Blood pressure medication should be routinely dosed at bedtime. An internist’s critical appraisal of the editorial by Rainhold Kreutz et al. (2020). Blood pressure medication should not be routinely dosed at bedtime. We must disregard the data from the HYGIA project. Blood Pressure. 29 (3):135–136

ABSTRACT

The history of hypertension the past hundred years is a successful story of the fall of myths, beliefs, and assumptions under the weight of evidence. The recent editorial by Kreutz et al. (2020),”Blood pressure medication should not be routinely dosed at bedtime. We must disregard the data from the HYGIA project”, published in Blood Pressure, conveys unjustified concerns founded on baseless doubts and suspicions about the Hygia Chronotherapy Trial. The physicians of Portugal are beginning to incorporate into routine clinical practice the proven methods of the Hygia Chronotherapy Trial – 48-hour ambulatory blood pressure monitoring and bedtime hypertension chronotherapy – to improve in a cost-effective matter the diagnosis and management of hypertension and to reduce the overwhelming burden of cardiovascular morbidity and mortality in our country.     

Cardiovascular Risk of Resistant Hypertension: Dependence on Treatment-Time Regimen of Blood Pressure–Lowering Medications

In resistant hypertension, ingesting one or more blood pressure (BP)-lowering medications at bedtime is associated with significant reduction of sleep-time BP, a sensitive prognostic marker of cardiovascular disease (CVD) risk. This randomized trial investigated if bedtime therapy with at least one hypertension medication exerts better BP control and CVD risk reduction than conventional, morning-time therapy with all medications. We conducted a prospective, open-label, blinded-endpoint trial on 776 patients (387 men/389 women) with resistant hypertension, 61.6?±?11.2 (mean?±?SD) yrs of age. Patients were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. BP was measured by ambulatory monitoring for 48?h at baseline, and again annually or more frequently (quarterly) if treatment adjustment was required. After a median follow-up of 5.4 yrs (range, .5–8.5 yrs), participants ingesting ≥1 hypertension medications at bedtime showed a significantly lower hazard ratio (HR) of total CVD events (adjusted by age, sex, and diabetes) than those ingesting all medications upon awakening (.38 [95% CI: .27–.55]; number of events 102 vs. 41; p?<?.001). The difference between groups in the adjusted HR of major CVD events (a composite of CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also statistically significant (.35 [95% CI: .18–.68]; number of events 32 vs. 12; p?=?.002). At the last evaluation, patients treated with the bedtime versus awakening-time-treatment regimen showed significantly lower sleep-time systolic/diastolic BP mean values (121.6/65.4 vs. 113.0/61.1?mm Hg; p?<?.001) and higher prevalence of controlled ambulatory BP (61% vs. 46%; p?<?.001). The progressive decrease in the sleep-time systolic BP mean during follow-up was the most significant predictor of event-free survival (15% risk reduction per 5?mm Hg decreased asleep systolic BP mean). Among patients with resistant hypertension, ingestion of at least one hypertension medication at bedtime, compared with all medications upon waking, resulted in improved ambulatory BP control and fewer hard and soft CVD events. (Author correspondence: rhermida@uvigo.es)     

Bedtime hypertension chronotherapy best reduces cardiovascular disease risk as corroborated by the Hygia Chronotherapy Trial. Rebuttal to European Society of Hypertension officials.

ABSTRACT

Reinhold Kreutz and colleagues in a recent editorial claim the Hygia Chronotherapy Trial lacks credibility because of deficient methods, thereby dismissing both the plausibility and clinical significance of its reported findings. They misstate and misrepresent crucial information, findings and conclusions unambiguously detailed in the published report of the Hygia Chronotherapy Trial. The purpose of this communication is to provide a complete rebuttal to each and every one of the misleading and scientifically unsupported claims by Kreutz et al. that calls into question their expertise to decry the merits, advantages, limitations and validity of correctly designed and conducted ambulatory blood pressure monitoring-based chronotherapy trials.     

