, we studied the time-dependent effect of aspirin

on morning platelet reactivity in healthy subjects.32 The results
of this study confirm these findings for patients using aspirin on a daily basis. Our study suggests that morning platelet
reactivity can be reduced by taking aspirin at bedtime instead
of on awakening. This effect was homogeneously present in

Table 2. Mean 24-Hour, Day and Night Ambulatory Blood
Pressure Values (mmHg) According to Time of Aspirin
Administration in the Primary Analysis Population (n=263)
Value
Mean Difference
(BedtimeAwakening)
Aspirin on Awakening Aspirin at Bedtime
(95% CI)*
24-hour SBP
12712
12712
0.1 [1.0 to 0.9]
24-hour DBP
799
788
0.6 [1.2 to 0.0]
Day SBP
13112
13112
Day DBP
829
819
Night SBP
11715
11714
0.1 [1.4 to 1.1]
Night DBP
6910
699
0.4 [1.2 to 0.3]
0.0 [1.0 to 1.0]

0.6 [1.2 to 0.1]
*Mean difference and 95% CI obtained with paired t-tests. Values are
meanstandard deviation.
CI indicates confidence interval; DBP, diastolic blood pressure; and SBP,
systolic blood pressure.
all subgroups, except in diabetic subjects. However, the size

of this subgroup was too small (n=18) to rule out any effect in
diabetic patients. Additionally, diabetic patients have higher
platelet turnover, and twice daily dosing of aspirin yields
more effective platelet inhibition over the whole day in diabetic patients.33,34 The reduction of platelet reactivity during
the vulnerable morning hours might be beneficial for patients
with CVD, who have higher platelet turnover, and of which
in 25%, platelet reactivity is inadequately inhibited 24 hours
after aspirin intake.31,35
Clinical Interpretation
It has been shown that the risk for recurrent cardiovascular
events is increased in patients with higher VerifyNow-aspirin
platelet reactivity values.36,37 Stable CVD patients with platelet
reactivity >550 ARU had an absolute risk of 15.6% for developing the composite cardiovascular end point, whereas this
was only 5.3% in patients with ARU values <550.37 In another
study, the absolute risk for the primary end point (all-cause
death and recurrent cardiovascular events) was 13.3% in
patients >454 ARU and 5.9% in patients <454 ARU.36 These
observational studies suggest that a reduction in platelet reactivity could result in clinical benefit for patients with CVD.
Because the CVD morning peak is a multifactorial process,
we do not expect that bedtime aspirin would abolish the CVD
morning peak completely.38 Still, given the high prevalence of
CVD, already a modest reduction of the morning peak would
lead to a large absolute benefit. For example, 280.000 recurrent cardiovascular events occur in the United States (US)
every year, with a known excess of 40% during the morning
hours.39 If aspirin intake at bedtime would reduce this morning peak by 20%, it would lead to an absolute reduction of
4853 recurrent events each year in the United States alone. So,
switching to bedtime aspirin intake is a simple and possible
effective intervention. Future studies should evaluate whether
this indeed translates in a reduction of cardiovascular events.
Strengths and Limitations

The major strength of our study is its crossover design, which
yields high statistical power and enables comparison of treatment effects within each patient. Furthermore, this is the first
study in this field which registered the actual time of aspirin
intake with electronic pill boxes, which is of major importance to study time-dependent effects.
The main limitation of our study is that only 150/263 (57%)
patients complied perfectly with the study protocol. This was
mainly because of invalid ABPM (n=57) or compliance of
<90% within the prespecified time of intake (n=42). However,
sensitivity analysis among patients with complete follow-up
and compliance revealed the same results with narrow confidence intervals (Table S2). Regarding platelet reactivity
measurements, it is a limitation that we measured platelet
reactivity at only 1 time point during the morning, although
comparability within subjects was optimized by drawing
blood at the same time at each visit. A large proportion of the
potentially eligible patients did not respond or did not want
to participate in this study. However, the included patients
resembled a general CVD population with regard to age, sex,
medical history, and medication use.
Perspectives
In this study, bedtime aspirin did not reduce blood pressure
in patients with stable CVD using low-dose aspirin on a daily
basis. So, we would not recommend switching to bedtime
intake of aspirin to reduce blood pressure in those patients.
Yet, bedtime aspirin intake did reduce platelet reactivity during morning hours. Future studies are needed to assess the
effect of this simple intervention on the excess of cardiovascular events during morning hours.
Figure 4. Effect of low-dose aspirin intake at bedtime versus on
awakening on morning platelet reactivity. Black bar represents
VerifyNow platelet reactivity values after aspirin intake on
awakening. Gray dashed bar represents values after aspirin
intake at bedtime.
Acknowledgments
We thank all laboratory technicians of the Leiden University Medical
Center (LUMC) Einthoven Laboratory for Experimental Vascular
Medicine for processing the biomaterial and all data managers of

the department of Clinical Epidemiology of the LUMC for their help
with the randomization of study subjects. We acknowledge Prof T.
Stijnen of the Department of Medical Statistics of the LUMC for
his statistical advice. We thank Margot de Waal and Henk de Jong
of the Department of Public Health and Primary care of the LUMC
for their help to include study participants. We express our gratitude
to the general practitioners and all patients who participated in this
study. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed
interpretation
Sources of Funding
This work was supported by the Netherlands Heart Foundation (grant
number 2010B171).
Disclosures
None.
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Domnguez MJ, Covelo M. Administration time-dependent effects of aspirin on blood pressure in untreated hypertensive patients. Hypertension.
2003;41:12591267. doi: 10.1161/01.HYP.0000072335.73748.0D.
9. Hermida RC, Ayala DE, Iglesias M. Administration time-dependent influence of aspirin on blood pressure in pregnant women. Hypertension.
2003;41(3 Pt 2):651656. doi: 10.1161/01.HYP.0000047876.63997.EE.
10. Hermida RC, Ayala DE, Calvo C, Lpez JE. Aspirin administered at
bedtime, but not on awakening, has an effect on ambulatory blood pressure in hypertensive patients. J Am Coll Cardiol. 2005;46:975983. doi:
10.1016/j.jacc.2004.08.071.
11. Hermida RC, Ayala DE, Mojn A, Fernndez JR. Ambulatory blood pressure control with bedtime aspirin administration in subjects with prehypertension. Am J Hypertens. 2009;22:896903. doi: 10.1038/ajh.2009.83.
12. Snoep JD, Hovens MM, Pasha SM, Frlich M, Pijl H, Tamsma JT,
Huisman MV. Time-dependent effects of low-dose aspirin on plasma
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2009;54:11361142. doi: 10.1161/HYPERTENSIONAHA.109.134825.
13. Hermida RC, Ayala DE, Calvo C, Lpez JE, Mojn A, Rodrguez M,
Fernndez JR. Differing administration time-dependent effects of aspirin
on blood pressure in dipper and non-dipper hypertensives. Hypertension.
2005;46:10601068. doi: 10.1161/01.HYP.0000172623.36098.4e.
14. Cohen MD, Rohtla BS, Lavery BS, Muller MD, Mittleman MD. Metaanalysis of the morning excess of acute myocardial infarction and sudden
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15. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich
SN, Gleason RE, Williams GH, Muller JE. Concurrent morning increase
in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:15141518. doi: 10.1056/
NEJM198706113162405.
16. Di Minno G, Silver MJ, Murphy S. Monitoring the entry of new platelets
into the circulation after ingestion of aspirin. Blood. 1983;61:10811085.
17. Patrono C, Ciabattoni G, Patrignani P, Pugliese F, Filabozzi P, Catella F,
Dav G, Forni L. Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation. 1985;72:11771184.
18. Grove EL, Hvas AM, Mortensen SB, Larsen SB, Kristensen SD. Effect
of platelet turnover on whole blood platelet aggregation in patients
with coronary artery disease. J Thromb Haemost. 2011;9:185191. doi:
10.1111/j.1538-7836.2010.04115.x.
19. Wrtz M, Hvas AM, Jensen LO, Kaltoft AK, Tilsted HH, Kristensen SD,
Grove EL. 24-hour antiplatelet effect of aspirin in patients with previous definite stent thrombosis. Int J Cardiol. 2014;175:274279. doi:
10.1016/j.ijcard.2014.05.013.
20. Cornlissen G, Halberg F, Prikryl P, Dankov E, Siegelov J, Dusek J.
Prophylactic aspirin treatment: the merits of timing. International Wombto-Tomb Chronome Study Group. JAMA. 1991;266:31283129.
21. Kriszbacher I, Ajtay Z, Koppn M, Bdis J. Can the time of taking
aspirin influence the frequency of cardiovascular events? Am J Cardiol.
2005;96:608610. doi: 10.1016/j.amjcard.2005.03.068.
22. Smith DH, Neutel JM, Lacourcire Y, Kempthorne-Rawson J. Prospective,
randomized, open-label, blinded-endpoint (PROBE) designed trials yield
the same results as double-blind, placebo-controlled trials with respect to
ABPM measurements. J Hypertens. 2003;21:12911298. doi: 10.1097/01.
hjh.0000059068.43904.0a.
23. Coleman JL, Wang JC, Simon DI. Determination of individual response to
aspirin therapy using the Accumetrics Ultegra RPFA-ASA System. Point
of Care. 2004;3:7782.
24. Madsen EH, Saw J, Kristensen SR, Schmidt EB, Pittendreigh C, MaurerSpurej E. Long-term aspirin and clopidogrel response evaluated by
light transmission aggregometry, VerifyNow, and thrombelastography
in patients undergoing percutaneous coronary intervention. Clin Chem.
2010;56:839847. doi: 10.1373/clinchem.2009.137471.
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HJH.0b013e328334f220.
26. Vaduganathan M, Alviar CL, Arikan ME, Tellez A, Guthikonda S,
DeLao T, Granada JF, Kleiman NS, Ballantyne CM, Lev EI. Platelet
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ahj.2008.08.002.
27. Abdali K, Taghizadeh R, Amoei S, Tabatabai SHR. Comparison between
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28. Dimitrov Y, Baguet JP, Hottelart C, Marboeuf P, Tartiere JM, Ducher M,
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29. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and
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30. Scheer FA, Michelson AD, Frelinger AL III, Evoniuk H, Kelly EE,
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31. Henry P, Vermillet A, Boval B, Guyetand C, Petroni T, Dillinger JG,
Sideris G, Sollier CB, Drouet L. 24-hour time-dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost.
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32. Bonten TN, Saris A, van Oostrom MJ, Snoep JD, Rosendaal FR, Zwaginga
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at bedtime versus on awakening on circadian rhythm of platelet reactivity.
A randomised cross-over trial. Thromb Haemost. 2014;112:12091218.
doi: 10.1160/TH14-05-0453.
33. Christensen KH, Grove EL, Wurtz M, Kristensen SD, Hvas AM. Reduced
antiplatelet effect of aspirin during 24 hours in patients with coronary
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34. Dillinger JG, Drissa A, Sideris G, Bal dit Sollier C, Voicu S, Manzo
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35. Perneby C, Walln NH, Rooney C, Fitzgerald D, Hjemdahl P. Doseand time-dependent antiplatelet effects of aspirin. Thromb Haemost.
2006;95:652658.

36. Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ten Berg
JM, Hackeng CM. High on-aspirin platelet reactivity as measured with aggregation-based, cyclooxygenase-1 inhibition sensitive platelet function tests is associated with the occurrence of
atherothrombotic events. J Thromb Haemost. 2010;8:21402148. doi:

10.1111/j.1538-7836.2010.04017.x.
37. Chen WH, Cheng X, Lee PY, Ng W, Kwok JY, Tse HF, Lau CP. Aspirin
resistance and adverse clinical events in patients with coronary artery disease. Am J Med. 2007;120:631635. doi: 10.1016/j.amjmed.2006.10.021.
38. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset
of acute cardiovascular disease. Circulation. 1989;79:733743.
39. Elliott WJ. Cyclic and circadian variations in cardiovascular events.
Am J Hypertens. 2001;14:291S295S.
Novelty and Significance

What Is New?
The blood pressure lowering effect of aspirin intake at bedtime has never
been studied in patients using aspirin for cardiovascular disease prevention

Whether aspirin intake at bedtime compared with intake on awakening
reduces morning platelet reactivity has never been studied.
What Is Relevant?
Taking aspirin at bedtime compared with on awakening did not reduce
blood pressure, which is in contrast with previous studies in healthy subjects
Platelet reactivity during morning hours was reduced by taking aspirin

at bedtime, which could possibly be beneficial for patients taking aspirin
on a daily basis.
Summary
In contrast to previous studies in other patient groups, bedtime intake of aspirin did not reduce blood pressure of patients taking
aspirin for prevention of cardiovascular disease. However, bedtime
intake of aspirin reduced platelet reactivity during the high risk
morning hours.
Time-Dependent Effects of Aspirin on Blood Pressure and Morning Platelet Reactivity: A

Randomized Cross-Over Trial
Tobias N. Bonten, Jaapjan D. Snoep, Willem J.J. Assendelft, Jaap Jan Zwaginga, Jeroen
Eikenboom, Menno V. Huisman, Frits R. Rosendaal and Johanna G. van der Bom
Hypertension. 2015;65:743-750; originally published online February 17, 2015;
doi: 10.1161/HYPERTENSIONAHA.114.04980
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2015 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
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World Wide Web at:
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http://hyper.ahajournals.org/content/suppl/2015/02/17/HYPERTENSIONAHA.114.04980.DC1.html
http://hyper.ahajournals.org/content/suppl/2016/04/10/HYPERTENSIONAHA.114.04980.DC2.html
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CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic
Item
No Checklist item
Reported
on page No
Title and abstract

1a
1b
Identification as a randomised trial in the title

Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts)
1
2,3
2a
2b
Scientific background and explanation of rationale

Specific objectives or hypotheses
4
5
Interventions
3a
3b
4a
4b
5
5,6
n.a
5,6
5,6
5,6
Outcomes
6a
Sample size
6b
7a
7b
Description of trial design (such as parallel, factorial) including allocation ratio

Important changes to methods after trial commencement (such as eligibility criteria), with reasons
Eligibility criteria for participants
Settings and locations where the data were collected
The interventions for each group with sufficient details to allow replication, including how and when they were
actually administered
Completely defined pre-specified primary and secondary outcome measures, including how and when they
were assessed
Any changes to trial outcomes after the trial commenced, with reasons
How sample size was determined
When applicable, explanation of any interim analyses and stopping guidelines
8a
8b
9
Method used to generate the random allocation sequence

Type of randomisation; details of any restriction (such as blocking and block size)
Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),
describing any steps taken to conceal the sequence until interventions were assigned
6
6
6
10
Who generated the random allocation sequence, who enrolled participants, and who assigned participants to
interventions
If done, who was blinded after assignment to interventions (for example, participants, care providers, those
5,6
Introduction
Background and
objectives
Methods
Trial design
Participants
Randomisation:
Sequence
generation
Allocation
concealment
mechanism
Implementation
Blinding
CONSORT 2010 checklist
11a
6,7,8
n.a
8
n.a.
n.a
Page 1
Statistical methods
Results
Participant flow (a
diagram is strongly
recommended)
Recruitment
11b
12a
12b
n.a
8,9
8,9
Ancillary analyses
17b
18
Harms
19
For each group, the numbers of participants who were randomly assigned, received intended treatment, and
were analysed for the primary outcome
For each group, losses and exclusions after randomisation, together with reasons
Dates defining the periods of recruitment and follow-up
Why the trial ended or was stopped
A table showing baseline demographic and clinical characteristics for each group
For each group, number of participants (denominator) included in each analysis and whether the analysis was
by original assigned groups
For each primary and secondary outcome, results for each group, and the estimated effect size and its
precision (such as 95% confidence interval)
For binary outcomes, presentation of both absolute and relative effect sizes is recommended
Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing
pre-specified from exploratory
All important harms or unintended effects in each group (for specific guidance see CONSORT for harms)
Discussion
Limitations
Generalisability
Interpretation
20
21
22
Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses
Generalisability (external validity, applicability) of the trial findings
Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence
16,17
17
15,16
Other information
Registration
Protocol
23
24
Registration number and name of trial registry

Where the full trial protocol can be accessed, if available
Funding
25
Sources of funding and other support (such as supply of drugs), role of funders
3, 5
Available from
authors
10
Baseline data
Numbers analysed
Outcomes and
estimation
13a
assessing outcomes) and how

