monitoring the entry of new platelets into the circulation after ingestion of aspirin

743

Cardiovascular disease (CVD) is still a leading cause of mor-tality and morbidity worldwide.1,2 One of the most impor-

tant 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 awak-ening considerably reduced blood pressure.6–11 Additionally, we previously found that aspirin intake at bedtime compared with on awakening reduced plasma renin activity and cortisol, dopa-mine and norepinephrine excretions over 24 hours.12 However, all previous studies included healthy subjects, pregnant women, or patients with mild hypertension.6–11,13 If the effect of bedtime aspirin intake on blood pressure also holds for patients who

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 plate-let 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 plate-let 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

Abstract—Aspirin 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] mm Hg). 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 ■ chronotherapy ■ platelet activation

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 Box 9600, 2300 RC Leiden, the Netherlands. E-mail [email protected]

Time-Dependent Effects of Aspirin on Blood Pressure and Morning Platelet ReactivityA 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

© 2015 American Heart Association, Inc.

Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.114.04980

Clinical Trials

by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from

http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.114.04980/-/DC1



mailto:[email protected]

http://hyper.ahajournals.org/
























744 Hypertension April 2015

platelet reactivity, we conducted a randomized crossover trial in patients using low-dose aspirin for prevention of CVD.

Methods

Design OverviewAn overview of the study design is depicted in Figure 1. A prospec-tive, 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 ParticipantsPatients between 18 and 75 years of age using low-dose (80–100 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 mm Hg, use of other antiplatelet or anticoagulant drugs, change of antihypertensive medication in the 3 months before baseline, use of nonsteroidal anti-inflammatory drugs, employment as shift worker, evidence of secondary arterial hypertension (eg, pheochromocytoma), and pregnancy.

Randomization and InterventionsRandomization was performed with a computer-generated random-ization code by an independent person at the Department of Clinical Epidemiology of the LUMC and was inaccessible to the investiga-tors. 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 (Figure 1). The 2 inter-vention periods were not separated by a wash-out period because withholding aspirin to the included patients was considered unethi-cal. The duration of each intervention period was analogous to pre-vious studies.9–11 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 PressureBaseline BP was measured by an automatic device (Mobil-O-Graph NG device; IEM GmbH, Germany) every 2 minutes in seated posi-tion 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 dia-stolic 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 awak-ening 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 ReactivityAs 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 PreferenceSubjects 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 per-formed 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 AnalysisTo detect an interindividual difference of 3 mm Hg in blood pres-sure with 80% power at a 5% significance level, we calculated a required sample size of 250 patients. We assumed an intraindivid-ual standard deviation of 12.9 mm Hg, 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 reac-tivity was measured in the first consecutive 160 patients, yielding a power of 90% to detect a difference of 17 ARU at a 5% signifi-cance level. For this calculation, we used an intraindividual standard deviation of 46.85 ARU.24 Continuous characteristics are described as mean±standard 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 × × nnight measurements) + nr day measurements nr night measuremments

Mean day and night BP was calculated as sum day or night measurements

day or night nr measurements

The start of day- and nighttimes was obtained from diaries. The pri-mary end point was assessed in a primary and secondary analysis popu-lation. 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 β-blockers, inhibi-tors of the renin–angiotensin system (users versus nonusers), users of no- versus ≥1 blood pressure lowering drugs, and subjects with baseline systolic BP of >140 versus ≤140 mm Hg.

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.

by guest on May 3, 2016http://hyper.ahajournals.org/Downloaded from

http://www.clinicaltrials.gov/ct2/show/NCT01379079


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 be-cause obesity, as a marker for metabolic syndrome, may be associated with platelet reactivity.26 Side effects and patient preferences were analyzed descriptively and using McNemar’s 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 ComplianceBetween 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; Figure 2). A total of 290 subjects were randomized, and base-line characteristics were similar between groups (Table 1). 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 plate-let 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%]).

Blood PressureThe circadian 24-hour ABPM profile after 3 months aspi-rin intake on awakening and 3 months intake at bedtime is depicted in Figure 3. The mean (SD) 24-hour systolic and dia-stolic blood pressures were 127 (12) and 79 (9) mm Hg with aspirin intake on awakening, whereas these were 127 (12) and 78 (8) with aspirin at bedtime. This resulted in differences of −0.1 mm Hg (95% confidence interval, −1.0 to 0.9) and −0.6 mm Hg (95% confidence interval, −1.2 to 0.0). Furthermore, systolic and diastolic blood pressures during day- and night-time did not differ by the timing of aspirin intake (Table 2). Mixed model analysis showed the same results and no evi-dence for carry-over or period effects (data not shown). Additionally, findings among subgroups of subjects using or not using β-blockers, angiotensin inhibitors, blood pressure lowering drugs in general, or subjects with baseline office BP >140 or ≤140 mm Hg were similar to the overall results (Table S1 in the online-only Data Supplement). Finally, in the sec-ondary analysis, comprising only patients with valid ABPM at both visits who did not change their antihypertensive medica-tion between visit 2 and 3 and were ≥90% compliant as regis-tered with electronic pill boxes, aspirin intake at bedtime was not associated with a reduction of mean 24-hour blood pres-sure or day- and nighttime blood pressure (Table S2).

Platelet ReactivityThree subjects forgot to take aspirin on the day before platelet reactivity measurements and were excluded from this analy-sis. In the remaining 133 subjects, aspirin intake at bedtime reduced morning platelet reactivity (mean difference −22 ARU

Assessed for eligibility (n=3479)

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) 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)

Crossed over to evening intake (n=139)


Participation too aggravating (n=7) Stopped aspirin use (n=2)

Crossed over to morning intake (n=136)



Completed 6 month study period (n=134)

Allocation

Study start: September 2011

Study completion: September 2013



Completed 6 month study period (n=130)

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)

Primary analysis populationPrimary 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)

Primary analysis population Primary endpoint: ABPM (n=134) Secondary endpoint: Platelet reactivity (n=71)

Follow-up

Analysis populations

Allocated to evening intake (n=145)

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.




[95% confidence interval −35 to −9]; P=0.001; Figure 4). Subgroup analysis showed that, besides in subjects with dia-betes mellitus, aspirin intake at bedtime reduced platelet reac-tivity in all subgroups (Table S3).

Side Effects and Patient PreferenceThree 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

entry. A total of 32/264 (12%) switched from intake on awak-ening 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.

DiscussionIn 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 awak-ening. However, aspirin intake at bedtime was associated with lower morning platelet reactivity.

Comparison With Previous StudiesMultiple previous studies, mostly from a single source in this field, reported a blood pressure lowering effect of bedtime aspirin intake.6–11,13,27 Subsequently, our group found a bio-logical 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 find-ing 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 sub-jects who did not use blood pressure lowering drugs, such as β-blockers or inhibitors of the renin–angiotensin–aldo-sterone 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–angiotensin–aldosterone system and catecholamine activity over 24 hours.12 However, we did not find an effect in both users and nonusers of β-blockers or renin–angiotensin–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 bed-time aspirin in patients using aspirin for CVD prevention.

The circadian rhythm of platelet reactivity and its rela-tion with the morning peak of cardiovascular events has been thoroughly studied.15,30 Previous authors suggested that plate-let 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 com-pared platelet function 12 hours after aspirin intake (bedtime

Table 1. Baseline Clinical Characteristics of Randomized Study Participants (n=290)*

VariableAwakening—Bedtime

Group (n=145)Bedtime—Awakening

Group (n=145)

Sex (M/F) 106/39 106/39

Age, y 64±7 64±7

Current smokers 21 (15) 28 (19)

Body mass index, kg/m2 28.4±4.7 28·1±4.6

Systolic blood pressure, mm Hg

137±10 137±10

Diastolic blood pressure, mm Hg

88±8 88±8

Diabetics 17 (12) 14 (10)

Cardiovascular history

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)

Other† 3 (2) 1 (1)

Aspirin use at baseline

On awakening 106 (73) 100 (69)

Duration, y 6 (3–11) 6 (4–14)

Medication use

Number of blood pressure lowering drugs‡

2 (1–2.5) 2 (1–3)

β-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)

Lipid lowering drugs 116 (80) 123 (85)

*Continuous values are presented as means±standard 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: β-blockers, α-blockers, ace-inhibitors, angiotensin-II inhibitors, calcium antagonists, thiazide and loop diuretics, nitrates (daily use).




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 aspi-rin 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

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.