Administration-Time-Dependent Effects of Doxazosin GITS on Ambulatory Blood Pressure of Hypertensive Subjects

Previous studies have shown that a single nighttime dose of standard doxazosin, an α-adrenergic antagonist, reduces blood pressure (BP) throughout the 24 h. We investigated the administration-time-dependent effects of the new doxazosin gastrointestinal therapeutic system (GITS) formulation. We studied 91 subjects (49 men and 42 women), 56.7 ± 11.2 (mean ± SD) yrs of age with grade 1–2 essential hypertension; 39 patients had been previously untreated, and the remaining 52 had been treated with two antihypertensive medications with inadequate control of their hypertension. The subjects of the two groups, the monotherapy and polytherapy groups, respectively, were randomly assigned to receive the single daily dose of doxazosin GITS (4 mg/day) either upon awakening or at bedtime. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours just before and after 3 months of treatment. After 3 months of doxazosin GITS therapy upon awakening, there was a small and nonstatistically significant reduction in BP (1.8 and 3.2 mm Hg in the 24 h mean of systolic and diastolic BP in monotherapy; 2.2 and 1.9 mm Hg in polytherapy), mainly because of absence of any effect on nocturnal BP. The 24 h mean BP reduction was larger and statistically significant (6.9 and 5.9 mm for systolic and diastolic BP, respectively, in monotherapy; 5.3 and 4.5 mm Hg in polytherapy) when doxazosin GITS was scheduled at bedtime. This BP-lowering effect was similar during both the day and nighttime hours. Doxazosin GITS ingested daily on awakening failed to provide full 24 h therapeutic coverage. Bedtime dosing with doxazosin GITS, however, significantly reduced BP throughout the 24 h both when used as a monotherapy and when used in combination with other antihypertensive pharmacotherapy. Knowledge of the chronopharmacology of doxazosin GITS is key to optimizing the efficiency of its BP-lowering effect, and this must be taken into consideration when prescribing this medication to patients.     

Effects of Time-of-Day of Hypertension Treatment on Ambulatory Blood Pressure and Clinical Characteristics of Patients With Type 2 Diabetes

Generally, hypertensive patients ingest all their blood pressure (BP)-lowering agents in the morning. However, many published prospective trials have reported clinically meaningful morning-evening, treatment-time differences in BP-lowering efficacy, duration of action, and safety of most classes of hypertension medications, and it was recently documented that routine ingestion of ≥1 hypertension medications at bedtime, compared with ingestion of all of them upon awakening, significantly reduces cardiovascular disease (CVD) events. Non-dipping (<10% decline in asleep relative to awake BP mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and is associated with increased CVD risk. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and analytical parameters of hypertensive patients with type 2 diabetes evaluated by 48-h ABPM. This cross-sectional study involved 2429 such patients (1465 men/964 women), 65.9?±?10.6 (mean?±?SD) yrs of age, enrolled in the Hygia Project, involving primary care centers of northwest Spain and designed to evaluate prospectively CVD risk by ABPM. Among the participants, 1176 were ingesting all BP-lowering medications upon awakening, whereas 1253 patients were ingesting ≥1 medications at bedtime. Among the latter, 336 patients were ingesting all BP-lowering medications at bedtime, whereas 917 were ingesting the full daily dose of some hypertension medications upon awakening and the full dose of others at bedtime. Those ingesting ≥1 medications at bedtime versus those ingesting all medications upon awakening had lower likelihood of metabolic syndrome and chronic kidney disease (CKD); had significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; and had higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. Moreover, patients ingesting all medications at bedtime had lowest fasting glucose, serum creatinine, uric acid, and prevalence of proteinuria and CKD. Ingestion of ≥1 medications at bedtime was also significantly associated with lower asleep systolic (SBP) and diastolic BP (DBP) means than treatment with all medications upon awakening. Sleep-time relative SBP and DBP decline was significantly attenuated in patients ingesting all medications upon awakening (p?<?.001). Thus, the prevalence of non-dipping was significantly higher when all hypertension medications were ingested upon awakening (68.6%) than when ≥1 of them was ingested at bedtime (55.8%; p?<?.001 between groups), and even further attenuated (49.7%) when all of them were ingested at bedtime (p?<?.001). Additionally, prevalence of the riser BP pattern, associated with highest CVD risk, was much greater (23.6%) among patients ingesting all medications upon awakening, compared with those ingesting some (20.0%) or all medications at bedtime (12.2%; p?<?.001 between groups). The latter group also showed significantly higher prevalence of properly controlled ambulatory BP (p <?.001) that was achieved by a significantly lower number of hypertension medications (p?<?.001) compared with patients treated upon awakening. Our findings demonstrate significantly lower asleep SBP mean and attenuated prevalence of a blunted nighttime BP decline, i.e., lower prevalence of markers of CVD risk, and improved metabolic profile in patients with type 2 diabetes ingesting hypertension medications at bedtime than in those ingesting all of them upon awakening. These collective findings indicate that bedtime hypertension treatment, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of hypertension and avoid treatment-induced nocturnal hypotension, should be the preferred therapeutic scheme for type 2 diabetes. (Author correspondence: rhermida@uvigo.es)     