If relevant, description of the similarity of interventions
Statistical methods used to compare groups for primary and secondary outcomes
Methods for additional analyses, such as subgroup analyses and adjusted analyses
13b
14a
14b
15
16
17a
11
11 (+figure 2)
11
n.a.
Table 1
11 + figure 2
11,12
n.a.
11,12
12,13
*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also
recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.
Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.
CONSORT 2010 checklist
Page 2
Online Supplement
Aspirin intake at bedtime: does it lower blood pressure and morning platelet
reactivity in patients with stable cardiovascular disease? A randomized crossover trial
Table S1
Table S2
Table S3
Table S4
Table S5
Table S1. Subgroup analysis of the effect of Aspirin intake on awakening or at bedtime on
mean 24-hour blood pressure
Subgroup
Difference (Bedtime
P-value
Awakening)
[95% CI]*
-blocker use
No
121
-0.3 [-1.7 to 1.2] / -0.8 [-1.7 to 0.2]
Yes
142
0.1 [-1.1 to 1.3] / -0.3 [-1.2 to 0.4]
No
106
-0.2 [-1.5 to 1.0] / -1.0 [-1.9 to -0.2]
Yes
157
0.0 [-1.3 to 1.4] / -0.2 [-1.0 to 0.6]
No
51
0.3 [-1.5 to 2.1] / -1.3 [-2.7 to 0.0]
Yes
212
-0.2 [-1.2 to 0.9] / -0.4 [-1.0 to 0.3]
>140 mmHg
92
0.9 [-0.8 to 2.5] / 0.0 [-1.1 to 1.2]
140 mmHg
171
-0.6 [-1.7 to 0.6] / -0.9 [-1.6 to -0.2]
0.80
Angiotensin inhibitor use
0.68
Blood pressure lowering drugs

use
0.78
Baseline systolic office blood

pressure
0.14
All blood pressure differences are depicted as systolic [95% CI] / diastolic [95% CI] blood
2
pressure, in mmHg;
*Mean difference and 95% confidence interval (CI) obtained from paired t-test within each
subgroup; P-value for interaction obtained from linear mixed model analysis; Angiotensin
receptor inhibitors: use of ace-inhibitors and/or angiotensin-2-inhibitors. Blood pressure
lowering drugs: -blockers, -blockers, ace-inhibitors, angiotensin-II inhibitors, calcium
antagonists, thiazide and loop diuretics, nitrates (daily use).
Table S2. Mean 24-hour, day- and night ambulatory blood pressure values
(mmHg) according to time of aspirin administration in the secondary analysis
population (n=150)
Value
Aspirin on
Aspirin at
Mean difference
awakening
bedtime
(bedtime
awakening)
[95% CI]*
24-hour SBP
125 10
125 9
0.0 [-1.1 to 1.1]
24-hour DBP
78 8
77 8
-0.4 [-1.2 to 0.3]
Day SBP
129 10
129 10
0.1 [-1.2 to 1.3]
Day DBP
81 9
80 8
-0.5 [-1.3 to 0.2]
Night SBP
115 12
115 12
0.0 [-1.5 to 1.5]
Night DBP
68 10
68 9
-0.2 [-1.2 to 0.7]
*Mean difference and 95% CI obtained with paired t-tests. Values are mean
standard deviation.
SBP: systolic blood pressure; DBP: diastolic blood pressure; CI: confidence
interval
Table S3. Subgroup analysis of the effect of low-dose aspirin intake on awakening or at
bedtime on morning platelet reactivity (n=133)
Subgroup
Aspirin on
Aspirin at
awakening
bedtime
Difference
(Bedtime - Awakening)
Pvalue
[95% CI]*
Diabetes
No
115
455 61
429 50
-26 [-40 to -13]
Yes
18
455 55
463 71
8 [-34 to 50]
18.5 25
37
452 52
425 52
-27 [-47 to -8]
25 30
60
454 66
439 58
-15 [-36 to 7]
0.41
30
36
459 58
432 51
-27 [-53 to -1]
0.94
No
110
453 60
433 57
-20 [-35 to -5]
Yes
23
463 61
433 43
-29 [-58 to -1]
441 57
424 57
-16 [-93 to 9]
0.03
BMI (kg/m2)
Smoking
Mean platelet
volume (fl),
quartile
(range)
1 (9.1
0.77
10.1)
2 (10.2
457 60
441 55
-10 [-46 to 25]
0.77
471 68
443 55
-25 [-53 to 4]
0.49
445 48
427 59
-18 [-45 to 9]
0.98
10.6)
3 (10.7
11.3)
4 (11.4
12.6)
All platelet reactivity values are depicted in Aspirin Reaction Units (ARU)standard
deviation. Higher ARU represents higher platelet reactivity.
* Mean difference and 95% CI obtained from paired t-test within each subgroup
P-value for interaction obtained from linear mixed model analysis
BMI classified according to World Health Organizations classification of obesity
P-value for interaction with the first group as reference group
Table S4. Side effects and relation with timing of aspirin intake of subjects that did not complete
study follow-up (n=26)
Patient
Period
Timing of
code
of drop-
Aspirin intake
side effect of
out
at drop-out
aspirin
At bedtime
105
Reason drop-out
Stopped aspirin use after advise
Related to
No
cardiologist
113
On awakening
Stomach pain after switch from
Yes
evening intake to intake on

awakening
132
At bedtime
Study participation too aggravating
No
151
On awakening
Withdrawal of consent to participate
No
in other clinical trial

173
At bedtime
No
180
At bedtime
No
250
On awakening
Stomach pain after switch from
Yes
evening intake to intake on

awakening
251
At bedtime
No
327
On awakening
No
329
At bedtime
Stopped aspirin use after head
No
trauma; advise of first aid physician

365
At bedtime

7
No
436
On awakening
No
447
On awakening
No
455
At bedtime
No
462
At bedtime
No
203
At bedtime
No
271
At bedtime
No
334
On awakening
Stopped aspirin use after advise
No
cardiologist
344
On awakening
No
366
On awakening
Switch to vitamin k antagonist
No
instead of aspirin after advise

cardiologist
368
On awakening
No

cardiologist
387
At bedtime
No

cardiologist
405
At bedtime
Did not want to take aspirin at
No
bedtime due to practical reasons

417
On awakening
No
465
At bedtime
Headache after switch from morning Possible

intake to intake at bedtime
437
On awakening
No
Table S5. Self-reported side effects of randomized study subjects at baseline and
subjects who completed study follow-up
Side effect
At Baseline
During study follow-up
(n=290), n (%)
(n=264), n (%)
Aspirin
Aspirin
on awakening
at bedtime
p-value*
Dyspepsia
15 (5.2)
12 (4.5)
12 (4.5)
1.00
Nausea
8 (2.8)
4 (1.5)
9 (3.4)
0.18
Heartburn
27 (9.3)
16 (6.1)
20 (7.6)
0.50
Nose bleeding
13 (4.5)
9 (3.4)
6 (2.3)
0.55
Bruises
45 (15.5)
32 (12.1)
35 (13.3)
0.75
Bloody stool
4 (1.4)
5 (1.9)
5 (1.9)
1.00
*P-value obtained by McNemars test
Ensayos clnicos
Efectos de la aspirina dependientes del tiempo sobre la
presin arterial y la reactividad plaquetaria por la maana
Estudio cruzado aleatorizado
Tobias N. Bonten, Jaapjan D. Snoep, Willem J.J. Assendelft, Jaap Jan Zwaginga,
Jeroen Eikenboom, Menno V. Huisman, Frits R. Rosendaal, Johanna G. van der Bom
Resumen: la aspirina es utilizada por millones de pacientes a diario para la prevencin de enfermedades cardiovasculares (ECV). Estudios anteriores sugieren que la toma de aspirina al acostarse reduce la presin arterial en comparacin con la toma al despertarse, hecho
que nunca se ha estudiado en pacientes con ECV. Adems, la reactividad plaquetaria y la incidencia de ECV son mayores durante las
horas de la maana. La toma de aspirina al acostarse puede atenuar la reactividad plaquetaria por la maana. El presente estudio clnico examin el efecto de la toma de aspirina al acostarse en comparacin con la toma al despertarse en la medicin ambulatoria de la
presin arterial de 24 horas y la reactividad plaquetaria por la maana en pacientes que utilizaban aspirina para la prevencin de ECV.
En el presente estudio aleatorizado, cruzado y sin enmascaramiento se aleatoriz a 290 pacientes a fin de que tomaran 100 mg de aspirina al despertarse o al acostarse durante 2 perodos de 3 meses. Al final de cada perodo, se analizaron la presin arterial de 24 horas
y la reactividad plaquetaria por la maana. La poblacin de anlisis primario incluy 263 pacientes (presin arterial) y 133 pacientes
(reactividad plaquetaria). La toma de aspirina al acostarse no redujo la presin arterial en comparacin con la toma al despertarse (diferencia sistlica/diastlica: 0,1 [intervalo de confianza del 95%, 1,0; 0,9]/0,6 [intervalo de confianza del 95%, 1,2; 0,0] mm Hg).
La reactividad plaquetaria en horas de la maana se redujo con la toma de aspirina al acostarse (diferencia: 22 unidades de reaccin a
la aspirina [intervalo de confianza del 95%, 35; 9]). La toma de una dosis baja de aspirina al acostarse en comparacin con la toma
al despertarse no redujo la presin arterial en pacientes con ECV. No obstante, la aspirina al acostarse redujo la actividad plaquetaria
por la maana. Se requieren futuros estudios para evaluar el efecto de esta prometedora y simple intervencin en el exceso de eventos
cardiovasculares durante las horas de alto riesgo de la maana. (Hypertension. 2015;65:743-750. DOI: 10.1161/ HYPERTENSIONAHA.114.04980.) Suplemento de informacin on-line
Palabras clave: aspirina presin arterial cronoterapia activacin plaquetaria
a enfermedad cardiovascular (ECV) contina siendo la