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 dia-betic 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 InterpretationIt 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 devel-oping 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 reac-tivity 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 recur-rent 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 morn-ing 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 LimitationsThe major strength of our study is its crossover design, which yields high statistical power and enables comparison of treat-ment 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 impor-tance 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 con-fidence 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.

PerspectivesIn 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 dur-ing morning hours. Future studies are needed to assess the effect of this simple intervention on the excess of cardiovas-cular events during morning hours.

AcknowledgmentsWe 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

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.

Table 2. Mean 24-Hour, Day and Night Ambulatory Blood Pressure Values (mm Hg) According to Time of Aspirin Administration in the Primary Analysis Population (n=263)

Value Aspirin on Awakening Aspirin at Bedtime

Mean Difference (Bedtime–Awakening)

(95% CI)*

24-hour SBP 127±12 127±12 −0.1 [−1.0 to 0.9]

24-hour DBP 79±9 78±8 −0.6 [−1.2 to 0.0]

Day SBP 131±12 131±12 0.0 [−1.0 to 1.0]

Day DBP 82±9 81±9 −0.6 [−1.2 to 0.1]

Night SBP 117±15 117±14 −0.1 [−1.4 to 1.1]

Night DBP 69±10 69±9 −0.4 [−1.2 to 0.3]

*Mean difference and 95% CI obtained with paired t-tests. Values are mean±standard deviation.

CI indicates confidence interval; DBP, diastolic blood pressure; and SBP, systolic blood pressure.




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 reliabil-ity and freedom from bias of the data presented and their discussed interpretation

Sources of FundingThis work was supported by the Netherlands Heart Foundation (grant number 2010B171).

DisclosuresNone.

References 1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association

Statistics Committee and Stroke Statistics Subcommittee. Heart dis-ease and stroke statistics–2013 update: a report from the American Heart Association. Circulation. 2013;127:e6–e245. doi: 10.1161/CIR.0b013e31828124ad.

2. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe: epidemiological update. Eur Heart J. 2013;34:3028–3034. doi: 10.1093/eurheartj/eht356.

3. Turnbull F; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovas-cular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527–1535.

4. Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation. 2011;124:1046–1058. doi: 10.1161/CIRCULATIONAHA.111.030189.

5. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflamma-tory drugs affect blood pressure? A meta-analysis. Ann Intern Med. 1994;121:289–300.

6. Hermida RC, Fernández JR, Ayala DE, Iglesias M, Halberg F. Time-dependent effects of ASA administration on blood pressure in healthy subjects. Chronobiologia. 1994;21:201–213.

7. Hermida RC, Ayala DE, Fernández JR, Mojón A, Alonso I, Silva I, Ucieda R, Codesido J, Iglesías M. Administration time-dependent effects of aspi-rin in women at differing risk for preeclampsia. Hypertension. 1999;34(4 Pt 2):1016–1023.

8. Hermida RC, Ayala DE, Calvo C, López JE, Fernández JR, Mojón A, Domínguez MJ, Covelo M. Administration time-dependent effects of aspi-rin on blood pressure in untreated hypertensive patients. Hypertension. 2003;41:1259–1267. doi: 10.1161/01.HYP.0000072335.73748.0D.

9. Hermida RC, Ayala DE, Iglesias M. Administration time-dependent influ-ence of aspirin on blood pressure in pregnant women. Hypertension. 2003;41(3 Pt 2):651–656. doi: 10.1161/01.HYP.0000047876.63997.EE.

10. Hermida RC, Ayala DE, Calvo C, López JE. Aspirin administered at bedtime, but not on awakening, has an effect on ambulatory blood pres-sure in hypertensive patients. J Am Coll Cardiol. 2005;46:975–983. doi: 10.1016/j.jacc.2004.08.071.

11. Hermida RC, Ayala DE, Mojón A, Fernández JR. Ambulatory blood pres-sure control with bedtime aspirin administration in subjects with prehy-pertension. Am J Hypertens. 2009;22:896–903. doi: 10.1038/ajh.2009.83.

12. Snoep JD, Hovens MM, Pasha SM, Frölich M, Pijl H, Tamsma JT, Huisman MV. Time-dependent effects of low-dose aspirin on plasma renin activity, aldosterone, cortisol, and catecholamines. Hypertension. 2009;54:1136–1142. doi: 10.1161/HYPERTENSIONAHA.109.134825.

13. Hermida RC, Ayala DE, Calvo C, López JE, Mojón A, Rodríguez M, Fernández JR. Differing administration time-dependent effects of aspirin on blood pressure in dipper and non-dipper hypertensives. Hypertension. 2005;46:1060–1068. doi: 10.1161/01.HYP.0000172623.36098.4e.

14. Cohen MD, Rohtla BS, Lavery BS, Muller MD, Mittleman MD. Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol. 1997;79:1512–1516.

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 sud-den cardiac death. N Engl J Med. 1987;316:1514–1518. 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;61:1081–1085.

17. Patrono C, Ciabattoni G, Patrignani P, Pugliese F, Filabozzi P, Catella F, Davì G, Forni L. Clinical pharmacology of platelet cyclooxygenase inhi-bition. Circulation. 1985;72:1177–1184.

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;9:185–191. doi: 10.1111/j.1538-7836.2010.04115.x.

19. Würtz M, Hvas AM, Jensen LO, Kaltoft AK, Tilsted HH, Kristensen SD, Grove EL. 24-hour antiplatelet effect of aspirin in patients with previ-ous definite stent thrombosis. Int J Cardiol. 2014;175:274–279. doi: 10.1016/j.ijcard.2014.05.013.

20. Cornélissen G, Halberg F, Prikryl P, Danková E, Siegelová J, Dusek J. Prophylactic aspirin treatment: the merits of timing. International Womb-to-Tomb Chronome Study Group. JAMA. 1991;266:3128–3129.

21. Kriszbacher I, Ajtay Z, Koppán M, Bódis J. Can the time of taking aspirin influence the frequency of cardiovascular events? Am J Cardiol. 2005;96:608–610. doi: 10.1016/j.amjcard.2005.03.068.

22. Smith DH, Neutel JM, Lacourcière 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;21:1291–1298. 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;3:77–82.

24. Madsen EH, Saw J, Kristensen SR, Schmidt EB, Pittendreigh C, Maurer-Spurej E. Long-term aspirin and clopidogrel response evaluated by light transmission aggregometry, VerifyNow, and thrombelastography in patients undergoing percutaneous coronary intervention. Clin Chem. 2010;56:839–847. doi: 10.1373/clinchem.2009.137471.

25. Octavio JA, Contreras J, Amair P, Octavio B, Fabiano D, Moleiro F, Omboni S, Groppelli A, Bilo G, Mancia G, Parati G. Time-weighted vs. conventional quantification of 24-h average systolic and diastolic ambu-latory blood pressures. J Hypertens. 2010;28:459–464. doi: 10.1097/HJH.0b013e328334f220.

26. Vaduganathan M, Alviar CL, Arikan ME, Tellez A, Guthikonda S, DeLao T, Granada JF, Kleiman NS, Ballantyne CM, Lev EI. Platelet reactivity and response to aspirin in subjects with the metabolic syn-drome. Am Heart J. 2008;156:1002.e1–1002.e7. doi: 10.1016/j.ahj.2008.08.002.

27. Abdali K, Taghizadeh R, Amoei S, Tabatabai SHR. Comparison between aspirin and placebo on the mean of 24 hour blood pressure in pregnant women at preeclampsia risk, a double blind randomized controlled clini-cal trial. IJCBNM. 2013;1:83–91.

28. Dimitrov Y, Baguet JP, Hottelart C, Marboeuf P, Tartiere JM, Ducher M, Fauvel JP. Is there a BP benefit of changing the time of aspirin administra-tion in treated hypertensive patients? Eur J Prev Cardiol. 2012;19:706–711. doi: 10.1177/1741826711418165.

29. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25:932–943. doi: 10.1161/01.ATV.0000160548.78317.29.

30. Scheer FA, Michelson AD, Frelinger AL III, Evoniuk H, Kelly EE, McCarthy M, Doamekpor LA, Barnard MR, Shea SA. The human endog-enous circadian system causes greatest platelet activation during the bio-logical morning independent of behaviors. PLoS One. 2011;6:e24549. doi: 10.1371/journal.pone.0024549.