Relationship Between Metabolic Syndrome,Circadian Treatment Time,and Blood Pressure Non-Dipping Profile in Essential Hypertension

There is a strong association between metabolic syndrome (MS) and increased cardiovascular risk. Moreover, elevated nighttime blood pressure (BP) and non-dipping (subjects with <10% decline in the asleep relative to the awake BP mean) have been also linked to increased cardiovascular morbidity and mortality. We investigated the relation between MS, circadian time of hypertension treatment, and impaired nighttime BP decline in a cross-sectional study on 3352 (1576 men/1776 women) non-diabetic hypertensive subjects, 53.7?±?13.1 (mean?±?SD) yrs of age. Among them, 2056 were ingesting all their prescribed hypertension medication upon awakening, and 1296 were ingesting at least one of their BP medications at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours to substantiate reproducibility of the dipping pattern. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate mean BP when awake and asleep for each subject. MS was present in 52.6% of the subjects. The prevalence of an altered non-dipper BP profile was significantly higher among subjects with MS (52.0% vs. 39.5% in subjects without MS, p < .001). Non-dipping was significantly more prevalent among subjects ingesting all BP-lowering medications upon awakening (56.8%) than among those ingesting at least one of their BP medications at bedtime (29.1%; p < .001). Subjects with MS had significantly higher values of uric acid (6.0 vs. 5.3?mg/dL, p < .001), plasma fibrinogen (331 vs. 315?mg/dL, p < .001), and erythrocyte sedimentation rate (14.8 vs. 12.4?mm, p < .001). Non-dipping was significantly associated with the presence of MS and treatment upon awakening in a multiple logistic regression model adjusted by significant confounding factors, including age, creatinine, erythrocyte sedimentation rate, and cigarette smoking. This cross-sectional study documents a significant increase of a blunted sleep-time BP decline in treated hypertensive subjects with MS. Even in the presence of MS, treatment at bedtime is significantly associated with lower prevalence of a high-risk non-dipper BP profile. (Author correspondence: rhermida@uvigo.es)     

Prevalence and Clinical Characteristics of Isolated-Office and True Resistant Hypertension Determined by Ambulatory Blood Pressure Monitoring