causa principal de morbimortalidad a nivel mundial.1,2 Uno
de los factores de riesgo modificable y de mayor importancia de
la ECV es la presin arterial. Incluso pequeas reducciones de la
presin arterial disminuyen significativamente el riesgo de infarto de miocardio y accidente cerebrovascular.3 No obstante, casi
la mitad de los pacientes con hipertensin continan sin controlarla, a pesar del uso de antihipertensivos.4 Por esta razn, resultan necesarias pequeas intervenciones para mejorar el control
de la presin arterial. Tradicionalmente se haba asumido que
la aspirina no produca ningn efecto sobre la presin arterial,5
pero en estudios recientes se demostr que la toma de aspirina
al acostarse en comparacin con la toma al despertarse redujo
considerablemente la presin arterial.6-11 Adems, anteriormente
hallamos que la toma de aspirina al acostarse en comparacin
la toma al despertarse redujo la actividad de la renina plasmtica y las excreciones de cortisol, dopamina y norepinefrina en el
transcurso de 24 horas.12 Sin embargo, todos los estudios pre-
vios incluyeron sujetos sanos, mujeres embarazadas o pacientes

con hipertensin leve.6-11,13 Si el efecto de la toma de aspirina al
acostarse sobre la presin arterial tambin se da en el caso de los
pacientes que ya estaban usando aspirina para la prevencin de
ECV, el simple cambio del momento de la toma de la hora de
despertarse a la hora de acostarse podra reducir sustancialmente
el riesgo de eventos cardiovasculares recurrentes.
Por otra parte, la agregacin plaquetaria alcanza su punto mximo durante las horas de la maana, lo que se considera que contribuye con el pico observado de ECV entre las 6 y las 12 a. m.14,15
Debido a su breve semivida, la aspirina solamente inhibe las
plaquetas que estn presentes en el horario de la toma, mientras
que en sujetos sanos se liberan nuevas plaquetas a una velocidad
del 10% por da.16,17 Por consiguiente, justo antes de cada toma
de aspirina, estas plaquetas recin liberadas no son inhibidas y
pueden inducir agregacin plaquetaria.18,19 No obstante, sera deseable lograr una inhibicin ptima de la agregacin plaquetaria,
en particular durante las horas de la maana de alto riesgo. Con-
Recibido el 25 de noviembre de 2014; primera decisin el 11 de diciembre de 2014; revisin aceptada el 25 de enero de 2015.
Del Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, los Pases Bajos (T.N.B., J.D.S., F.R.R., J.G.v.d.B.);
Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, los Pases Bajos (W.J.J.A.); Department of
Public Health and Primary Care, Leiden University Medical Center, Leiden, los Pases Bajos (W.J.J.A.); JJ van Rood Center for Clinical
Transfusion Research, Sanquin Research, Leiden, los Pases Bajos (J.J.Z., J.G.v.d.B.); y Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, los Pases Bajos (J.E., M.V.H.).
El suplemento de informacin con este artculo se encuentra disponible nicamente on-line en http://hyper.ahajourna]s.org/lookup/suppl/
doi:10.1161/HYPERTENSIONAHA. 114.04980/-/DC1
Dirigir la correspondencia a: T.N. Bonten, Leiden University Medical Center, Department of Clinical Epidemiology, C7-P, PO Box 9600,
2300 RC Leiden, The Netherlands. Correo electrnico t.n.bonten@lumc.nl
2015 American Heart Association, Inc.
Hypertension se encuentra disponible en http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.114.04980
Hypertension # 2-V2.indd 40
27/05/2015 10:40:16 a.m.
Bonten et al
forme a lo sugerido por autores anteriores, la toma de aspirina al

acostarse podra atenuar el pico de reactividad plaquetaria por la
maana, pero ese hecho nunca se evalu en un estudio clnico.20,21
Para evaluar si la toma de aspirina al acostarse en comparacin
con la toma al despertarse reduce la presin arterial y la reactividad plaquetaria por la maana, efectuamos un estudio cruzado y
aleatorizado en pacientes que utilizaban dosis bajas de aspirina
para la prevencin de ECV.
Mtodos
41
Presin arterial y toma de aspirina al acostarse
extraccin de sangre el da 2 fueron similares para cada paciente

en cada visita.
Criterios de valoracin
Presin arterial
Se midi la PA inicial mediante un dispositivo automtico (dispositivo Mobil-O-Graph NG; IEM GmbH, Alemania) cada 2
minutos en posicin sentada, despus de 10 minutos de descanso.
Se us un promedio de 6 mediciones para determinar la presin
Resumen del diseo
La Figura 1 presenta el resumen del diseo del estudio. Se efectu un estudio prospectivo, aleatorizado, sin enmascaramiento,
con criterio de valoracin enmascarado (PROBE), cruzado y con
2 perodos, en un centro nico en los Pases Bajos, y se registr en www.clinicaltrials.gov/ct2/show/NCT01379079. Se han
documentado previamente los beneficios del diseo PROBE y
su validez para estudios que miden la presin arterial ambulatoria.22 El estudio se efectu de conformidad con la Declaracin
de Helsinki, fue aprobado por el Comit de tica de Leiden University Medical Center (LUMC), y todos los sujetos otorgaron su
consentimiento informado por escrito.
Contexto y participantes
Se reclutaron pacientes de entre 18 y 75 aos de edad que tomaban dosis bajas (80-100 mg) de aspirina para la prevencin de
ECV secundaria, provenientes de consultorios de mdicos de
cabecera en Leiden, los Pases Bajos. Los criterios de exclusin
fueron presin arterial (PA) inicial <120/70 o >160/100 mm
Hg, uso de otros antiagregantes plaquetarios o anticoagulantes,
cambio de antihipertensivos en los 3 meses previos al perodo
inicial, uso de antiinflamatorios no esteroideos, tener un empleo
por turnos, indicios de hipertensin arterial secundaria (p. ej., feocromocitoma) y embarazo.
Aleatorizacin e intervenciones
Se llev a cabo la aleatorizacin con un cdigo de aleatorizacin