31. Henry P, Vermillet A, Boval B, Guyetand C, Petroni T, Dillinger JG, Sideris G, Sollier CB, Drouet L. 24-hour time-dependent aspirin effi-cacy in patients with stable coronary artery disease. Thromb Haemost. 2011;105:336–344. doi: 10.1160/TH10-02-0082.

32. Bonten TN, Saris A, van Oostrom MJ, Snoep JD, Rosendaal FR, Zwaginga J, Eikenboom J, van der Meer PF, van der Bom JG. Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity. A randomised cross-over trial. Thromb Haemost. 2014;112:1209–1218. 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 artery disease and type 2 diabetes. Platelets. In press.

34. Dillinger JG, Drissa A, Sideris G, Bal dit Sollier C, Voicu S, Manzo Silberman S, Logeart D, Drouet L, Henry P. Biological efficacy of twice




daily aspirin in type 2 diabetic patients with coronary artery disease. Am Heart J. 2012;164:600–606.e1. doi: 10.1016/j.ahj.2012.06.008.

35. Perneby C, Wallén NH, Rooney C, Fitzgerald D, Hjemdahl P. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost. 2006;95:652–658.

36. Breet NJ, van Werkum JW, Bouman HJ, Kelder JC, Ten Berg JM, Hackeng CM. High on-aspirin platelet reactivity as mea-sured with aggregation-based, cyclooxygenase-1 inhibition sen-sitive platelet function tests is associated with the occurrence of

atherothrombotic events. J Thromb Haemost. 2010;8:2140–2148. 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 dis-ease. Am J Med. 2007;120:631–635. 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;79:733–743.

39. Elliott WJ. Cyclic and circadian variations in cardiovascular events. Am J Hypertens. 2001;14:291S–295S.

What Is New?•The blood pressure lowering effect of aspirin intake at bedtime has never

been studied in patients using aspirin for cardiovascular disease preven-tion

•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 sub-jects

•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 in-take 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.

Novelty and Significance



Eikenboom, Menno V. Huisman, Frits R. Rosendaal and Johanna G. van der BomTobias N. Bonten, Jaapjan D. Snoep, Willem J.J. Assendelft, Jaap Jan Zwaginga, Jeroen

Randomized Cross-Over TrialTime-Dependent Effects of Aspirin on Blood Pressure and Morning Platelet Reactivity: A

Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 2015 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Hypertension doi: 10.1161/HYPERTENSIONAHA.114.04980

2015;65:743-750; originally published online February 17, 2015;Hypertension.

http://hyper.ahajournals.org/content/65/4/743World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://hyper.ahajournals.org/content/suppl/2016/04/10/HYPERTENSIONAHA.114.04980.DC2.html http://hyper.ahajournals.org/content/suppl/2015/02/17/HYPERTENSIONAHA.114.04980.DC1.html

Data Supplement (unedited) at:

http://hyper.ahajournals.org//subscriptions/

is online at: Hypertension Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer this process is available in the

click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialHypertensionin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:


http://hyper.ahajournals.org/content/65/4/743

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

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://hyper.ahajournals.org//subscriptions/


CONSORT 2010 checklist Page 1

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 Identification as a randomised trial in the title 1

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

Introduction

Background and

objectives

2a Scientific background and explanation of rationale 4

2b Specific objectives or hypotheses 5

Methods

Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 5,6

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons n.a

Participants 4a Eligibility criteria for participants 5,6

4b Settings and locations where the data were collected 5,6

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were

actually administered

5,6

Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they

were assessed

6,7,8

6b Any changes to trial outcomes after the trial commenced, with reasons n.a

Sample size 7a How sample size was determined 8

7b When applicable, explanation of any interim analyses and stopping guidelines n.a.

Randomisation:

Sequence

generation

8a Method used to generate the random allocation sequence 6

8b Type of randomisation; details of any restriction (such as blocking and block size) 6

Allocation

concealment

mechanism

9 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

Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to

interventions

5,6

Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those n.a

CONSORT 2010 checklist Page 2

assessing outcomes) and how

11b If relevant, description of the similarity of interventions n.a

Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 8,9

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 8,9

Results

Participant flow (a

diagram is strongly

recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and

were analysed for the primary outcome

11

13b For each group, losses and exclusions after randomisation, together with reasons 11 (+figure 2)

Recruitment 14a Dates defining the periods of recruitment and follow-up 11

14b Why the trial ended or was stopped n.a.

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group Table 1

Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was

by original assigned groups

11 + figure 2

Outcomes and

estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and its

precision (such as 95% confidence interval)

11,12

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended n.a.

Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing

pre-specified from exploratory

11,12

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) 12,13

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 16,17

Generalisability 21 Generalisability (external validity, applicability) of the trial findings 17

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 15,16

Other information

Registration 23 Registration number and name of trial registry 3, 5

Protocol 24 Where the full trial protocol can be accessed, if available Available from

authors

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 10

*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.

http://www.consort-statement.org/

1

Online Supplement

Aspirin intake at bedtime: does it lower blood pressure and morning platelet

reactivity in patients with stable cardiovascular disease? A randomized cross-

over trial

Table S1

Table S2

Table S3

Table S4

Table S5

2

Table S1. Subgroup analysis of the effect of Aspirin intake on awakening or at bedtime on

mean 24-hour blood pressure

Subgroup n Difference (Bedtime –

Awakening)

[95% CI]*

P-value†

β-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] 0.80

Angiotensin inhibitor use‡

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] 0.68

Blood pressure lowering drugs

use§

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] 0.78

Baseline systolic office blood

pressure

>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] 0.14

All blood pressure differences are depicted as systolic [95% CI] / diastolic [95% CI] blood

3

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: β-blockers, α-blockers, ace-inhibitors, angiotensin-II inhibitors, calcium

antagonists, thiazide and loop diuretics, nitrates (daily use).

4

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

awakening

Aspirin at

bedtime

Mean difference

(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

5

Table S3. Subgroup analysis of the effect of low-dose aspirin intake on awakening or at

bedtime on morning platelet reactivity (n=133)

Subgroup n Aspirin on

awakening

Aspirin at

bedtime

Difference

(Bedtime - Awakening)

[95% CI]*

P-

value†

Diabetes

No 115 455 ± 61 429 ± 50 -26 [-40 to -13]

Yes 18 455 ± 55 463 ± 71 8 [-34 to 50] 0.03

BMI (kg/m2)‡

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§

Smoking

No 110 453 ± 60 433 ± 57 -20 [-35 to -5]

Yes 23 463 ± 61 433 ± 43 -29 [-58 to -1] 0.77

Mean platelet

volume (fl),

quartile

(range)

1 (9.1 – 441 ± 57 424 ± 57 -16 [-93 to 9]

6

10.1)

2 (10.2 –

10.6)

457 ± 60 441 ± 55 -10 [-46 to 25] 0.77§

3 (10.7 –

11.3)

471 ± 68 443 ± 55 -25 [-53 to 4] 0.49§

4 (11.4 –

12.6)

445 ± 48 427 ± 59 -18 [-45 to 9] 0.98§

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

7

Table S4. Side effects and relation with timing of aspirin intake of subjects that did not complete

study follow-up (n=26)

Patient

code

Period

of drop-

out

Timing of

Aspirin intake

at drop-out

Reason drop-out Related to

side effect of

aspirin

105 1 At bedtime Stopped aspirin use after advise

cardiologist

No

113 1 On awakening Stomach pain after switch from

evening intake to intake on

awakening

Yes

132 1 At bedtime Study participation too aggravating No

151 1 On awakening Withdrawal of consent to participate

in other clinical trial

No



250 1 On awakening Stomach pain after switch from

evening intake to intake on

awakening

Yes


327 1 On awakening Study participation too aggravating No

329 1 At bedtime Stopped aspirin use after head

trauma; advise of first aid physician

No


8







334 2 On awakening Stopped aspirin use after advise

cardiologist

No


366 2 On awakening Switch to vitamin k antagonist

instead of aspirin after advise

cardiologist

No

368 2 On awakening Switch to vitamin k antagonist


cardiologist

No

387 2 At bedtime Switch to vitamin k antagonist


cardiologist

No

405 2 At bedtime Did not want to take aspirin at

bedtime due to practical reasons

No


465 2 At bedtime Headache after switch from morning

intake to intake at bedtime

Possible


9

Table S5. Self-reported side effects of randomized study subjects at baseline and

subjects who completed study follow-up

Side effect At Baseline

(n=290), n (%)

During study follow-up

(n=264), n (%)

Aspirin

on awakening

Aspirin

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 McNemar’s test

Ensayos clínicosEfectos de la aspirina dependientes del tiempo sobre la

presión arterial y la reactividad plaquetaria por la mañanaEstudio 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

Recibido el 25 de noviembre de 2014; primera decisión el 11 de diciembre de 2014; revisión aceptada el 25 de enero de 2015.Del Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, los Países 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 Países Bajos (W.J.J.A.); Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, los Países Bajos (W.J.J.A.); JJ van Rood Center for Clinical Transfusion Research, Sanquin Research, Leiden, los Países Bajos (J.J.Z., J.G.v.d.B.); y Department of Thrombosis and Hemostasis, Lei-den University Medical Center, Leiden, los Países Bajos (J.E., M.V.H.).