Hypertension is defined as resistant to treatment when a therapeutic plan including ≥3 hypertension medications failed to sufficiently lower systolic (SBP) and diastolic (DBP) blood pressures (BPs). Most individuals, including those under hypertension therapy, show a “white-coat” effect that could cause an overestimation of their real BP. The prevalence and clinical characteristics of “white-coat” or isolated-office resistant hypertension (RH) has always been evaluated by comparing clinic BP values with either daytime home BP measurements or the awake BP mean obtained from ambulatory monitoring (ABPM), therefore including patients with either normal or elevated asleep BP mean. Here, we investigated the impact of including asleep BP mean as a requirement for the definition of hypertension on the prevalence, clinical characteristics, and estimated cardiovascular (CVD) risk of isolated-office RH. This cross-sectional study evaluated 3042 patients treated with ≥3 hypertension medications and evaluated by 48-h ABPM (1707 men/1335 women), 64.2?±?11.6 (mean?±?SD) yrs of age, enrolled in the Hygia Project. Among the participants, 522 (17.2%) had true isolated-office RH (elevated clinic BP and controlled awake and asleep ambulatory BPs while treated with 3 hypertension medications), 260 (8.6%) had false isolated-office RH (elevated clinic BP, controlled awake SBP/DBP means, but elevated asleep SBP or DBP mean while treated with 3 hypertension medications), and the remaining 2260 (74.3%) had true RH (elevated awake or asleep SBP/DBP means while treated with 3 medications, or any patient treated with ≥4 medications). Patients with false, relative to those with true, isolated-office RH had higher prevalence of microalbuminuria and chronic kidney disease (CKD), significantly higher albumin/creatinine ratio (p <?.001), significantly higher 48-h SBP/DBP means by 9.6/5.3?mm Hg (p?<?.001), significantly lower sleep-time relative SBP and DBP decline (p?<?.001), and significantly greater prevalence of a non-dipper BP profile (96.9% vs. 38.9%; p?<?.001). Additionally, the prevalence of the riser BP pattern, which is associated with highest CVD risk, was much greater, 40.4% vs. 5.0% (p?<?.001), among patients with false isolated-office RH. The estimated hazard ratio of CVD events, using a fully adjusted model including the significant confounding variables of sex, age, diabetes, chronic kidney disease, asleep SBP mean, and sleep-time relative SBP decline, was significantly greater for patients with false compared with those with true isolated-office RH (2.13 [95% confidence interval: 1.95–2.32]; p?<?.001). Patients with false isolated-office hypertension and true RH, however, were equivalent for the prevalence of obstructive sleep apnea, metabolic syndrome, obesity, diabetes, microalbuminuria, and chronic kidney disease, and they had an equivalent estimated hazard ratio of CVD events (1.04 [95% confidence interval: .97–1.12]; p?=?.265). Our findings document a significantly elevated prevalence of a blunted nighttime BP decline in patients here categorized as either false isolated-office RH and true RH, jointly accounting for 82.8% of the studied sample. Previous reports of much lower prevalence of true RH plus a nonsignificant increased CVD risk of this condition compared with isolated-office RH are misleading by disregarding asleep BP mean for classification. Our results further indicate that classification of RH patients into categories of isolated-office RH, masked RH, and true RH cannot be based on the comparison of clinic BP with either daytime home BP measurements or awake BP mean from ABPM, as so far customary in the available literature, totally disregarding the highly significant prognostic value of nighttime BP. Accordingly, ABPM should be regarded as a clinical requirement for proper diagnosis of true RH. (Author correspondence: rhermida@uvigo.es)     

Administration‐Time‐Dependent Effects of Olmesartan on the Ambulatory Blood Pressure of Essential Hypertension Patients

Previous studies established that a single daily dose of olmesartan remains effective for the entire 24 h without alteration of the day‐night blood pressure (BP) pattern. On the other hand, the administration of valsartan or telmisartan at bedtime, as opposed to upon wakening, improves the sleep‐time relative BP decline toward a greater dipper pattern without loss of 24 h efficacy. Yet to be determined is whether this administration‐time‐dependent efficacy is a class‐related feature, characteristic of all angiotensin‐receptor‐blocker (ARB) medications. We studied 123 grade 1 and 2 hypertensive patients, 46.6±12.3 yrs of age, randomly assigned to receive olmesartan (20 mg/day) as a monotherapy either upon awakening or at bedtime for three months. BP was measured by ambulatory monitoring for 48 consecutive hours before and after treatment. The 24 h BP reduction was similar for both treatment times. Administration of olmesartan at bedtime, however, was significantly more efficient than morning administration in reducing the nocturnal BP mean. The sleep‐time relative BP decline was slightly reduced with olmesartan ingestion upon awakening but significantly increased with ingestion at bedtime, thus reducing the prevalence of non‐dipping from baseline by 48%. Olmesartan administration at bedtime, as opposed to in the morning, improved the awake/asleep BP ratio toward a greater dipper pattern without loss of 24 h efficacy. Nocturnal BP regulation was significantly better achieved with bedtime as compared to morning dosing of olmesartan. These effects are comparable to those previously reported for valsartan and telmisartan, thus suggesting that they may be class‐related features of ARB medications in spite of differences in their half‐life kinetics. These administration‐time‐dependent effects should be taken into account when prescribing ARB medications for treatment of essential hypertension     