generado por computadora por parte de una persona independiente del Departamento de Epidemiologa Clnica del LUMC, el
cual fue inaccesible para los investigadores. Se aleatoriz a los
sujetos elegibles (proporcin 1:1) para tomar aspirina al despertarse, seguido de aspirina al acostarse, o en el orden opuesto, durante 2 perodos de intervencin de 3 meses (Figura 1). Los 2
perodos de intervencin no fueron separados por un perodo de
lavado debido a que no se consider tico la interrupcin de la
aspirina en los pacientes incluidos en el estudio. La duracin de
cada perodo de intervencin fue anloga a los estudios anteriores.9-11 Todos los sujetos recibieron 100 mg de aspirina efervescente (carbasalato clcico, Vemeda Manufacturing, los Pases
Bajos). Al final de cada perodo de intervencin, los sujetos visitaron el centro de investigacin durante 2 das consecutivos.
El da 1, se inici la medicin ambulatoria de la presin arterial
(MAPA) de 24 horas, entre las 8 y las 12 a. m. y los sujetos tomaron aspirina en el mismo horario que lo hicieron durante los 3
meses anteriores. El da 2, los sujetos se abstuvieron de tomar
aspirina por la maana, se detuvo la MAPA, y se les extrajo una
muestra de sangre. El horario del inicio de la MAPA el da 1 y la
Visita 1
Visita 2
3 meses
Visita 3
3 meses
Aspirina al despertarse
Aspirina al acostarse
290 pacientes
Figura 1. Diseo del estudio. Visita 1, Seleccin en funcin de los

criterios de inclusin y exclusin. Visitas 2 y 3, medicin ambulatoria
de presin arterial (MAPA), extraccin de sangre durante las horas de
la maana, cuestionario.
arterial inicial. Como criterio de valoracin primario, se llev a

cabo la MAPA durante la rutina diaria normal de los participantes
con un dispositivo Mobil-O-Graph NG (IEM GmbH, Alemania)
validado y calibrado. Las mediciones comenzaron entre las 8 y
12 a. m., y se us el mismo dispositivo en cada visita. Se ajust
el manguito del esfigmomanmetro a la circunferencia del brazo
y se coloc en el brazo no dominante. Se midieron automticamente la PA sistlica y diastlica cada 20 minutos durante el da y
cada 30 minutos por la noche durante 24 horas consecutivas, con
la pantalla apagada para que los sujetos no vieran las mediciones
de la PA. En el diario se registraron los horarios en los que el
sujeto se acost y se despert. La MAPA se consider vlida si
70% de las mediciones resultaron vlidas, si el tiempo de sueo
durante la MAPA fue de entre 6 y 12 horas, y si no faltaron datos
durante > 2 horas.
Reactividad plaquetaria
Como criterio de valoracin secundario, se midi la reactividad

plaquetaria durante las horas de la maana (entre las 8 y 12 a. m.).
La maana que se extrajo la muestra de sangre, los sujetos se abstuvieron de tomar aspirina. Se extrajeron muestras de sangre sin
estasis de la vena antecubital, se midi la reactividad plaquetaria
con VerifyNow Aspirin Assay (Accumetrics, San Diego, EE.
UU.) y se inform en unidades de reaccin a la aspirina (aspirin
reaction units, ARU).23
Cuestionarios, cumplimiento y preferencia del

paciente
Los sujetos completaron un cuestionario para evaluar los

criterios de elegibilidad, los antecedentes mdicos, el uso de
medicamentos y el ritmo cronobiolgico en el perodo inicial.
27/05/2015 10:40:16 a.m.
42
Hypertension
Junio 2015
Se complet la informacin faltante con los registros del mdico

de cabecera o de la farmacia. En cada visita de seguimiento, se
registraron los efectos secundarios y el cambio de medicacin
mediante cuestionarios. Los sujetos recibieron indicaciones de
tomar la aspirina dentro de la hora de haberse despertado o una
hora antes de acostarse. Se evalu el cumplimiento y se optimiz
con pastilleros electrnicos (Evalan, msterdam, los Pases
Bajos) que registraron el horario de la toma del medicamento y
enviaron un mensaje de texto (SMS) en caso de que los sujetos
no cumplieran. Adems, en cada visita se realiz el recuento
de comprimidos. Los participantes y los mdicos de cabecera
recibieron indicaciones de no cambiar un medicamento ni iniciar
la administracin de uno nuevo durante el estudio, lo que se
verific mediante cuestionarios en cada visita de seguimiento.
Anlisis estadstico
Para detectar una diferencia interindividual de 3 mm Hg en la

presin arterial con 80% de potencia en un nivel de significacin
del 5%, calculamos un tamao de muestra requerido de 250 pacientes. Asumimos una desviacin estndar intraindividual de
12,9 mm Hg, segn result de un estudio anterior.12 Con una es-
Inicio del estudio: septiembre de 2011

Finalizacin del estudio: septiembre 2013
timacin de abandono del 10% y una MAPA invlida del 5%,

aleatorizamos a 290 sujetos. Tal como se planific de antemano,
se midi la reactividad plaquetaria en los primeros 160 pacientes
consecutivos, lo cual arroj una potencia del 90% para detectar
una diferencia de 17 ARU a un nivel de significacin del 5%.
Para este clculo, usamos una desviacin estndar intraindividual
de 46,85 ARU.24 Las caractersticas continuas se describen como
media desviacin estndar (DE) si se distribuyen normalmente;
de lo contrario, se describen como mediana (amplitud intercuartlica [AIC]). Las variables categricas se expresan como nmeros (porcentajes). Los valores de MAPA se editaron de acuerdo
con los criterios convencionales para eliminar los errores de
medicin y los valores atpicos. Debido a que la frecuencia de la
toma de muestras fue ms densa durante el da (3 veces/hora) que
durante la noche (2 veces/hora), calculamos una media ponderada de la PA general, tal como se sugiri previamente 25:
(media de PA diurna x cantidad de mediciones diurnas) + (media de PA nocturna x cantidad de mediciones nocturnas)
cantidad de mediciones diurnas + cantidad de mediciones nocturnas
Se calcul la media de PA diurna y nocturna como
Evaluados a los fines de

elegibilidad (n = 3.479)
Aleatorizados (n = 290)
Asignados a toma diurna (n = 145)

Visita 2 (3 meses)
Retiro de consentimiento (n = 6)
Participacin muy agravante (n = 4)
Dispepsia (n = 2)
Asignacin
Seguimiento
suma de las mediciones diurnas o nocturnas

cantidad de mediciones diurnas o nocturnas
No incluidos (n = 3.189)
No cumplieron con los criterios de inclusin
(n =1.704)
Rehusaron participar (n = 655)
No respondieron la invitacin (n = 527)
Excluidos por otras razones* (n = 303)
Asignados a la toma nocturna (n = 145)

Visita 2 (3 meses)
Dej de tomar aspirina (n = 2)
Pasaron a toma nocturna (n = 139)
Pasaron a toma diurna (n = 136)
Visita 3 (6 meses)
Dej de tomar aspirina (n = 1)
Visita 3 (6 meses)
Dej de tomar aspirina (n = 3))
Completaron el perodo del estudio de

6 meses (n = 134)
Completaron el perodo del estudio de

6 meses (n = 130)
Poblacin de anlisis primario

Criterio de valoracin primario: MAPA (n = 134)
Criterio de valoracin secundario: reactividad
plaquetaria (n = 71)
Poblacin de anlisis secundario (n = 73)
Excluidos (n = 61)
MAPA invlida en visita 1 y/o visita 2 (n = 30)
Cambio de antihipertensivos (n = 8)
Cumplimiento durante todo el estudio
<90% (n = 23)
Poblaciones de anlisis
Poblacin de anlisis primario

