Prophylactic Aspirin Treatment: The Merits of Timing

Cornélissen, Germaine; Halberg, Franz; Prikryl, P; Dankova, E; Siègelovà, Jarmila; Dušek, J.

doi:10.1001/jama.1991.03470220044018

Cited by 35 publications

(11 citation statements)

References 4 publications

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“…Thus, the effects of ASA on lipoperoxides ␣-and ␤-adrenergic receptors and BP in clinically healthy subjects depend on the circadian timing of ASA administration. 9 Moreover, ASA has also been shown to produce an administration time-dependent Ͼ30% inhibition of angiotensin II, associated to the documented effects of ASA on plasma renin activity. 10 Most important, the administration time-dependent influence of ASA on BP was demonstrated previously in a randomized trial on healthy women 9 and other independent double-blind, randomized, placebo-controlled clinical trials conducted: first on clinically healthy subjects, 11 a second on normotensive and hypertensive subjects, 12 a third on pregnant women at high risk for preeclampsia, 13 and a fourth in untreated patients with mild hypertension.…”

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“…9 Moreover, ASA has also been shown to produce an administration time-dependent Ͼ30% inhibition of angiotensin II, associated to the documented effects of ASA on plasma renin activity. 10 Most important, the administration time-dependent influence of ASA on BP was demonstrated previously in a randomized trial on healthy women 9 and other independent double-blind, randomized, placebo-controlled clinical trials conducted: first on clinically healthy subjects, 11 a second on normotensive and hypertensive subjects, 12 a third on pregnant women at high risk for preeclampsia, 13 and a fourth in untreated patients with mild hypertension. 14 The findings of these BP studies, all of which used ambulatory BP monitoring (ABPM) to derive primary outcome variables, are consistent; BP-lowering effect of low-dose ASA is achieved when administered at bedtime but not on awakening.…”

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Differing Administration Time-Dependent Effects of Aspirin on Blood Pressure in Dipper and Non-Dipper Hypertensives

et al. 2005

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Abstract-Aspirin is a potent antioxidative agent that reduces vascular production of superoxide, prevents angiotensin II-induced hypertension, and induces NO release. Low-dose aspirin administered at bedtime, but not on awakening, has also been shown to reduce blood pressure, possibly enhancing the nocturnal trough in NO production. Because endothelium-dependent vasodilation is blunted through a decrease in NO release in non-dipper compared with dipper patients, we compared the administration time-dependent influence of aspirin on ambulatory blood pressure in dipper and non-dipper hypertensive subjects. We studied 257 patients with mild hypertension (98 men and 159 women), 44.6Ϯ12.5 years of age, randomly assigned to receive 100 mg per day of aspirin either on awakening or at bedtime. Ambulatory blood pressure was measured for 48 hours at baseline and after 3 months of intervention. Blood pressure was slightly elevated after aspirin on awakening (increase of 1.5/1.0 mm Hg in the 24-hour mean of systolic/diastolic blood pressure; PϽ0.028). A highly significant blood pressure reduction was observed in patients who received aspirin at bedtime (decrease of 7.2/4.9 mm Hg in systolic/diastolic blood pressure; PϽ0.001). The reduction in nocturnal blood pressure mean was double in non-dippers (11.0/7.1 mm Hg) compared with dippers (5.5/3.3 mm Hg; PϽ0.001). This prospective trial corroborates the significant administration time-dependent effect of low-dose aspirin on blood pressure, mainly in non-dipper hypertensive patients. The timed administration of low-dose aspirin could thus provide a valuable approach, beyond prevention of cardiovascular disease, in the blood pressure control of patients with mild hypertension. Key Words: blood pressure monitoring, ambulatory Ⅲ hypertension, mild Ⅲ nitric oxide Ⅲ circadian rhythm A cetylsalicylic acid (ASA; aspirin) is a nonsteroidal anti-inflammatory drug (NSAID) with demonstrated inhibitory effects on cyclooxygenases (COXs) responsible for arachidonic acid metabolism and prostaglandin production. 1 Previous studies have demonstrated that ASA is a potent antioxidative agent that markedly reduces vascular production of superoxide in normotensive and hypertensive rats. 2 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. 3 Moreover, recent results have demonstrated that ASA induces NO release from vascular endothelium. 4,5 This effect appears to be attributable to a direct acetylation of the endothelial NO synthase protein.No attention has been paid so far in these studies to potential administration time dependencies in the effects of ASA. However, a significant circadian variation has been demonstrated in several oxidative stress markers, including 8-hydroxydeoxyguanosine, malondialdehyde, and 8-isoprostane. 6 The peak concentrations of the 3 markers occurred early in the evening, with trough values obtained during nocturnal sleep. These p...