INFLUENCE OF CIRCADIAN TIME OF HYPERTENSION TREATMENT ON CARDIOVASCULAR RISK: RESULTS OF THE MAPEC STUDY

Clinical studies have documented morning-evening, administration-time differences of several different classes of hypertension medications in blood pressure (BP)-lowering efficacy, duration of action, safety profile, and/or effects on the circadian BP pattern. In spite of these published findings, most hypertensive subjects, including those under combination therapy, are instructed by their physicians and pharmacists to ingest all of their BP-lowering medications in the morning. The potential differential reduction of cardiovascular (CVD) morbidity and mortality risk by a bedtime versus upon-awakening treatment schedule has never been evaluated prospectively. The prospective MAPEC study was specifically designed to test the hypothesis that bedtime chronotherapy with ≥1 hypertension medications exerts better BP control and CVD risk reduction than conventional therapy, i.e., all medications ingested in the morning. A total of 2156 hypertensive subjects, 1044 men/1112 women, 55.6?±?13.6 (mean?±?SD) yrs of age, were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00?h and at 30-min intervals at night for 48?h. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Despite lack of differences in ambulatory BP between groups at baseline, subjects ingesting medication at bedtime showed at their last available evaluation significantly lower mean sleep-time BP, higher sleep-time relative BP decline, reduced prevalence of non-dipping (34% versus 62%; p?<?.001), and higher prevalence of controlled ambulatory BP (62% versus 53%; p?<?.001). After a median follow-up of 5.6 yrs, subjects ingesting ≥1 BP-lowering medications at bedtime exhibited a significantly lower relative risk of total CVD events than those ingesting all medications upon awakening (0.39 [0.29–0.51]; number of events 187 versus 68; p?<?.001). The difference between the treatment-time groups in the relative risk of major events (including CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also highly statistically significant (0.33 [0.19–0.55]; number of events: 55 versus 18; p?<?.001). The progressive decrease in asleep BP and increase in sleep-time relative BP decline towards a more normal dipping pattern, two novel therapeutic targets requiring proper patient evaluation by ambulatory BP, were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival. Bedtime chronotherapy with ≥1 BP-lowering medications, compared to conventional upon-waking treatment with all medications, more effectively improved BP control, better decreased the prevalence of non-dipping, and, most importantly, significantly reduced CVD morbidity and mortality. (Author correspondence: rhermida@uvigo.es)     

血浆Apelin-36水平与高血压病的相关性研究

目的：探讨原发性高血压（EH）患者24小时平均血压水平与血浆Apelin-36水平的相关性。方法：选择2009年6月一2010年6月在我院心内二科住院的EH患者146例为观察组,选择144例血压正常者作为对照组。抽取空腹静脉血,采用放射免疫法（RIA）检测所有研究对象的血浆Apelin-36水平。结果：①血压正常组血浆Apelin-36水平24.65±4.10pmol/l;EH组20.81±4.98 pmol/l;两组间比较有显著统计学差异（P〈0.01）。②EH患者者血浆Apelin-36水平与24小时平均收缩压、白天平均收缩压、夜间平均收缩压均呈负相关（P〈0.05）。结论：EH组血浆Apelin-36水平显著低于正常对照组,24小时平均血压越高,血浆Apelin-36水平越低,且血浆Apelin-36水平与24小时平均血压水平呈负相关。     

Chronotherapy With Valsartan/Hydrochlorothiazide Combination in Essential Hypertension: Improved Sleep-Time Blood Pressure Control With Bedtime Dosing

