Hypertension affects approximately 1 billion individuals worldwide and more than 50 million people in the United States alone [1]. There is a direct and stepwise relationship between hypertension grades and stroke, myocardial infarction, renal disease, and heart failure. This relationship is independent of other risk factors. The benefit of antihypertensive therapy has been widely demonstrated [2]. Intensive blood pressure lowering is associated with further reduction of major cardiovascular events [3]. Although improvements have been reported, according to the National Heart, Lung and Blood Institute awareness (70%), treatment (59%), and control (34%) of hypertension remain suboptimal [1]. Poor compliance with lifestyle changes and antihypertensive treatment leads to persistence of high-risk status in patients with hypertension and leaves room for improvement. Recent data tend to show that low-dose aspirin may be an effective, well-tolerated, and low-cost treatment to improve outcome in such patients.
BIOLOGICAL AND PHYSIOLOGICAL BASES OF ASPIRIN’S VASCULAR EFFECTS
Aspirin has been used for more than 100 years for its action on pain, fever, and inflammation. During the past 30 years, aspirin’s widely demonstrated antiplatelet effect via an irreversible acetylation of platelet cyclooxygenase leads to a permanent inhibition of thromboxane A2 [4]. This action has led millions of people—of those many high-risk patients—to use it worldwide for the secondary, as well as primary, prevention of cardiovascular disease [5].
More recently, the role of oxidative stress in the development of hypertension and atherosclerosis has been highlighted [6]. Concomitantly, beneficial effects of low-dose aspirin in populations such as hypertensive patients with high diastolic blood pressure in the Hypertension Optimal Treatment (HOT) trial [3] generated the hypothesis that such benefit may not be explained only by aspirin’s antiplatelet effects but also by its anti-inflammatory and antioxidative action.
The link between inflammation and enhanced super-oxide anion (O2-) production is well established. Enhanced O2- production has been associated with impaired endothelial vasodilatation and reported to play a role in the development of hypertension in both animal models [7] and humans [8]. Recent data suggest an antioxidative action of aspirin and a link between such action and endothelial function and subsequent effects on hypertension.
In vitro models show that low-dose aspirin administration is associated with an increase in the production of nitric oxide (NO) and O2- scavenging. The effect on NO synthesis is likely to be related to a direct acetylation of endothelial NO synthase and independent of both the cyclooxygenase inhibitory action and O2- scavenging effect. The effect appears to be specific to aspirin as neither aspirin’s metabolite salicylic acid nor indomethacin have any effect on NO production in the same model [9,10].
Another antioxidant pathway described is the aspirin induction of the stress protein heme oxygenase 1, which has been reported to have cytoprotective and antioxidant effects [11-13]. Heme oxygenase 1 is the enzyme catalyzing the degradation of heme. The degradation of heme leads to the generation of bilirubin, iron, and carbon monoxide. Bilirubin has been linked to antioxidant and antiatherogenic effects [14,15]; iron activates the translational expression of ferritin, which has been associated with cytoprotective and antioxidant [16] actions; and finally both antiapoptotic and vasodilator effects have been reported in association with carbon monoxide. The aspirin-related induction of heme oxygenase 1 may be a consequence of enhanced NO production, triggered itself by 15-epi-lipoxin A4, a mediator of aspirin’s anti-inflammatory effect [17].
Very recently, a 12-week treatment of different doses of aspirin (from 81 to 1300 mg) was reported to be associated with a marked increase of NO formation in 70 patients with metabolic syndrome in a randomized double-blinded trial [18]. The absence of effect modification by dose, reported by the authors, supports the use of low-dose aspirin in this primary prevention setting.
The antioxidant effect of aspirin has been linked to reduced vascular tone and prevention of hypertension in some recent studies. Such effects have been reported in both normotensive and spontaneously hypertensive rats where long-term aspirin therapy is associated with reduced vascular O2- production by lowering tissue nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity and inhibited angiotensin-II-induced superoxide production and blood pressure elevation [19]. In the same hypertensive rat model, the subsequent age-dependent development of hypertension was attenuated by long-term aspirin therapy, but no hypotensive effect was noted once hypertension was established—similar to what was found in normotensive rats. In another in vitro and in vivo rat model, Wu et al demonstrated a prevention of angiotensin-II-induced O2- production, hypertension, and cardiac hypertrophy by chronic aspirin therapy, but not by its unacetylated metabolite salicylic acid or indomethacin and ibuprofen [20].
