Time-dependent effects of ASA administration on blood pressure in healthy subjects

Several studies aimed at testing the effects of low-dose acetylsalicylic acid treatment (ASA, aspirin) in the prevention of preeclampsia conclude that beneficial effects of such treatment outweigh adverse ones. Since recent results suggest that desired effects upon lipoperoxides and beta-adrenergic receptors are dependent on the circadian timing of ASA administration, we aim to study if ASA therapy can be optimized by timing according to the rest-activity cycle. Accordingly, before conducting clinical trials on pregnant women, we have examined in clinically healthy subjects the possibility that effects of ASA upon blood pressure could indeed be time-dependent. We studied 55 healthy subjects (35 men and 20 women), 19-24 years of age (mean +/- SD: 20.9 +/- 1.8). Subjects were living on their usual diurnal waking (approximately 08:00 to approximately 24:00), nocturnal resting routine during sampling, following every-day life conditions without any restriction. The systolic, mean arterial and diastolic blood pressures and heart rates of each subject were automatically monitored every 30 min. for 48 hrs with an ABPM-630 Colin (Komaki, Japan) device before and after a one-week course of aspirin (500 mg/day). Subjects were randomly assigned to one of three groups, according to the circadian timing of administration of the daily dose of ASA: within two hours of awakening (R x 1), seven to nine hours after awakening (R x 2), or within two hours before bedtime (R x 3). The second blood pressure profile was obtained during the sixth and seventh days of treatment (to avoid differences in activity dependent on the day of the week). Results indicate a statistically significant blood pressure reduction (negative mean area between the blood pressure profiles obtained before and after aspirin administration) only when ASA was given seven to nine hours after awakening (R x 2; P = .012, .003, and .006 for systolic, mean arterial and diastolic blood pressure, respectively). These results were corroborated by a non-parametric (sign) test, also indicating the significant reduction in systolic and diastolic BP for R x 2 (P = .003 and .010, respectively). Non-invasive BP monitoring combined with the proper analysis of the time series thus obtained could then provide a cost-effective approach for testing the circadian optimization of long-term ASA administration for both cardiovascular disease prophylaxis and prevention of preeclampsia.