Comparison of Awakening Versus Bedtime Dosing of Aspirin in Pre-Hypertension or Mild Essential Hypertension

University of Vigo

Status and phase: Terminated; Phase 4

Conditions: Mild Essential Hypertension; High-Normal Blood Pressure

Treatments: Device: Ambulatory blood pressure monitoring; Procedure: Chronotherapy, timing of medication; Drug: Placebo; Drug: Aspirin 100 mg

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00449618

ASA100-2004/2

2006-004652-21

2004-004987-65

Details and patient eligibility

About

Aspirin (ASA) has been shown to provide marked benefits in the prevention of cardiovascular events, although the potential direct effects of ASA on cardiovascular function remain uncertain. Previous studies have demonstrated that ASA is a potent antioxidative agent that markedly reduces vascular production of superoxide in normotensive and hypertensive rats. In addition, ASA was found to prevent angiotensin II-induced hypertension and cardiovascular hypertrophy, mainly through its antioxidative properties in preventing the generation of superoxide, although ASA apparently did not appear to reduce hypertensive levels of blood pressure (BP). Moreover, recent results have demonstrated that ASA induces nitric oxide (NO) release from vascular endothelium. No attention has been paid, so far, to potential administration time-dependent effects in these studies.

Previous laboratory animal and clinical trial research convincingly demonstrates administration time-dependent (with reference to circadian rhythms) effects of ASA. Thus, the effects of ASA upon lipoperoxides, β-adrenergic receptors, and BP in clinically healthy subjects depend on the circadian timing of ASA administration. Most important, the administration time-dependent influence of ASA on BP was previously demonstrated in a randomized trial on healthy women and in other independent, double-blind, randomized, placebo-controlled clinical trials. The first was conducted on clinically healthy subjects, a second one on normotensive and hypertensive subjects, a third one on pregnant women at high risk for preeclampsia and a fourth one in previously untreated patients with mild hypertension. The findings of these BP studies are consistent; the BP-lowering effect of low-dose ASA is achieved when administered at bedtime but not upon awakening.

In keeping with the chronopharmacological effects of ASA and the previous findings suggesting that ASA at low dose may have a potential beneficial effect on BP, this prospective, randomized, double-blind, crossover study will investigate the potential influence of ASA on BP in subjects with either high-normal BP or diagnosis of mild (grade 1) hypertension. The subjects will receive low-dose ASA or placebo at different times of the day according to their rest-activity cycle, and will be evaluated by 48-hour ambulatory BP monitoring before and after 6 weeks of pharmacologic intervention.

Full description

This is a multi-center, prospective, randomized, four-arm, crossover study with double-blind design.

At Visit 1 (week -1) patients will be assessed for eligibility for study participation. Subjects will be advised that study entry cannot be fully determined until the completion of the screening period when all exclusion/inclusion criteria are entirely assessed. Subjects will perform Visit 2 as soon as their laboratory results of Visit 1 are available. At baseline (Visit 2/Day 1), a total of 300 subjects whose eligibility is confirmed will be randomized in a 1:1:1 ratio to one of the treatment groups (aspirin upon awakening, aspirin at bedtime, or placebo--half on awakening, half at bedtime). Subjects will start a first double-blind treatment phase with a total duration of 6 weeks. During this period the subjects will be receiving either aspirin 100 mg or placebo at two different circadian times (either after awakening from nighttime sleep or before bedtime) until the end of this study phase (Visit 3). After this first treatment phase, all subjects will undergo a 2-week wash-out phase with placebo. At Visit 4 (week 8), all subjects will be crossed-over in terms of the circadian time, but keeping their original treatment (either aspirin or placebo), and followed up for a second treatment phase of 6 weeks.

The study duration including all the phases will be 15 weeks.

Safety and efficacy will be assessed at the end of every treatment phase, i.e., at Visits 3 and 5. Safety will also be assessed by phone calls 2 weeks after the initiation of each active treatment phase (weeks 2 and 10). Subjects may be requested to attend the clinic for further evaluation on those weeks if they present any adverse effect.

Enrollment: 23 patients

Sex: All

Ages: 18+ years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• High-normal blood pressure
• Mild essential hypertension

Exclusion criteria

• Moderate-severe hypertension.
• Secondary hypertension.
• Grade III/IV hypertensive retinopathy.
• Type 1 diabetes.
• Body mass index ≥ 35 kg/m2
• Cerebrovascular or cardiovascular event during the last 12 months prior to inclusion.
• Pregnant or lactating females.
• History of malignancy within the past five years.
• Shift workers.
• Obstructive sleep apnea.
• Use of disallowed concomitant medication.
• Intolerant to ambulatory BP monitoring (ABPM).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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23 participants in 4 patient groups, including a placebo group

1

Active Comparator group

Description:

Aspirin 100 mg on awakening

Treatment:

Drug: Aspirin 100 mg

Device: Ambulatory blood pressure monitoring

Procedure: Chronotherapy, timing of medication

2

Active Comparator group

Description:

Aspirin 100 mg at bedtime

Treatment:

Drug: Aspirin 100 mg

Device: Ambulatory blood pressure monitoring

Procedure: Chronotherapy, timing of medication

3

Placebo Comparator group

Description:

Placebo on awakening

Treatment:

Device: Ambulatory blood pressure monitoring

Procedure: Chronotherapy, timing of medication

Drug: Placebo

4

Placebo Comparator group

Description:

Placebo at bedtime

Treatment:

Device: Ambulatory blood pressure monitoring

Procedure: Chronotherapy, timing of medication

Drug: Placebo