A Prospective, Randomized, Multi-Center, Double-Blind Crossover Study to Compare Awakening Versus Bedtime Administration of 100 mg Aspirin or Placebo in Subjects With High-Normal Blood Pressure or Mild Essential Hypertension

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.