Criterio de valoracin primario: MAPA (n = 129 )
Criterio de valoracin secundario: reactividad
plaquetaria (n = 65)
Poblacin de anlisis secundario (n = 77)
Excluidos (n = 52)
MAPA invlida en visita 1 y/o visita 2 (n = 27)
Cambio de antihipertensivos (n = 6)
Cumplimiento durante todo el estudio
< 90% (n = 19)
Figura 2. Distribucin de pacientes. MAPA indica medicin ambulatoria de la presin arterial. *Otras razones: dej de tomar aspirina antes de la
inclusin, no pudo participar en el estudio clnico segn el criterio del mdico de cabecera, se mud, no habla holands. Un sujeto se neg a la
MAPA en la ltima visita de seguimiento.
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Bonten et al
Tabla 1. Caractersticas clnicas iniciales de los participantes

del estudio aleatorizados (n = 290)*
Variable
Sexo (M/F)
Edad, aos
Grupo de toma
de aspirina al
despertarseal
acostarse (n =
145)
Grupo de toma
de aspirina al
acostarseal
despertarse (n =
145)
106/39
106/39
647
647
21 (15)
28 (19)
ndice de masa corporal, kg/m2
28,44,7
28-14,6
Presin arterial sistlica, mm Hg
13710
13710
Fumadores actuales
Presin arterial diastlica, mm Hg
888
888
17 (12)
14 (10)
Infarto de miocardio
53 (37)
59 (41)
Angina de pecho estable
59 (41)
61 (42)
Accidente cerebrovascular /
accidente isqumico transitorio
28 (19)
23 (16)
Fibrilacin auricular
14 (10)
13 (9)
Arteriopata perifrica
12 (8)
9 (6)
Otro
3 (2)
1 (1)
Diabetes
Antecedentes cardiovasculares
Uso de aspirina en el perodo

inicial
Al despertarse
106 (73)
100 (69)
Duracin, aos
6 (3-11)
6 (4-14)
Cantidad de frmacos antihipertensivos
2 (1-2,5)
2 (1-3)
-bloqueantes
74 (51)
80 (55)
Inhibidores de la ECA
60 (41)
55 (38)
Inhibidores de la angiotensina II
37 (26)
33 (23)
Antagonistas del calcio
29 (20)
27 (19)
Uso de medicacin
Diurticos
37 (26)
46 (32)
Hipolipemiantes
116 (80)
123 (85)
*Los valores continuos se presentan como media desviacin estndar

(DE) o medianas + amplitud intercuartlica si se distribuyen normalmente.
Los valores categricos se presentan como nmero (%).
Otras enfermedades cardiovasculares: enfermedad de la vlvula
cardaca (n = 3), sndrome mielodisplsico (n = 1).
Antihipertensivos: -bloqueantes, -bloqueantes, inhibidores de la
ECA, inhibidores de la angiotensina II, antagonistas del calcio, diurticos
tiazdicos y del asa, nitratos (uso diario).
De los diarios se obtuvieron los horarios de inicio del da o

de la noche. El criterio de valoracin primario se evalu en la
poblacin de anlisis primario y secundario. La poblacin de
anlisis primario incluy a todos los sujetos aleatorizados que
completaron las mediciones de los criterios de valoracin. La poblacin de anlisis secundario excluy a sujetos con 1 MAPA
invlida, cambio de antihipertensivos o cumplimiento < 90%.
Se realizaron las pruebas de la t para datos apareados a fin de
analizar la PA diurna, nocturna y media general despus de la
toma de aspirina al despertarse y al acostarse. Adems, se usaron
modelos lineales mixtos para evaluar los efectos del tratamiento y
43
los efectos del perodo o residuales. Se especificaron previamente

anlisis de subgrupos para usuarios de -bloqueantes, inhibidores
del sistema renina-angiotensina (usuarios frente a no usuarios),
usuarios frente a no usuarios de 1 antihipertensivo y sujetos
con PA sistlica inicial > 140 frente a 140 mm Hg.
Se analiz criterio de valoracin secundario de reactividad
plaquetaria con la prueba de la t para datos apareados y modelos lineales mixtos. Los sujetos que olvidaron tomar aspirina el
da anterior a la medicin de la reactividad plaquetaria (n = 3)
quedaron excluidos del anlisis. Se especificaron previamente los
anlisis de subgrupos para sujetos con diabetes, fumadores actuales (s vs. no) y valores promedio del volumen plaquetario (dividido en cuartiles). A pesar de que no se especific previamente,
se llev a cabo un anlisis de subgrupo adicional en funcin del
ndice de masa corporal debido a que la obesidad, como marcador del sndrome metablico, puede estar relacionada con la reactividad plaquetaria.26 Los efectos secundarios y las preferencias
de los pacientes se analizaron de manera descriptiva y utilizando
la prueba de McNemar. Todos los anlisis se llevaron a cabo con
SPSS 20.0 (IBM corp., EE. UU.) y fueron bilaterales, con un nivel de significacin de 0,05.
Resultados
Poblacin del estudio y cumplimiento
Entre junio de 2011 y marzo de 2013, se seleccion a 3.479 sujetos en 30 consultorios de mdicos de cabecera de los cuales 1.704
no cumplieron con los criterios de inclusin, fundamentalmente
debido a la edad de > 75 aos (n = 1.080) y el uso de otros frmacos de inhibicin plaquetaria (n = 386; Figura 2). Se aleatoriz un
total de 290 sujetos, y las caractersticas iniciales fueron similares
entre los grupos (Tabla 1). El seguimiento del estudio se discontinu por parte de 26 sujetos, principalmente porque la participacin en el estudio era demasiado agravante (18/26; 70%). Las
poblaciones de anlisis primario y secundario comprendieron 263
y 150 sujetos, respectivamente, para la evaluacin del criterio de
valoracin primario. Las mediciones a los fines de la reactividad
plaquetaria del criterio de valoracin secundario estuvieron completas en 136 sujetos. El cumplimiento, conforme a lo medido
por los pastilleros electrnicos y el recuento de comprimidos, fue
elevado y similar entre la toma de aspirina al despertarse (99%
[97%-100%] y 100% [100%-100%], respectivamente) y la toma
al acostarse (98% [94%-100%] y 100% [100%-100%]).
Presin arterial
El perfil circadiano de MAPA de 24 horas despus de 3 meses

de toma de aspirina al despertarse y 3 meses de toma de aspirina al acostarse se exhibe en la Figura 3. La media (DE) de la
presin arterial sistlica y diastlica de 24 horas fue de 127 (12)
y 79 (9) mm Hg con toma de aspirina al despertarse, mientras
que con toma de aspirina al acostarse fue de 127 (12) y 78 (8);
esto dio como resultado diferencias de 0,1 mm Hg (intervalo
de confianza del 95%, 1,0 a 0,9) y 0,6 mm Hg (intervalo de
confianza del 95%, 1,2 a 0,0). Adems, los valores de la presin
arterial sistlica y diastlica diurna y nocturna no difirieron con
el horario de la toma de aspirina (Tabla 2). El anlisis de modelos
mixtos demostr los mismos resultados y ninguna evidencia de
efectos residuales o del perodo (datos no mostrados). Adems,
los hallazgos entre los subgrupos de sujetos que usaban o no
27/05/2015 10:40:17 a.m.
44
Hypertension
Junio 2015
Presin arterial sistlica (mm Hg)
Media de 24 horas al despertarse: 127,2

Media de 24 horas al acostarse: 127,2
Horario (horas despus de despertarse)

Presin arterial diastlica (mm Hg)
Media de 24 horas al despertarse: 78,6

Media de 24 horas al acostarse 78, 0
Horario (horas despus de despertarse)
Figura 3. Efecto de la toma de una dosis baja de aspirina al acostarse en comparacin con una toma al despertarse en el perfil de presin arterial
ambulatoria de 24 horas en la poblacin de anlisis primario (n = 263). A, presin arterial sistlica. B, presin arterial diastlica. Cada grfico muestra medias y errores estndar por hora de la presin arterial medida con una toma de dosis baja de aspirina al despertarse (lnea negra continua) y
una toma de dosis baja de aspirina al acostarse (lnea gris discontinua). Las horas en el eje x se refieren a las horas despus de despertarse de un
perodo de sueo nocturno. El rea sombreada representa el perodo nocturno promedio de todos los sujetos.
-bloqueantes, inhibidores de la angiotensina, antihipertensivos

en general o sujetos con PA inicial en consultorio de > 140 o
140 mm Hg fueron similares a los resultados generales (Tabla S1
del Suplemento de informacin on-line). Finalmente, en el anlisis secundario, que comprendi nicamente a los pacientes con
MAPA vlida en ambas visitas que no cambiaron su medicacin

antihipertensiva entre la visita 2 y la visita 3, y que cumplieron
el tratamiento 90%, segn lo registrado por los pastilleros electrnicos, la toma de aspirina al acostarse no se relacion con una
reduccin del valor promedio de la presin arterial de 24 horas o
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Bonten et al
Tabla 2. Valores promedio de presin arterial ambulatoria