Administration of angiotensin receptor blockers at bedtime results in greater reduction of nighttime blood pressure than dosing upon awakening, independent of the terminal half-life of each individual medication. To obtain blood pressure (BP) target goals most patients require treatment with more than one hypertension medication. However, the potential differing effects on BP regulation of combination therapy depending on the time-of-day of administration have scarcely been investigated. Accordingly, the authors prospectively evaluated the administration-time-dependent BP-lowering efficacy of valsartan/hydrochlorothiazide (HCTZ) combination therapy. The authors conducted a randomized, open-label, blinded-endpoint trial on 204 subjects with essential hypertension (95 men/109 women), 49.7?±?11.1 (mean?±?SD) yrs of age. The BP of participants in this trial was not properly controlled with respect to published ambulatory BP criteria after initially randomized to valsartan monotherapy (160?mg/day), whether routinely ingested upon awakening by one group or at bedtime by another group for 12 wks. Thus, HCTZ (12.5?mg/day) was added to valsartan as a single-pill formulation, maintaining the original treatment-time, i.e., upon awakening or at bedtime, of participants of the two groups, for another 12 wks. BP was measured by ambulatory monitoring for 48?h at inclusion and after each 12-wk span of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately define the beginning and end of daytime activity and nocturnal sleep so that the respective BP means for every participant at each evaluation could be precisely determined. Combination therapy resulted in a similar statistically significant reduction of the 48-h BP mean from baseline for both treatment-time groups (17.0/11.5?mm Hg in systolic/diastolic BP after combination therapy on awakening; 17.9/12.1?mm Hg reduction after combination treatment at bedtime; p?>?.542 between groups). The awake BP mean was reduced to a comparable extent in both treatment-time groups (p?>?.682). However, bedtime compared to morning dosing better reduced the asleep means of systolic BP (20.1 vs. 16.0?mm Hg; p?=?.015) and pulse pressure (6.5 vs. 4.0?mm Hg; p?=?.007 between groups). Accordingly, the proportion of subjects with a baseline non-dipper BP profile was significantly reduced from 59% to 23% only after bedtime combination treatment (p?<?.001). Moreover, the proportion of subjects with properly controlled ambulatory BP after combination therapy was significantly greater with bedtime than upon-awakening treatment (55 vs. 40%, p?=?.037). The improved efficacy in lowering the asleep BP mean, increased sleep-time relative BP decline, and greater proportion of controlled patients suggest that valsartan/HCTZ combination should be preferably administered at bedtime for treatment of subjects with essential hypertension requiring combination therapy to achieve proper BP control. (Author correspondence: rhermida@uvigo.es)     

Influence of Aspirin Usage on Blood Pressure: Dose and Administration-Time Dependencies

This study investigates the possible effects of acetylsalicylic acid (ASA; aspirin) on systolic (S) and diastolic (D) blood pressure (BP) in healthy and mildly hypertensive subjects receiving ASA at different times according to their rest-activity cycle. A double-blind, randomized, controlled trial was conducted in 73 healthy young adult volunteers and 18 previously untreated subjects with mild hypertension. The BP of each subject was automatically monitored every 30 minutes for 48h before the trial and at the end of a one-week course of placebo and a one-week course of ASA. Healthy volunteers were randomly assigned to one of six groups, defined according to the dose of ASA (either 500 mg/day, the usual commercial dose; or 100 mg/day) and timing of ASA and placebo (within 2h after awakening, Time 1; 7h to 9h after awakening, Time 2; or within 2h of bedtime, Time 3). Subjects with mild hypertension the low dose of 100 mg/day ASA, as well as one week of placebo, and were randomly assigned to one of the same three groups defined above according to the time of treatment. A small (?2 mmHg in the 24h mean of SBP), but statistically significant, BP reduction was found when 500 mg/day ASA was given to healthy volunteers at Time 2. With 100 mg/day, the effect of ASA in healthy subjects was comparable to the BP reduction found with the higher dose for Time 2; there was again no effect on BP at Time 1, but we found a statistically significant effect at Time 3 (2.3 mmHg reduction in the 24h mean of SBP), larger than for Time 2. For hypertensive patients, the BP reduction was again statistically significant for Time 2 and, to a greater extent, for Time 3 (?4.5 mmHg for both SBP and DBP); all patients in these two groups showed a BP reduction after one week of ASA. The effect was about three times as large as the BP reduction obtained in healthy subjects treated with 100 mg/day ASA. Results indicate a statistically significant time- and dose-dependent effect of ASA on BP. In any meta-analysis of ASA effects, inquiries about the time when subjects took the drug are indicated and may account for discrepancies in the literature. Moreover, the influence of ASA on BP demonstrated here indicates the need to identify and control for ASA effects in patients using ASA before or during their participation in antihypertension medication trials. (Chronobiology International, 14(6), 619–637, 1997)