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Differing Administration Time-Dependent Effects of Aspirin on Blood Pressure in Dipper and Non-Dipper Hypertensives

et al. 2005

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“…Thus, the articles Low-Dose Aspirin in Prehypertension effects of ASA upon lipoperoxides, α-and β-adrenergic receptors, and BP in clinically healthy subjects depend on the circadian timing of ASA administration. 16 ASA has also been shown to produce a >30% inhibition of angiotensin II only when administered at bedtime, associated to the documented administration-time-dependent effects of ASA on plasma renin activity. 17 Moreover, an administration-time-dependent influence of ASA on ambulatory BP was previously demonstrated in a double-blind placebo-controlled trial on pregnant women at high-risk for preeclampsia 18 and a prospective trial on patients with untreated mild hypertension.…”

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Ambulatory Blood Pressure Control With Bedtime Aspirin Administration in Subjects With Prehypertension

Hermida

Ayala

Mojón

et al. 2009

American Journal of Hypertension

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According to the Seventh Report of the Joint National Committee, 1 prehypertension is a designation chosen to identify individuals at high risk of developing hypertension and suffering cardiovascular events. 2,3 In a recent study, Hansen et al. 4 found that progression from optimal or normal blood pressure (BP) to high-normal BP or hypertension carries nearly the same risk for cardiovascular events as sustained high-normal BP or hypertension. The Trial of Preventing Hypertension study 5 has suggested that treating prehypertension with an angiotensin-receptor blocker might be effective in slowing the rate of progression to hypertension. Similar conclusions have been recently reported for the angiotensinconverting enzyme inhibitor ramipril. 6 Several criticisms, however, have been raised regarding the design, results, and conclusions derived from the Trial of Preventing Hypertension and its recommendation for pharmacologic treatment of prehypertension. 7,8 Moreover, current guidelines 1,9 indicate that individuals who are prehypertensive are not candidates for drug therapy on the basis of their level of BP and they should be advised to practice lifestyle modification in order to reduce their risk of developing hypertension in the future. Because subjects at low or moderate cardiovascular risk show poor compliance to lifestyle modification, 10 other low-cost and effective ways of controlling BP in prehypertension may be clinically relevant.Acetylsalicylic acid (aspirin, ASA) is a nonsteroidal antiinflammatory drug with demonstrated inhibitory effects on cyclooxygenases, responsible for arachidonic acid metabolism and prostaglandin production. 11 Previous studies have demonstrated that ASA is a potent antioxidative agent that markedly reduces vascular production of superoxide in normotensive and hypertensive rats. 12 In addition, ASA was found to prevent angiotensin II-induced hypertension and cardiovascular hypertrophy in rats, mainly through its antioxidative properties in preventing the generation of superoxide. 13 Moreover, recent results have demonstrated that ASA induces nitric oxide (NO) release from vascular endothelium. 14,15 This effect appears to be due to a direct acetylation of the endothelial NO synthase protein.Most relevant, previous clinical trials demonstrate effects of ASA that depend on the daily time of administration. Thus, the Background Aspirin has been found to prevent angiotensin II-induced hypertension and to induce nitric oxide (NO) release from vascular endothelium. Low-dose aspirin has also been shown to reduce blood pressure (BP) when administered at bedtime, as opposed to upon awakening, in untreated hypertensive patients and highrisk pregnant women. Accordingly, we investigated the effects on ambulatory BP of aspirin administered at different times of the day in prehypertension.