El suplemento de información con este artículo se encuentra disponible únicamente 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 electrónico [email protected]

© 2015 American Heart Association, Inc.

Resumen: la aspirina es utilizada por millones de pacientes a diario para la prevención de enfermedades cardiovasculares (ECV). Estudi-os anteriores sugieren que la toma de aspirina al acostarse reduce la presión arterial en comparación con la toma al despertarse, hecho que nunca se ha estudiado en pacientes con ECV. Además, la reactividad plaquetaria y la incidencia de ECV son mayores durante las horas de la mañana. La toma de aspirina al acostarse puede atenuar la reactividad plaquetaria por la mañana. El presente estudio clíni-co examinó el efecto de la toma de aspirina al acostarse en comparación con la toma al despertarse en la medición ambulatoria de la presión arterial de 24 horas y la reactividad plaquetaria por la mañana en pacientes que utilizaban aspirina para la prevención de ECV. En el presente estudio aleatorizado, cruzado y sin enmascaramiento se aleatorizó a 290 pacientes a fin de que tomaran 100 mg de aspi-rina al despertarse o al acostarse durante 2 períodos de 3 meses. Al final de cada período, se analizaron la presión arterial de 24 horas y la reactividad plaquetaria por la mañana. La población de análisis primario incluyó 263 pacientes (presión arterial) y 133 pacientes (reactividad plaquetaria). La toma de aspirina al acostarse no redujo la presión arterial en comparación con la toma al despertarse (dif-erencia sistólica/diastólica: –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 mañana se redujo con la toma de aspirina al acostarse (diferencia: –22 unidades de reacción a la aspirina [intervalo de confianza del 95%, –35; –9]). La toma de una dosis baja de aspirina al acostarse en comparación con la toma al despertarse no redujo la presión arterial en pacientes con ECV. No obstante, la aspirina al acostarse redujo la actividad plaquetaria por la mañana. Se requieren futuros estudios para evaluar el efecto de esta prometedora y simple intervención en el exceso de eventos cardiovasculares durante las horas de alto riesgo de la mañana. (Hypertension. 2015;65:743-750. DOI: 10.1161/ HYPERTENSIO-NAHA.114.04980.) • Suplemento de información on-line

Palabras clave: aspirina ■ presión arterial ■ cronoterapia ■ activación plaquetaria

La enfermedad cardiovascular (ECV) continúa 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 presión arterial. Incluso pequeñas reducciones de la presión arterial disminuyen significativamente el riesgo de infar-to de miocardio y accidente cerebrovascular.3 No obstante, casi la mitad de los pacientes con hipertensión continúan sin contro-larla, a pesar del uso de antihipertensivos.4 Por esta razón, resul-tan necesarias pequeñas intervenciones para mejorar el control de la presión arterial. Tradicionalmente se había asumido que la aspirina no producía ningún efecto sobre la presión arterial,5 pero en estudios recientes se demostró que la toma de aspirina al acostarse en comparación con la toma al despertarse redujo considerablemente la presión arterial.6-11 Además, anteriormente hallamos que la toma de aspirina al acostarse en comparación la toma al despertarse redujo la actividad de la renina plasmáti-ca 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 hipertensión leve.6-11,13 Si el efecto de la toma de aspirina al acostarse sobre la presión arterial también se da en el caso de los pacientes que ya estaban usando aspirina para la prevención de ECV, el simple cambio del momento de la toma –de la hora de despertarse a la hora de acostarse– podría reducir sustancialmente el riesgo de eventos cardiovasculares recurrentes.

Por otra parte, la agregación plaquetaria alcanza su punto máx-imo durante las horas de la mañana, lo que se considera que con-tribuye 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 están presentes en el horario de la toma, mientras que en sujetos sanos se liberan nuevas plaquetas a una velocidad del 10% por día.16,17 Por consiguiente, justo antes de cada toma de aspirina, estas plaquetas recién liberadas no son inhibidas y pueden inducir agregación plaquetaria.18,19 No obstante, sería de-seable lograr una inhibición óptima de la agregación plaquetaria, en particular durante las horas de la mañana de alto riesgo. Con-

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.

41Bonten et al Presión arterial y toma de aspirina al acostarse

forme a lo sugerido por autores anteriores, la toma de aspirina al acostarse podría atenuar el pico de reactividad plaquetaria por la mañana, pero ese hecho nunca se evaluó en un estudio clínico.20,21

Para evaluar si la toma de aspirina al acostarse en comparación con la toma al despertarse reduce la presión arterial y la reactivi-dad plaquetaria por la mañana, efectuamos un estudio cruzado y aleatorizado en pacientes que utilizaban dosis bajas de aspirina para la prevención de ECV.

MétodosResumen del diseñoLa Figura 1 presenta el resumen del diseño del estudio. Se efec-tuó un estudio prospectivo, aleatorizado, sin enmascaramiento, con criterio de valoración enmascarado (PROBE), cruzado y con 2 períodos, en un centro único en los Países Bajos, y se regis-tró en www.clinicaltrials.gov/ct2/show/NCT01379079. Se han documentado previamente los beneficios del diseño PROBE y su validez para estudios que miden la presión arterial ambulato-ria.22 El estudio se efectuó de conformidad con la Declaración de Helsinki, fue aprobado por el Comité de Ética de Leiden Uni-versity Medical Center (LUMC), y todos los sujetos otorgaron su consentimiento informado por escrito.

Contexto y participantesSe reclutaron pacientes de entre 18 y 75 años de edad que tom-aban dosis bajas (80-100 mg) de aspirina para la prevención de ECV secundaria, provenientes de consultorios de médicos de cabecera en Leiden, los Países Bajos. Los criterios de exclusión fueron presión 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 período inicial, uso de antiinflamatorios no esteroideos, tener un empleo por turnos, indicios de hipertensión arterial secundaria (p. ej., fe-ocromocitoma) y embarazo.

Aleatorización e intervencionesSe llevó a cabo la aleatorización con un código de aleatorización generado por computadora por parte de una persona independi-ente del Departamento de Epidemiología Clínica del LUMC, el cual fue inaccesible para los investigadores. Se aleatorizó a los sujetos elegibles (proporción 1:1) para tomar aspirina al desper-tarse, seguido de aspirina al acostarse, o en el orden opuesto, du-rante 2 períodos de intervención de 3 meses (Figura 1). Los 2 períodos de intervención no fueron separados por un período de lavado debido a que no se consideró ético la interrupción de la aspirina en los pacientes incluidos en el estudio. La duración de cada período de intervención fue análoga a los estudios anteri-ores.9-11 Todos los sujetos recibieron 100 mg de aspirina efer-vescente (carbasalato cálcico, Vemeda Manufacturing, los Países Bajos). Al final de cada período de intervención, los sujetos vis-itaron el centro de investigación durante 2 días consecutivos. El día 1, se inició la medición ambulatoria de la presión arterial (MAPA) de 24 horas, entre las 8 y las 12 a. m. y los sujetos toma-ron aspirina en el mismo horario que lo hicieron durante los 3 meses anteriores. El día 2, los sujetos se abstuvieron de tomar aspirina por la mañana, se detuvo la MAPA, y se les extrajo una muestra de sangre. El horario del inicio de la MAPA el día 1 y la

extracción de sangre el día 2 fueron similares para cada paciente en cada visita.