In human experiences, the beneficial effect of aspirin on endothelial function and vasodilator reserve has been demonstrated among patients with hypercholesterolemia, where administration of aspirin significantly improves the altered baseline brachial artery vasodilator response to acetylcholine, but does not change the endothelium-independent vasodilator response to nitroprusside [21]. Comparable effects of intraarterial infusion of aspirin or long-term oral administration of aspirin have also been reported on brachial artery’s endothelium-dependent vasodilator response among normal, hypertensive, hypercholesterolemic [22], and treated hypertensive-hypercholesterolemic patients [23].
Based on these findings, there is strong evidence that on top of its antiplatelet effects, aspirin improves endothelial function and participates in reducing vascular tone through antioxidant properties. Such effects may be of major interest in the management of patients with hypertension.
CLINICAL TRIALS OF ASPIRIN USE IN PATIENTS WITH HYPERTENSION
The benefit of aspirin in secondary prevention of cardiovascular disease is widely demonstrated. The use of aspirin in the setting of primary prevention among high-risk and healthy patients still remains controversial because of the bleeding risk. Moreover, a controversy appeared in the 1990s on a possible negative pharmacological interaction between aspirin, reducing vasodilator prostaglandin production, and antihypertensive therapy by angiotensin-converting enzyme (ACE) inhibitors (and later angiotensin II receptor blockers [ARBs]), acting through production of such prostaglandins [24].
Two major studies were designed to assess the benefit of aspirin therapy in hypertension or in the general setting of patients at risk of cardiovascular events (Table 1). The HOT trial was a randomized, open-label, blinded end point, evaluation trial with a 2x2 factorial design assessing on one hand the benefit of optimal treatment of diastolic blood pressure and, on the other, the benefit of low-dose (75 mg per day) aspirin therapy among patients with hypertension [3]. The study included 18,790 patients among whom <10% had a past history of cardio- or cerebrovascular disease. After a mean follow-up of 3.8 years, the analysis showed a significant association between aspirin and the reduction (relative risk 0.85 [0.73-0.99]) of the composite primary end point (cardiovascular death, myocardial infarction, or stroke), as well as rates of myocardial infarction (relative risk 0.64 [0.49-0.85]). Although rates of fatal bleeding were comparable between the two groups (0.07 vs 0.09%), aspirin use was associated with a 1.8 times higher risk of both nonfatal major (1.4 vs 0.8%) and minor (1.7 vs 0.9%) bleeding.
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TABLE 1. Studies with low-dose aspirin in patients with hypertension |
The benefit of aspirin was consistent among all subgroups of patients with a trend toward more benefit among patients at high cardiovascular risk and a significantly greater benefit among those with serum creatinine levels >1.3 mg dL-1 [25].
The HOT trial also put an end to the controversy concerning the possible negative interaction between aspirin and antihypertensive therapy—in particular, the ACE inhibitors. The trial showed that there were similar antihypertensive effects in aspirin or placebo groups and identical benefit of aspirin whether or not patients received ACE inhibitors [26].
To clarify a similar controversy on the interaction between aspirin and ARBs, a secondary analysis was conducted. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial [27] stratified aspirin use at baseline (1970 out of 9103 patients). The analysis showed similar blood pressure levels in patients with aspirin and losartan, compared to those with aspirin and atenolol. Surprisingly, the authors found a positive statistical interaction between aspirin and studied treatments. The benefit of losartan was greater among those treated with aspirin at baseline than it was among those not treated with aspirin. Whether this finding is a true pharmacological interaction or selection bias remains unclear. Then again such a finding excludes a negative interaction between aspirin and inhibitors of the renin-angiotensin-aldosterone pathway.
Similar to the HOT trial, the Primary Prevention Project (PPP) [28] assessed the benefit of 100 mg aspirin daily and vitamin E in a 2x2 factorial design, which employed 4495 patients with no past history of cardiovascular disease but at least 1 major risk factor—hypertension (68%). This trial showed a reduction of cardiovascular mortality (relative risk 0.56 [0.31-0.99]) and total cardiovascular events and diseases (relative risk 0.77 [0.62-0.95]). Concordantly, the PPP trial showed an excess of nonfatal major or minor bleeding associated with aspirin use (1.1 vs 0.3%, p = .0008) after a mean follow-up of 3.6 years, while only 1 of 4 deaths related to bleeding occurred in the aspirin group.