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“…14 Moreover, the inhibition of collagen-induced platelet aggregation produced by ASA is circadian time-dependent. 15 Another factor to be taken into consideration is the pharmacokinetic observation that ASA has a faster rate of clearance when administered during the morning as compared with the evening.…”

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Administration Time–Dependent Effects of Aspirin on Blood Pressure in Untreated Hypertensive Patients

et al. 2003

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Abstract-Previous studies on the potential influence of aspirin on blood pressure have not taken into consideration the chronopharmacological effects of nonsteroidal anti-inflammatory drugs. This pilot study investigates the effects of aspirin on blood pressure in untreated hypertensive patients who received aspirin at different times of the day according to their rest-activity cycle. We studied 100 untreated patients with mild hypertension (34 men and 66 women), 42.5Ϯ11.6 (meanϮSD) years of age, randomly divided into 3 groups: nonpharmacological hygienic-dietary recommendations; the same recommendations and aspirin (100 mg/d) on awakening; or the same recommendations and aspirin before bedtime. Blood pressure was measured every 20 minutes during the day and every 30 minutes at night for 48 consecutive hours before and after 3 months of intervention. The circadian pattern of blood pressure in each group was established by population multiple-component analysis. After 3 months of nonpharmacological intervention, there was a small, nonsignificant reduction of blood pressure (Ͻ1.1 mm Hg; PϾ0.341). There was no change in blood pressure when aspirin was given on awakening (Pϭ0.229). A highly significant blood pressure reduction was, however, observed in the patients who received aspirin before bedtime (decrease of 6 and 4 mm Hg in systolic and diastolic blood pressure, respectively; PϽ0.001). Results indicate a statistically significant administration time-dependent effect of low-dose aspirin on blood pressure in untreated patients with mild hypertension. The influence of aspirin on blood pressure demonstrated in this study indicates the need to quantify and control for aspirin effects in patients using this drug in combination with antihypertensive medication. Key Words: antihypertensive agents Ⅲ blood pressure monitoring, ambulatory Ⅲ heart rate Ⅲ hypertension, mild Ⅲ drug therapy Ⅲ circadian rhythm T here is an extensive literature on the effects of acetylsalicylic acid (ASA, or aspirin), one of the most commonly consumed nonsteroidal anti-inflammatory drugs (NSAID), mainly in the prevention of cardiovascular events. 1-3 Although some of these studies reported average values of office blood pressure (BP) measurements for the patients before and after long-term administration of ASA or placebo, the study of a possible effect from ASA on BP was not a primary objective. In fact, the effect of ASA on BP was evaluated only in a few small studies. 4 -6 It has been reported that NSAID may increase BP both in normotensive and hypertensive subjects. 4,[7][8][9] The effects appear more marked in hypertensive subjects under treatment. 4,7 The mechanisms whereby NSAID may increase BP are not fully understood, nor it is known whether the increase in BP is a long-term effect. In any event, the dose of ASA regularly used to show anti-inflammatory effects is markedly larger than the dose used as anticoagulant 10 and recommended for prevention of cardiovascular events. [1][2][3] ASA use in hypertensive patients is expected to inc...

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Prophylactic Aspirin Treatment: The Merits of Timing

Cited by 35 publications

References 4 publications

Differing Administration Time-Dependent Effects of Aspirin on Blood Pressure in Dipper and Non-Dipper Hypertensives

Differing Administration Time-Dependent Effects of Aspirin on Blood Pressure in Dipper and Non-Dipper Hypertensives

Ambulatory Blood Pressure Control With Bedtime Aspirin Administration in Subjects With Prehypertension

Administration Time–Dependent Effects of Aspirin on Blood Pressure in Untreated Hypertensive Patients

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