Criterios de valoración

Presión arterialSe midió la PA inicial mediante un dispositivo automático (dis-positivo Mobil-O-Graph NG; IEM GmbH, Alemania) cada 2 minutos en posición sentada, después de 10 minutos de descanso. Se usó un promedio de 6 mediciones para determinar la presión

arterial inicial. Como criterio de valoración primario, se llevó 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 usó el mismo dispositivo en cada visita. Se ajustó el manguito del esfigmomanómetro a la circunferencia del brazo y se colocó en el brazo no dominante. Se midieron automática-mente la PA sistólica y diastólica cada 20 minutos durante el día 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 acostó y se despertó. La MAPA se consideró válida si ≥ 70% de las mediciones resultaron válidas, si el tiempo de sueño durante la MAPA fue de entre 6 y 12 horas, y si no faltaron datos durante > 2 horas.

Reactividad plaquetariaComo criterio de valoración secundario, se midió la reactividad plaquetaria durante las horas de la mañana (entre las 8 y 12 a. m.). La mañana que se extrajo la muestra de sangre, los sujetos se ab-stuvieron de tomar aspirina. Se extrajeron muestras de sangre sin estasis de la vena antecubital, se midió la reactividad plaquetaria con VerifyNow® Aspirin Assay (Accumetrics, San Diego, EE. UU.) y se informó en unidades de reacción a la aspirina (aspirin reaction units, ARU).23

Cuestionarios, cumplimiento y preferencia del pacienteLos sujetos completaron un cuestionario para evaluar los criterios de elegibilidad, los antecedentes médicos, el uso de medicamentos y el ritmo cronobiológico en el período inicial.

Visita 1

290 pacientes

Aspirina al despertarse

Aspirina al acostarse



Visita 2

3 meses 3 meses

Visita 3

Figura 1. Diseño del estudio. Visita 1, Selección en función de los criterios de inclusión y exclusión. Visitas 2 y 3, medición ambulatoria de presión arterial (MAPA), extracción de sangre durante las horas de la mañana, cuestionario.


42 Hypertension Junio 2015

Análisis estadísticoPara detectar una diferencia interindividual de 3 mm Hg en la presión arterial con 80% de potencia en un nivel de significación del 5%, calculamos un tamaño de muestra requerido de 250 pa-cientes. Asumimos una desviación estándar intraindividual de 12,9 mm Hg, según resultó de un estudio anterior.12 Con una es-

suma de las mediciones diurnas o nocturnas

cantidad de mediciones diurnas o nocturnas Se calculó la media de PA diurna y nocturna como

(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

Evaluados a los fines deelegibilidad (n = 3.479) No incluidos (n = 3.189)

No cumplieron con los criterios de inclusión (n =1.704)Rehusaron participar (n = 655)No respondieron la invitación (n = 527)Excluidos por otras razones* (n = 303)

Aleatorizados (n = 290)

Asignados a la toma nocturna (n = 145)

Visita 2 (3 meses)Retiro de consentimiento (n = 6)

Participación muy agravante (n = 4)Dispepsia (n = 2)

Pasaron a toma nocturna (n = 139)


Participación muy agravante (n = 7)Dejó de tomar aspirina (n = 2)

Pasaron a toma diurna (n = 136)


Participación muy agravante (n = 4)Dejó de tomar aspirina (n = 1)

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

Asignación

Inicio del estudio: septiembre de 2011Finalización del estudio: septiembre 2013


Participación muy agravante (n = 3)Dejó de tomar aspirina (n = 3))

Completaron el período del estudio de 6 meses (n = 130)

Población de análisis secundario (n = 73)Excluidos (n = 61)

MAPA inválida en visita 1 y/o visita 2 (n = 30)Cambio de antihipertensivos (n = 8)Cumplimiento durante todo el estudio <90% (n = 23)

Población de análisis primarioCriterio de valoración primario: MAPA (n = 129 †)Criterio de valoración secundario: reactividad plaquetaria (n = 65)

Población de análisis secundario (n = 77)Excluidos (n = 52)

MAPA inválida en visita 1 y/o visita 2 (n = 27)Cambio de antihipertensivos (n = 6)Cumplimiento durante todo el estudio < 90% (n = 19)

Población de análisis primarioCriterio de valoración primario: MAPA (n = 134)Criterio de valoración secundario: reactividad plaquetaria (n = 71)

Seguimiento

Poblaciones de análisis

Asignados a toma diurna (n = 145)

Figura 2. Distribución de pacientes. MAPA indica medición ambulatoria de la presión arterial. *Otras razones: dejó de tomar aspirina antes de la inclusión, no pudo participar en el estudio clínico según el criterio del médico de cabecera, se mudó, no habla holandés. †Un sujeto se negó a la MAPA en la última visita de seguimiento.

timación de abandono del 10% y una MAPA inválida del 5%, aleatorizamos a 290 sujetos. Tal como se planificó de antemano, se midió la reactividad plaquetaria en los primeros 160 pacientes consecutivos, lo cual arrojó una potencia del 90% para detectar una diferencia de 17 ARU a un nivel de significación del 5%. Para este cálculo, usamos una desviación estándar intraindividual de 46,85 ARU.24 Las características continuas se describen como media ± desviación estándar (DE) si se distribuyen normalmente; de lo contrario, se describen como mediana (amplitud intercuar-tílica [AIC]). Las variables categóricas se expresan como númer-os (porcentajes). Los valores de MAPA se editaron de acuerdo con los criterios convencionales para eliminar los errores de medición y los valores atípicos. Debido a que la frecuencia de la toma de muestras fue más densa durante el día (3 veces/hora) que durante la noche (2 veces/hora), calculamos una media pondera-da de la PA general, tal como se sugirió previamente 25:

Se completó la información faltante con los registros del médico de cabecera o de la farmacia. En cada visita de seguimiento, se registraron los efectos secundarios y el cambio de medicación mediante cuestionarios. Los sujetos recibieron indicaciones de tomar la aspirina dentro de la hora de haberse despertado o una hora antes de acostarse. Se evaluó el cumplimiento y se optimizó con pastilleros electrónicos (Evalan, Ámsterdam, los Países 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. Además, en cada visita se realizó el recuento de comprimidos. Los participantes y los médicos de cabecera recibieron indicaciones de no cambiar un medicamento ni iniciar la administración de uno nuevo durante el estudio, lo que se verificó mediante cuestionarios en cada visita de seguimiento.



De los diarios se obtuvieron los horarios de inicio del día o de la noche. El criterio de valoración primario se evaluó en la población de análisis primario y secundario. La población de análisis primario incluyó a todos los sujetos aleatorizados que completaron las mediciones de los criterios de valoración. La po-blación de análisis secundario excluyó a sujetos con ≥ 1 MAPA inválida, 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 después de la toma de aspirina al despertarse y al acostarse. Además, se usaron modelos lineales mixtos para evaluar los efectos del tratamiento y

los efectos del período o residuales. Se especificaron previamente análisis de subgrupos para usuarios de β-bloqueantes, inhibidores del sistema renina-angiotensina (usuarios frente a no usuarios), usuarios frente a no usuarios de ≥ 1 antihipertensivo y sujetos con PA sistólica inicial > 140 frente a ≤ 140 mm Hg.

Se analizó criterio de valoración secundario de reactividad plaquetaria con la prueba de la t para datos apareados y mod-elos lineales mixtos. Los sujetos que olvidaron tomar aspirina el día anterior a la medición de la reactividad plaquetaria (n = 3) quedaron excluidos del análisis. Se especificaron previamente los análisis de subgrupos para sujetos con diabetes, fumadores actu-ales (sí vs. no) y valores promedio del volumen plaquetario (di-vidido en cuartiles). A pesar de que no se especificó previamente, se llevó a cabo un análisis de subgrupo adicional en función del índice de masa corporal debido a que la obesidad, como marca-dor del síndrome metabólico, puede estar relacionada con la reac-tividad plaquetaria.26 Los efectos secundarios y las preferencias de los pacientes se analizaron de manera descriptiva y utilizando la prueba de McNemar. Todos los análisis se llevaron a cabo con SPSS 20.0 (IBM corp., EE. UU.) y fueron bilaterales, con un niv-el de significación de 0,05.