diurna y nocturna (mm Hg), de 24 horas, de acuerdo con el horario de administracin de aspirina en la poblacin de anlisis
primario (n = 263)
Aspirina al
despertarse
Aspirina al
acostarse
Diferencia
promedio (al
acostarseal
despertarse)
(IC del 95%)*
PAS de 24 horas
12712
12712
0,1 [1,0 a 0,9]
PAD de 24 horas
799
788
0,6 [1,2 a 0,0]
PAS diurna
13112
13112
0,0 [1,0 a 1,0]
PAD diurna
829
819
0,6 [1,2 a 0,1]
PAS nocturna
11715
11714
0,1 [1,4 a 1,1]
PAD nocturna
6910
699
0,4 [1,2 a 0,3]
Valor
*La diferencia promedio y el IC del 95% obtenidos con pruebas de la t

apareadas. Los valores son media desviacin estndar.
IC indica intervalo de confianza; PAD, presin arterial diastlica; y PAS,
presin arterial sistlica.
la presin arterial diurna y nocturna (Tabla S2).
45
9]; P = 0,001; Figura 4). El anlisis de subgrupos demostr que,

adems de los sujetos con diabetes mellitus, la toma de aspirina al
acostarse redujo la reactividad plaquetaria en todos los subgrupos
(Tabla S3).
Efectos secundarios y preferencia del paciente
Tres sujetos no completaron el estudio a causa de efectos secundarios (Tabla S4). La frecuencia de los efectos secundarios de la
aspirina ya conocidos (dispepsia, nuseas, ardor de estmago)
fue similar entre la toma de aspirina al despertarse y al acostarse
(Tabla S5).
Despus de completar el estudio, 53/264 (20%) prefirieron
cambiar el horario de la toma de aspirina en comparacin con antes del ingreso al estudio. Un total de 32/264 (12%) pasaron de la
toma al despertarse a la toma al acostarse, y 21/264 (8%) pasaron
de la toma al acostarse a la toma al despertarse. En consecuencia,
no se hall una preferencia clara por parte de los pacientes en
cuanto al horario de la toma de aspirina.
Discusin
En este estudio cruzado a gran escala realizado en pacientes que

usaban una dosis baja de aspirina para la prevencin de ECV, la
presin arterial de 24 horas no present diferencia con la toma
de aspirina al acostarse y la toma de aspirina al despertarse. No
obstante, la toma de aspirina al acostarse se relacion con una
menor reactividad plaquetaria por la maana.
Reactividad plaquetaria
Hubo tres sujetos que olvidaron tomar aspirina el da anterior a

la medicin de reactividad plaquetaria (n = 3) y fueron excluidos
del anlisis. En el resto de los 133 sujetos, la toma de aspirina al
acostarse redujo la reactividad plaquetaria por la maana (diferencia promedio 22 ARU [intervalo de confianza del 95% 35 a
Diferencia promedio: 22 ARU (p = 0,001)
Al despertarse
Al acostarse
Hora de toma de la aspirina
Figura 4. Efecto de la toma de una dosis baja aspirina al acostarse

versus al despertarse en la reactividad plaquetaria por la maana. La
barra negra representa los valores de reactividad plaquetaria segn
VerifyNow despus de la toma de aspirina al despertarse. La barra
gris discontinua representa los valores despus de la toma de aspirina
al acostarse.
Comparacin con estudios previos
Numerosos estudios previos, en su mayora provenientes de una

nica fuente en este campo, informaron un efecto reductor de la
presin arterial con la toma de aspirina al acostarse.6-11,13,27 Posteriormente, nuestro grupo hall un mecanismo biolgico admisible subyacente a este fenmeno: la toma de aspirina al acostarse,
en comparacin con la toma al despertarse, redujo la actividad
de la renina plasmtica y las excreciones de cortisol, dopamina y
norepinefrina a lo largo de 24 horas.12 De esta manera, el hallazgo
de que la toma de aspirina al acostarse en comparacin con la
toma al despertarse no reduce la presin arterial se opone a estos
estudios anteriores. Esto puede explicarse por las diferencias en
las poblaciones de estudio. En primer lugar, los estudios previos
incluyeron sujetos que no usaban antihipertensivos, como -bloqueantes o inhibidores del sistema renina-angiotensina-aldosterona. Se trata de una diferencia importante debido a que el mecanismo detrs del efecto de la aspirina dependiente del tiempo sobre
la presin arterial estaba relacionado previamente con una reduccin en el sistema renina-angiotensina-aldosterona y la actividad
de las catecolaminas en el transcurso de 24 horas.12 No obstante,
no se hall ningn efecto con el uso o no de -bloqueantes o inhibidores del sistema renina-angiotensina-aldosterona. Incluso en
el subgrupo que no us ningn antihipertensivo, no se registr
ningn efecto. Nuestros hallazgos corroboran aquellos de un estudio anterior que tampoco hall un efecto reductor de la presin
arterial con la toma de aspirina al acostarse en los pacientes hipertensos tratados.28 En segundo lugar, los pacientes de todos los
estudios previos no usaban aspirina antes de su ingreso al estudio. En contraposicin, todos los pacientes de nuestro estudio
tenan indicacin mdica de tomar aspirina y lo hicieron durante
una mediana de 6 aos. Es posible que el efecto de la aspirina
dependiente del tiempo sobre la presin arterial se debilite con
el transcurso del tiempo debido al aumento de rigidez arterial.29
27/05/2015 10:40:17 a.m.
46
Hypertension
Junio 2015
No obstante, un posible efecto reductor de la presin arterial con

la toma de aspirina al acostarse solo sera relevante en trminos
clnicos en pacientes que ya usaban aspirina para la prevencin
de ECV, y nosotros somos los primeros en este campo en incluir
a este grupo de pacientes relevante desde el punto de vista clnico.
Dada la ausencia de un efecto reductor de la presin arterial con
la aspirina al acostarse en cualquiera de los subgrupos de nuestro
estudio, en nuestra opinin, no se requieren estudios adicionales
para evaluar el efecto reductor de la presin arterial con la aspirina al acostarse en pacientes que usan aspirina para la prevencin
de ECV.
El ritmo circadiano de la reactividad plaquetaria y su relacin
con el pico matutino de eventos cardiovasculares se ha estudiado exhaustivamente.15,30 Los autores anteriores sugirieron que la
inhibicin plaquetaria durante las horas matutinas de alto riesgo podra optimizarse con la toma de aspirina al acostarse.20,21
Los estudios posteriores claramente demuestran que el efecto
antiagregante plaquetario de la aspirina declina durante el intervalo de administracin de 24 horas.18,19,31 En nuestro estudio,
comparamos la funcin plaquetaria 12 horas despus de la toma
de aspirina (toma al acostarse) con una toma 24 horas despus
(toma al despertarse). De esta manera, podra haberse esperado
una declinacin en la actividad plaquetaria durante las horas de
la maana. Sin embargo, a nuestro leal entender, esto nunca se
ha evaluado en un estudio clnico. Adems, la reduccin de la
reactividad plaquetaria durante las horas matutinas de alto riesgo
podra ser clnicamente relevante para los pacientes con ECV.
Previamente estudiamos el efecto de la aspirina dependiente
del tiempo sobre la reactividad plaquetaria por la maana en sujetos sanos.32 Los resultados de este estudio confirman estos hallazgos en pacientes que usan aspirina a diario. Nuestro estudio
sugiere que la reactividad plaquetaria por la maana puede reducirse mediante la toma de aspirina al acostarse en lugar de la toma
al despertarse. Este efecto estuvo presente homogneamente en
todos los subgrupos, excepto en el caso de los sujetos diabticos.
No obstante, el tamao de este subgrupo fue demasiado reducido (n = 18) para descartar cualquier efecto en los pacientes diabticos. Asimismo, los pacientes diabticos tienen un recambio
plaquetario mayor, y la administracin de aspirina dos veces al
da produce una inhibicin plaquetaria ms efectiva a lo largo de
todo el da en dichos pacientes.33,34 La reduccin de la reactividad plaquetaria durante las horas vulnerables de la maana podra
ser beneficiosa para los pacientes con ECV, quienes tienen mayor
recambio plaquetario, y de los cuales, en el 25%, la reactividad
plaquetaria es inhibida inadecuadamente 24 horas despus de la
toma de aspirina.31,35
tudios observacionales sugieren que una reduccin de la reactividad plaquetaria podra derivar en un beneficio clnico para los
pacientes con ECV. Debido a que el pico matutino de ECV es
un proceso multifactorial, no esperamos que la toma de aspirina al acostarse pueda abolir completamente el pico matutino de
ECV.38 Aun as, dada la alta prevalencia de ECV, una modesta
reduccin en el pico matutino dara como resultado un enorme
beneficio absoluto. Por ejemplo, en los Estados Unidos se producen 280.000 eventos cardiovasculares recurrentes al ao, con
un riesgo excedente conocido del 40% en horas de la maana.39
Si la toma de aspirina al acostarse redujera este pico matutino en
un 20%, dara como resultado una reduccin absoluta de 4.853
eventos recurrentes al ao, nicamente en los Estados Unidos.
Por lo tanto, el cambio a toma de aspirina al acostarse es una
intervencin simple y posiblemente efectiva. Futuros estudios
deberan evaluar si esto, de hecho, se traduce en una reduccin de
eventos cardiovasculares.
Interpretacin clnica
En el presente estudio, la aspirina al acostarse no redujo la presin