A secondary analysis of a small subgroup of the PPP trial treated patients with hypertension (n = 142) who had 24-h ambulatory monitoring of the blood pressure at baseline and follow-up. It failed to show a significant effect of aspirin on levels of either systolic or diastolic blood pressure [29]. However, such results should be considered with caution as the study is likely to be underpowered to demonstrate any difference.
TIME-DEPENDENT EFFECTS OF ASPIRIN ON BLOOD PRESSURE
Growing data support the hypothesis that aspirin may affect blood pressure differently depending upon the time of administration, which in turn points to a different mechanism of action than that of its long-lasting antiplatelet effects. A recently published, randomized, double-blind crossover study employing 16 grade 1 patients with hypertension compared the effects of aspirin 100 mg daily administered at bedtime versus the effects upon awakening. The bedtime administration was associated with a reduced average 24-h plasma renin activity and cortisol, dopamine, and norepinephrine excretion, while both groups experienced similar aldosterone levels [30].
In a series of randomized clinical trials, low-dose bedtime aspirin administration, compared with hygienic-dietary recommendations alone and/or other administration times, has been reported to be associated with significant blood pressure reduction on the average over a period of 24- or 48-h ambulatory blood pressure monitoring among a variety of patients [23,31-36]. Such groups include pregnant women [31,32] and pregnant women at risk of preeclampsia, those with untreated hypertension [33,34], patients with treated hypertension [23], mild hypertensive dippers and more interestingly nondippers [35], and finally those who are prehypertensive [36]. Although somewhat speculative, the circadian rhythms of α- and β-adrenergic stimulations, the nocturnal peak of plasma renin activity, and the enhanced nocturnal trough in the production of NO have been advanced as possible mechanisms of such administration–time-dependent responsiveness. Despite the modest magnitude of blood pressure reduction and its variability among different groups of patients, the data seem consistent. The clinical benefit of such blood pressure reduction needs to be assessed by adequately designed and sized trials.
ASPIRIN AND HYPERTENSION DURING PREGNANCY
Hypertension and preeclampsia, associated with maternal and neonatal mortality and morbidity, are reported to complicate 10 to 15% of pregnancies. Although the mechanism is still unclear, placental ischemia, platelet activation, and imbalance between prostacyclin and thromboxane A2 production have been advanced as pathophysiological explanations. Hence, based on aspirin’s cyclooxygenase inhibitor activity, several studies assessed the benefit of low-dose aspirin in the prevention of gestational hypertension and preeclampsia in the past decade, producing controversial data. Two recent meta-analyses of more than 30,000 patients in randomized trials report a significant but mild-to-moderate benefit of low-dose aspirin in the development of preeclampsia (relative risk 0.9 [0.83-0.98]) [37] and infant deaths (relative risk 0.84 [0.74-0.96]) [38]. In addition, there was no excess in antepartum bleeding but a trend toward more postpartum bleeding (relative risk 1.06 [1-1.13]). None of these studies succeeded in defining high-risk patients who would benefit most from aspirin therapy or did they provide strong enough evidence for a general use of aspirin in all pregnant women. As in other patient groups, the effect of low-dose aspirin on blood pressure among pregnant women seems to be time-dependent [31,32].
CONCLUSION
Low-dose aspirin is without a doubt associated with a reduction of cardiovascular events in patients with hypertension, as it is with an excess of nonfatal bleeding. Its association with antihypertensive therapy including ACE inhibitors and ARBs is safe. Its benefit seems to increase in a stepwise fashion with the baseline risk of cardiovascular events. Growing evidence tends to show that not only aspirin’s antiplatelet effect, but also its antioxidant and cytoprotective actions, may be beneficial in patients with hypertension. The latter effects may prevent endothelial dysfunction, restore vasodilator reserve, and subsequently lead to blood pressure lowering effects. Such effects seem to be synchronized on still unclear circadian rhythms, affecting the renin-angiotensin axis, cortisol production, and adrenergic mediators, with an optimal effect when aspirin is taken at bedtime.
The recent reappraisal of the European guidelines on hypertension management already recommends low-dose aspirin in hypertensive patients with previous cardiovascular events, history of cardiovascular disease, impaired renal function, or those at high cardiovascular risk [39]. Whether low-dose aspirin may have specific antihypertensive effects alone or in combination with the wide spectrum of antihypertensive agents requires specifically designed trials.
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