ResultadosPoblación del estudio y cumplimientoEntre junio de 2011 y marzo de 2013, se seleccionó a 3.479 suje-tos en 30 consultorios de médicos de cabecera de los cuales 1.704 no cumplieron con los criterios de inclusión, fundamentalmente debido a la edad de > 75 años (n = 1.080) y el uso de otros fárma-cos de inhibición plaquetaria (n = 386; Figura 2). Se aleatorizó un total de 290 sujetos, y las características iniciales fueron similares entre los grupos (Tabla 1). El seguimiento del estudio se discon-tinuó por parte de 26 sujetos, principalmente porque la partici-pación en el estudio era demasiado agravante (18/26; 70%). Las poblaciones de análisis primario y secundario comprendieron 263 y 150 sujetos, respectivamente, para la evaluación del criterio de valoración primario. Las mediciones a los fines de la reactividad plaquetaria del criterio de valoración secundario estuvieron com-pletas en 136 sujetos. El cumplimiento, conforme a lo medido por los pastilleros electrónicos 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%]).

Presión arterialEl perfil circadiano de MAPA de 24 horas después de 3 meses de toma de aspirina al despertarse y 3 meses de toma de aspi-rina al acostarse se exhibe en la Figura 3. La media (DE) de la presión arterial sistólica y diastólica 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). Además, los valores de la presión arterial sistólica y diastólica diurna y nocturna no difirieron con el horario de la toma de aspirina (Tabla 2). El análisis de modelos mixtos demostró los mismos resultados y ninguna evidencia de efectos residuales o del período (datos no mostrados). Además, los hallazgos entre los subgrupos de sujetos que usaban o no

Tabla 1. Características clínicas iniciales de los participantes del estudio aleatorizados (n = 290)*

Variable

Grupo de toma de aspirina al

despertarse–al acostarse (n =

145)

Grupo de toma de aspirina al acostarse–al

despertarse (n = 145)

Sexo (M/F) 106/39 106/39

Edad, años 64±7 64±7

Fumadores actuales 21 (15) 28 (19)

Índice de masa corporal, kg/m2 28,4±4,7 28-1±4,6

Presión arterial sistólica, mm Hg 137±10 137±10

Presión arterial diastólica, mm Hg 88±8 88±8

Diabetes 17 (12) 14 (10)

Antecedentes cardiovasculares

Infarto de miocardio 53 (37) 59 (41)

Angina de pecho estable 59 (41) 61 (42)

Accidente cerebrovascular / accidente isquémico transitorio

28 (19) 23 (16)

Fibrilación auricular 14 (10) 13 (9)

Arteriopatía periférica 12 (8) 9 (6)

Otro † 3 (2) 1 (1)

Uso de aspirina en el período inicial

Al despertarse 106 (73) 100 (69)

Duración, años 6 (3-11) 6 (4-14)

Uso de medicación

Cantidad de fármacos antihi-pertensivos ‡

2 (1-2,5) 2 (1-3)

β-bloqueantes 74 (51) 80 (55)

Inhibidores de la ECA 60 (41) 55 (38)

Inhibidores de la angioten-sina II

37 (26) 33 (23)

Antagonistas del calcio 29 (20) 27 (19)

Diuréticos 37 (26) 46 (32)

Hipolipemiantes 116 (80) 123 (85)

*Los valores continuos se presentan como media ± desviación estándar (DE) o medianas + amplitud intercuartílica si se distribuyen normalmente. Los valores categóricos se presentan como número (%).

† Otras enfermedades cardiovasculares: enfermedad de la válvula cardíaca (n = 3), síndrome mielodisplásico (n = 1).

‡ Antihipertensivos: β-bloqueantes, α-bloqueantes, inhibidores de la ECA, inhibidores de la angiotensina II, antagonistas del calcio, diuréticos tiazídicos y del asa, nitratos (uso diario).



β-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 información on-line). Finalmente, en el análi-sis secundario, que comprendió únicamente a los pacientes con

MAPA válida en ambas visitas que no cambiaron su medicación antihipertensiva entre la visita 2 y la visita 3, y que cumplieron el tratamiento ≥ 90%, según lo registrado por los pastilleros elec-trónicos, la toma de aspirina al acostarse no se relacionó con una reducción del valor promedio de la presión arterial de 24 horas o

Pres

ión

arte

rial s

istó

lica

(mm

Hg)

Horario (horas después de despertarse)


Media de 24 horas al despertarse: 127,2

Media de 24 horas al acostarse: 127,2

Media de 24 horas al despertarse: 78,6

Media de 24 horas al acostarse 78, 0


Aspirina al despertarseAspirina al acostarse

Horario (horas después de despertarse)

Pres

ión

arte

rial d

iast

ólic

a (m

m H

g)

Figura 3. Efecto de la toma de una dosis baja de aspirina al acostarse en comparación con una toma al despertarse en el perfil de presión arterial ambulatoria de 24 horas en la población de análisis primario (n = 263). A, presión arterial sistólica. B, presión arterial diastólica. Cada gráfico mues-tra medias y errores estándar por hora de la presión arterial medida con una toma de dosis baja de aspirina al despertarse (línea negra continua) y una toma de dosis baja de aspirina al acostarse (línea gris discontinua). Las horas en el eje x se refieren a las horas después de despertarse de un período de sueño nocturno. El área sombreada representa el período nocturno promedio de todos los sujetos.



la presión arterial diurna y nocturna (Tabla S2).

Reactividad plaquetariaHubo tres sujetos que olvidaron tomar aspirina el día anterior a la medición de reactividad plaquetaria (n = 3) y fueron excluidos del análisis. En el resto de los 133 sujetos, la toma de aspirina al acostarse redujo la reactividad plaquetaria por la mañana (difer-encia promedio –22 ARU [intervalo de confianza del 95% –35 a

–9]; P = 0,001; Figura 4). El análisis de subgrupos demostró que, además 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 pacienteTres sujetos no completaron el estudio a causa de efectos secund-arios (Tabla S4). La frecuencia de los efectos secundarios de la aspirina ya conocidos (dispepsia, náuseas, ardor de estómago) fue similar entre la toma de aspirina al despertarse y al acostarse (Tabla S5).

Después de completar el estudio, 53/264 (20%) prefirieron cambiar el horario de la toma de aspirina en comparación con an-tes 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 halló una preferencia clara por parte de los pacientes en cuanto al horario de la toma de aspirina.

DiscusiónEn este estudio cruzado a gran escala realizado en pacientes que usaban una dosis baja de aspirina para la prevención de ECV, la presión arterial de 24 horas no presentó diferencia con la toma de aspirina al acostarse y la toma de aspirina al despertarse. No obstante, la toma de aspirina al acostarse se relacionó con una menor reactividad plaquetaria por la mañana.

Comparación con estudios previosNumerosos estudios previos, en su mayoría provenientes de una única fuente en este campo, informaron un efecto reductor de la presión arterial con la toma de aspirina al acostarse.6-11,13,27 Poste-riormente, nuestro grupo halló un mecanismo biológico admisi-ble subyacente a este fenómeno: la toma de aspirina al acostarse, en comparación con la toma al despertarse, redujo la actividad de la renina plasmática 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 comparación con la toma al despertarse no reduce la presión 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 β-blo-queantes o inhibidores del sistema renina-angiotensina-aldoster-ona. Se trata de una diferencia importante debido a que el mecan-ismo detrás del efecto de la aspirina dependiente del tiempo sobre la presión arterial estaba relacionado previamente con una reduc-ción en el sistema renina-angiotensina-aldosterona y la actividad de las catecolaminas en el transcurso de 24 horas.12 No obstante, no se halló ningún efecto con el uso o no de β-bloqueantes o in-hibidores del sistema renina-angiotensina-aldosterona. Incluso en el subgrupo que no usó ningún antihipertensivo, no se registró ningún efecto. Nuestros hallazgos corroboran aquellos de un es-tudio anterior que tampoco halló un efecto reductor de la presión arterial con la toma de aspirina al acostarse en los pacientes hi-pertensos tratados.28 En segundo lugar, los pacientes de todos los estudios previos no usaban aspirina antes de su ingreso al estu-dio. En contraposición, todos los pacientes de nuestro estudio tenían indicación médica de tomar aspirina y lo hicieron durante una mediana de 6 años. Es posible que el efecto de la aspirina dependiente del tiempo sobre la presión arterial se debilite con el transcurso del tiempo debido al aumento de rigidez arterial.29

Figura 4. Efecto de la toma de una dosis baja aspirina al acostarse versus al despertarse en la reactividad plaquetaria por la mañana. La barra negra representa los valores de reactividad plaquetaria según VerifyNow después de la toma de aspirina al despertarse. La barra gris discontinua representa los valores después de la toma de aspirina al acostarse.