arterial en pacientes con ECV que tomaban una dosis baja aspirina a diario. Por lo tanto, no recomendaramos pasar a la toma
de aspirina al acostarse para reducir la presin arterial en dichos
pacientes. Aun as, la toma de aspirina al acostarse s redujo la
reactividad plaquetaria durante horas de la maana. Se requieren
futuros estudios para evaluar el efecto de esta simple intervencin
en el exceso de eventos cardiovasculares durante las horas de la
maana.
Se ha demostrado que el riesgo de eventos cardiovasculares recurrentes se incrementa en pacientes con valores ms elevados
de reactividad plaquetaria, segn VerifyNow-aspirin.36,37 Los
pacientes con ECV estable y con reactividad plaquetaria > 550
ARU tuvieron un riesgo absoluto del 15,6% de desarrollar el criterio de valoracin cardiovascular compuesto, mientras que en
los pacientes con valores ARU < 550 dicho riesgo fue slo del
5,3% .37 En otro estudio, el riesgo absoluto en funcin de criterio
de valoracin primario (muerte por todas las causas y eventos
cardiovasculares recurrentes) fue del 13,3% en pacientes con >
454 ARU y del 5,9% en pacientes con < 454 ARU.36 Estos es-
Fortalezas y limitaciones
La principal fortaleza de nuestro estudio es el diseo cruzado, que

arroja una alta potencia estadstica y permite la comparacin de
los efectos del tratamiento en cada paciente. Adems, el presente
estudio es el primero en este campo que registr el horario real
de la toma de aspirina mediante pastilleros electrnicos, lo cual
es de gran importancia para los efectos dependientes del tiempo
del estudio.
La principal limitacin de nuestro estudio es que solo 150/263
(57%) pacientes cumplieron el protocolo del estudio a la perfeccin. Esto se debi principalmente a una MAPA invlida (n =
57) o un cumplimiento < 90% dentro del horario preespecificado
para la toma de la aspirina (n = 42). No obstante, los anlisis de
sensibilidad entre los pacientes con seguimiento y cumplimiento completos revelaron los mismos resultados con intervalos de
confianza estrechos (Tabla S2). Respecto de las mediciones de reactividad plaquetaria, el hecho de medir la reactividad plaquetaria solamente en un momento predeterminado durante la maana
constituye una limitacin, a pesar de que la comparabilidad entre
sujetos se optimiz al extraer sangre a la misma hora en cada visita. Una amplia proporcin de los pacientes potencialmente elegibles no respondi o no quiso participar en el presente estudio. No
obstante, los pacientes incluidos se asemejaron a una poblacin
general con ECV en lo que respecta a edad, sexo, antecedentes
mdicos y uso de medicacin.
Perspectivas
Agradecimientos
Agradecemos a todos los tcnicos de laboratorio de Leiden Uni-
27/05/2015 10:40:17 a.m.
Bonten et al
versity Medical Center (LUMC) Einthoven Laboratory for Experimental Vascular Medicine por procesar el material biolgico, y a
todos los gerentes de datos del Departamento de Epidemiologa
Clnica del LUMC por su colaboracin en la aleatorizacin de los
sujetos del estudio. Agradecemos al Prof. T. Stijnen del Departamento de Estadstica Mdica del LUMC por su asesoramiento en
estadstica. Tambin agradecemos a Margot de Waal y Henk de
Jong del Departamento de Salud Pblica y Atencin Primaria del
LUMC por su ayuda con respecto a la inclusin de participantes
en el estudio. Expresamos nuestra gratitud a los mdicos de cabecera y todos los pacientes que fueron parte de este estudio. Todos los autores asumen su responsabilidad por todos los aspectos
referidos a la confiabilidad y la libertad de sesgos de los datos
presentados y su interpretacin analizada.
Fuentes de financiamiento
El presente trabajo fue financiado por Netherlands Heart Foundation (nmero de subsidio 2010B171).
Ninguno.
Conflictos de inters
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Novedad y Significado
Qu es nuevo?
El efecto reductor en la presin arterial con la toma de aspirina
al acostarse nunca se haba estudiado en pacientes que usaban
aspirina para la prevencin de enfermedad cardiovascular.
Nunca se ha estudiado si la toma de aspirina al acostarse en
comparacin con la toma al despertarse reduce la reactividad plaquetaria por la maana.
Qu es relevante?
La reactividad plaquetaria durante las horas de la maana se redujo con la toma de aspirina al acostarse, lo cual podra ser beneficioso para los pacientes que toman aspirina a diario.
Resumen
A diferencia de estudios previos realizados en otros grupos de pacientes,

la toma de aspirina al acostarse no redujo la presin arterial en pacientes
que tomaban aspirina para prevenir enfermedades cardiovasculares. No
obstante, la toma de aspirina al acostarse redujo la reactividad plaquetaria
durante las horas matutinas de alto riesgo.
La toma de aspirina al acostarse en comparacin con la toma

al despertarse no redujo la presin arterial, lo cual se opone a los
estudios previos realizados en pacientes sanos.
27/05/2015 10:40:17 a.m.

Monitoring The Entry of New Platelets Into The Circulation After Ingestion of Aspirin

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Monitoring The Entry of New Platelets Into The Circulation After Ingestion of Aspirin

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Clinical Trials

Time-Dependent Effects of Aspirin on Blood Pressure and

Key Words: aspirin

already use aspirin for CVD prevention, simply changing the

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744Hypertension April 2015

Setting and Participants

Randomization and Interventions

Baseline BP was measured by an automatic device (Mobil-O-Graph

to determine baseline blood pressure. As the primary end point,

As a secondary end point, platelet reactivity was measured during

Questionnaires, Compliance, and Patient Preference

Subjects completed a questionnaire to assess eligibility criteria, medical

Mean day and night BP was calculated as

Figure 1. Study design. Visit 1, Screening for inclusive and

sum day or night measurements

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Bonten et al Blood Pressure and Bedtime Aspirin 745

Assessed for eligibility (n=3479)

Study completion: September 2013

Allocated to evening intake (n=145)

Not included (n=3189)

Allocated to evening intake (n=145)

Crossed over to evening intake (n=139)

Crossed over to morning intake (n=136)

Completed 6 month study period (n=134)

Completed 6 month study period (n=130)

Primary analysis population

Primary analysis population

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746Hypertension April 2015

Body mass index, kg/m2

Systolic blood pressure,

Diastolic blood pressure,

Stable angina pectoris

Aspirin use at baseline

Lipid lowering drugs

Comparison With Previous Studies

*Continuous values are presented as meansstandard deviation (SD) or

[95% confidence interval 35 to 9]; P=0.001; Figure4).

Side Effects and Patient Preference

Multiple previous studies, mostly from a single source in this

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Bonten et al Blood Pressure and Bedtime Aspirin 747

intake) with 24 hours after intake (morning intake). So, a

Previously, we studied the time-dependent effect of aspirin

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748Hypertension April 2015

0.1 [1.0 to 0.9]

0.6 [1.2 to 0.0]

0.1 [1.4 to 1.1]

0.4 [1.2 to 0.3]

0.0 [1.0 to 1.0]

all subgroups, except in diabetic subjects. However, the size

Strengths and Limitations

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Bonten et al Blood Pressure and Bedtime Aspirin 749

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750Hypertension April 2015

atherothrombotic events. J Thromb Haemost. 2010;8:21402148. doi:

Novelty and Significance

been studied in patients using aspirin for cardiovascular disease prevention

Stable angina pectoris

Lipid lowering drugs