Tabla 2. Valores promedio de presión arterial ambulatoria diurna y nocturna (mm Hg), de 24 horas, de acuerdo con el ho-rario de administración de aspirina en la población de análisis primario (n = 263)

ValorAspirina al

despertarseAspirina al acostarse

Diferencia promedio (al acostarse–al despertarse)(IC del 95%)*

PAS de 24 horas 127±12 127±12 –0,1 [–1,0 a 0,9]

PAD de 24 horas 79±9 78±8 –0,6 [–1,2 a 0,0]

PAS diurna 131±12 131±12 0,0 [–1,0 a 1,0]

PAD diurna 82±9 81±9 –0,6 [–1,2 a 0,1]

PAS nocturna 117±15 117±14 –0,1 [–1,4 a 1,1]

PAD nocturna 69±10 69±9 –0,4 [–1,2 a 0,3]

*La diferencia promedio y el IC del 95% obtenidos con pruebas de la t apareadas. Los valores son media ± desviación estándar.

IC indica intervalo de confianza; PAD, presión arterial diastólica; y PAS, presión arterial sistólica.

Diferencia promedio: –22 ARU (p = 0,001)

Al acostarseAl despertarse

Hora de toma de la aspirina



No obstante, un posible efecto reductor de la presión arterial con la toma de aspirina al acostarse solo sería relevante en términos clínicos en pacientes que ya usaban aspirina para la prevención de ECV, y nosotros somos los primeros en este campo en incluir a este grupo de pacientes relevante desde el punto de vista clínico. Dada la ausencia de un efecto reductor de la presión arterial con la aspirina al acostarse en cualquiera de los subgrupos de nuestro estudio, en nuestra opinión, no se requieren estudios adicionales para evaluar el efecto reductor de la presión arterial con la aspiri-na al acostarse en pacientes que usan aspirina para la prevención de ECV.

El ritmo circadiano de la reactividad plaquetaria y su relación con el pico matutino de eventos cardiovasculares se ha estudia-do exhaustivamente.15,30 Los autores anteriores sugirieron que la inhibición plaquetaria durante las horas matutinas de alto ries-go podría 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 in-tervalo de administración de 24 horas.18,19,31 En nuestro estudio, comparamos la función plaquetaria 12 horas después de la toma de aspirina (toma al acostarse) con una toma 24 horas después (toma al despertarse). De esta manera, podría haberse esperado una declinación en la actividad plaquetaria durante las horas de la mañana. Sin embargo, a nuestro leal entender, esto nunca se ha evaluado en un estudio clínico. Además, la reducción de la reactividad plaquetaria durante las horas matutinas de alto riesgo podría ser clínicamente relevante para los pacientes con ECV.

Previamente estudiamos el efecto de la aspirina dependiente del tiempo sobre la reactividad plaquetaria por la mañana en su-jetos sanos.32 Los resultados de este estudio confirman estos hal-lazgos en pacientes que usan aspirina a diario. Nuestro estudio sugiere que la reactividad plaquetaria por la mañana puede redu-cirse mediante la toma de aspirina al acostarse en lugar de la toma al despertarse. Este efecto estuvo presente homogéneamente en todos los subgrupos, excepto en el caso de los sujetos diabéticos. No obstante, el tamaño de este subgrupo fue demasiado reduci-do (n = 18) para descartar cualquier efecto en los pacientes dia-béticos. Asimismo, los pacientes diabéticos tienen un recambio plaquetario mayor, y la administración de aspirina dos veces al día produce una inhibición plaquetaria más efectiva a lo largo de todo el día en dichos pacientes.33,34 La reducción de la reactivi-dad plaquetaria durante las horas vulnerables de la mañana podría 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 después de la toma de aspirina.31,35

Interpretación clínicaSe ha demostrado que el riesgo de eventos cardiovasculares re-currentes se incrementa en pacientes con valores más elevados de reactividad plaquetaria, según 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 cri-terio de valoración cardiovascular compuesto, mientras que en los pacientes con valores ARU < 550 dicho riesgo fue sólo del 5,3% .37 En otro estudio, el riesgo absoluto en función de criterio de valoración 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-

tudios observacionales sugieren que una reducción de la reactiv-idad plaquetaria podría derivar en un beneficio clínico para los pacientes con ECV. Debido a que el pico matutino de ECV es un proceso multifactorial, no esperamos que la toma de aspiri-na al acostarse pueda abolir completamente el pico matutino de ECV.38 Aun así, dada la alta prevalencia de ECV, una modesta reducción en el pico matutino daría como resultado un enorme beneficio absoluto. Por ejemplo, en los Estados Unidos se pro-ducen 280.000 eventos cardiovasculares recurrentes al año, con un riesgo excedente conocido del 40% en horas de la mañana.39

Si la toma de aspirina al acostarse redujera este pico matutino en un 20%, daría como resultado una reducción absoluta de 4.853 eventos recurrentes al año, únicamente en los Estados Unidos. Por lo tanto, el cambio a toma de aspirina al acostarse es una intervención simple y posiblemente efectiva. Futuros estudios deberían evaluar si esto, de hecho, se traduce en una reducción de eventos cardiovasculares.

Fortalezas y limitacionesLa principal fortaleza de nuestro estudio es el diseño cruzado, que arroja una alta potencia estadística y permite la comparación de los efectos del tratamiento en cada paciente. Además, el presente estudio es el primero en este campo que registró el horario real de la toma de aspirina mediante pastilleros electrónicos, lo cual es de gran importancia para los efectos dependientes del tiempo del estudio.La principal limitación de nuestro estudio es que solo 150/263 (57%) pacientes cumplieron el protocolo del estudio a la perfec-ción. Esto se debió principalmente a una MAPA inválida (n = 57) o un cumplimiento < 90% dentro del horario preespecificado para la toma de la aspirina (n = 42). No obstante, los análisis de sensibilidad entre los pacientes con seguimiento y cumplimien-to completos revelaron los mismos resultados con intervalos de confianza estrechos (Tabla S2). Respecto de las mediciones de re-actividad plaquetaria, el hecho de medir la reactividad plaquetar-ia solamente en un momento predeterminado durante la mañana constituye una limitación, a pesar de que la comparabilidad entre sujetos se optimizó al extraer sangre a la misma hora en cada vis-ita. Una amplia proporción de los pacientes potencialmente eleg-ibles no respondió o no quiso participar en el presente estudio. No obstante, los pacientes incluidos se asemejaron a una población general con ECV en lo que respecta a edad, sexo, antecedentes médicos y uso de medicación.

PerspectivasEn el presente estudio, la aspirina al acostarse no redujo la presión arterial en pacientes con ECV que tomaban una dosis baja aspi-rina a diario. Por lo tanto, no recomendaríamos pasar a la toma de aspirina al acostarse para reducir la presión arterial en dichos pacientes. Aun así, la toma de aspirina al acostarse sí redujo la reactividad plaquetaria durante horas de la mañana. Se requieren futuros estudios para evaluar el efecto de esta simple intervención en el exceso de eventos cardiovasculares durante las horas de la mañana.

AgradecimientosAgradecemos a todos los técnicos de laboratorio de Leiden Uni-



versity Medical Center (LUMC) Einthoven Laboratory for Exper-imental Vascular Medicine por procesar el material biológico, y a todos los gerentes de datos del Departamento de Epidemiología Clínica del LUMC por su colaboración en la aleatorización de los sujetos del estudio. Agradecemos al Prof. T. Stijnen del Departa-mento de Estadística Médica del LUMC por su asesoramiento en estadística. También agradecemos a Margot de Waal y Henk de Jong del Departamento de Salud Pública y Atención Primaria del LUMC por su ayuda con respecto a la inclusión de participantes en el estudio. Expresamos nuestra gratitud a los médicos de ca-becera y todos los pacientes que fueron parte de este estudio. To-dos los autores asumen su responsabilidad por todos los aspectos referidos a la confiabilidad y la libertad de sesgos de los datos presentados y su interpretación analizada.

Fuentes de financiamientoEl presente trabajo fue financiado por Netherlands Heart Founda-tion (número de subsidio 2010B171).

Conflictos de interésNinguno.

Referencias1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statis-

tics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2013 update: a report from the American Heart Association. Circu-lation. 2013; 127:e6-e245. doi: 10.1161/ CIR.0b013e31828124ad.

2. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe: epidemiological update. Eur Heart J. 2013;34:3028- 3034. doi: 10.1093/eurheartj/eht356.

3. Turnbull F; Blood Pressure Lowering Treatment Trialists’ Collaboration. Ef-fects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527-1535.

4. Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation. 2011;124:1046-1058. doi: 10.1161/ CIRCULATI0NA-HA.111.030189.

5. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med. 1994;121:289-300.

6. Hermida RC, Fernández JR, Ayala DE, Iglesias M, Halberg F. Time- de-pendent effects of ASA administration on blood pressure in healthy subjects. Chronobiologia. 1994;21:201-213.

7. Hermida RC, Ayala DE, Fernández JR, Mojón A, Alonso I, Silva I, Ucieda R, Codesido J, Iglesias M. Administration time-dependent effects of aspi-rin in women at differing risk for preeclampsia. Hypertension. 1999;34(4 Pt 2):1016-1023.

8. Hermida RC, Ayala DE, Calvo C, López JE, Fernández JR, Mojón A, Dominguez MJ, Covelo M. Administration time-dependent effects of as-pirin on blood pressure in untreated hypertensive patients. Hypertension. 2003;41:1259-1267. doi: 10.1161/01.HYP.0000072335.73748.0D.

9. Hermida RC, Ayala DE, Iglesias M. Administration time-dependent in-fluence of aspirin on blood pressure in pregnant women. Hypertension. 2003;41(3 Pt 2):651-656. doi: 10.1161/01.HYP.0000047876.63997.EE.

10. Hermida RC, Ayala DE, Calvo C, López JE. Aspirin administered at bed-time, but not on awakening, has an effect on ambulatory blood pressure in hypertensive patients. J Am Coll Cardiol. 2005;46:975-983. doi: 10.1016/j.jacc.2004.08.071.

11. Hermida RC, Ayala DE, Mojón A, Fernández JR. Ambulatory blood pres-sure control with bedtime aspirin administration in subjects with prehyper-tension. Am J Hypertens. 2009;22:896-903. doi: 10.1038/ajh.2009.83.

12. Snoep JD, Hovens MM, Pasha SM, Frolich M, Pijl H, Tamsma JT Huisman MV. Time-dependent effects of low-dose aspirin on plasma renin activity, al-dosterone, cortisol, and catecholamines. Hypertension. 2009;54:1136-1142. doi: 10.1161/HYPERTENSIONAHA.109.134825.

13. Hermida RC, Ayala DE, Calvo C, López JE, Mojón A, Rodriguez M, Fernández JR. Differing administration time-dependent effects of aspirin on blood pressure in dipper and non-dipper hypertensives. Hypertension.

2005;46:1060-1068. doi: 10.1161/01.HYP.0000172623.36098.4e.14. Cohen MD, Rohtla BS, Lavery BS, Muller MD, Mittleman MD. Metaanaly-

sis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol. 1997;79:1512-1516.

15. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Wil-lich SN, Gleason RE, Williams GH, Muller JE. Concurrent morning in-crease in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987;316:1514-1518. 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;61:1081-1085.

17. Patrono C, Ciabattoni G, Patrignani P, Pugliese F, Filabozzi P, Catella F, Davi G, Forni L. Clinical pharmacology of platelet cyclooxygenase inhibition. Circulation. 1985;72:1177-1184.

18. Grove EL, Hvas AM, Mortensen SB, Larsen SB, Kristensen SD. Ef-fect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost. 2011;9:185-191. doi: 10.1111/j.1538-7836.2010.04115.x.

19. Würtz 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;175:274-279. doi: 10.1016/j.ijcard.2014.05.013.

20. Cornélissen G, Halberg F, Prikryl P, Danková E, Siegelová J, Dusek J. Prophylactic aspirin treatment: the merits of timing. International Womb- to-Tomb Chronome Study Group. JAMA. 1991;266:3128-3129.

21. Kriszbacher I, Ajtay Z, Koppán M, Bódis J. Can the time of taking aspirin in-fluence the frequency of cardiovascular events? Am J Cardiol. 2005;96:608-610. doi: 10.1016/j.amjcard.2005.03.068.

22. Smith DH, Neutel JM, Lacourciere 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. JHypertens. 2003;21:1291-1298. 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;3:77-82.

24. Madsen EH, Saw J, Kristensen SR, Schmidt EB, Pittendreigh C, Maurer- Spurej E. Long-term aspirin and clopidogrel response evaluated by light transmission aggregometry, VerifyNow, and thrombelastography in patients undergoing percutaneous coronary intervention. Clin Chem. 2010;56:839-847. doi: 10.1373/clinchem.2009.137471.

25. Octavio JA, Contreras J, Amair P, Octavio B, Fabiano D, Moleiro F, Omboni S, Groppelli A, Bilo G, Mancia G, Parati G. Time-weighted vs. conventional quantification of 24-h average systolic and diastolic ambulatory blood pres-sures. J Hypertens. 2010;28:459-464. doi: 10.1097/ HJH.0b013e328334f220.

26. Vaduganathan M, Alviar CL, Arikan ME, Tellez A, Guthikonda S, DeLao T, Granada JF, Kleiman NS, Ballantyne CM, Lev EI. Platelet reactivity and response to aspirin in subjects with the metabolic syndrome. Am Heart J. 2008;156:1002.e1-1002.e7. doi: 10.1016/j. ahj.2008.08.002.

27. Abdali K, Taghizadeh R, Amoei S, Tabatabai SHR. Comparison between aspirin and placebo on the mean of 24 hour blood pressure in pregnant wom-en at preeclampsia risk, a double blind randomized controlled clinical trial. IJCBNM. 2013;1:83-91.

28. Dimitrov Y, Baguet JP, Hottelart C, Marboeuf P, Tartiere JM, Ducher M, Fauvel JP. Is there a BP benefit of changing the time of aspirin administration in treated hypertensive patients? Eur J Prev Cardiol. 2012;19:706- 711. doi: 10.1177/1741826711418165.

29. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25:932- 943. doi: 10.1161/01.ATV.0000160548.78317.29.

30. Scheer FA, Michelson AD, Frelinger AL III, Evoniuk H, Kelly EE, McCa-rthy M, Doamekpor LA, Barnard MR, Shea SA. The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors. PLoS One. 2011;6:e24549. doi: 10.1371/journal.pone.0024549.

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. 2011;105:336-344. doi: 10.1160/TH10-02-0082.

32. Bonten TN, Saris A, van Oostrom MJ, Snoep JD, Rosendaal FR, Zwaginga J, Eikenboom J, van der Meer PF, van der Bom JG. Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity. A randomised cross-over trial. Thromb Haemost. 2014;112:1209-1218. 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 artery



disease and type 2 diabetes. Platelets. In press.34. Dillinger JG, Drissa A, Sideris G, Bal dit Sollier C, Voicu S, Manzo Silber-

man S, Logeart D, Drouet L, Henry P. Biological efficacy of twice daily aspirin in type 2 diabetic patients with coronary artery disease. Am Heart J. 2012;164:600-606.e1. doi: 10.1016/j.ahj.2012.06.008.

35. Perneby C, Wallén NH, Rooney C, Fitzgerald D, Hjemdahl P. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost. 2006;95:652-658.

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 associat-ed with the occurrence of atherothrombotic events. J Thromb Haemost. 2010;8:2140-2148. 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 re-sistance and adverse clinical events in patients with coronary artery disease. Am J Med. 2007;120:631-635. 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;79:733-743.

39. Elliott WJ. Cyclic and circadian variations in cardiovascular events. Am J Hypertens. 2001;14:291S-295S.

Novedad y Significado

¿Qué es nuevo?•Elefectoreductorenlapresiónarterialconlatomadeaspirinaal acostarse nunca se había estudiado en pacientes que usaban aspirina para la prevención de enfermedad cardiovascular.•Nunca se ha estudiado si la toma de aspirina al acostarse encomparación con la toma al despertarse reduce la reactividad pla-quetaria por la mañana.

¿Qué es relevante?•La tomade aspirina al acostarse en comparación con la tomaal despertarse no redujo la presión arterial, lo cual se opone a los estudios previos realizados en pacientes sanos.

•Lareactividadplaquetariadurantelashorasdelamañanasere-dujo con la toma de aspirina al acostarse, lo cual podría ser benefi-cioso para los pacientes que toman aspirina a diario.

ResumenA diferencia de estudios previos realizados en otros grupos de pacientes,

la toma de aspirina al acostarse no redujo la presión 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.


monitoring the entry of new platelets into the circulation after ingestion of aspirin

Documents