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Nocturnal fall of blood pressure with antihypertensive therapy and recurrence of ischaemic stroke: ‘the lower the better’ revisited

Sierra, Cristina; Coca, Antonio

doi: 10.1097/01.hjh.0000170372.26140.c3
Editorial commentaries

Hypertension Unit, Instituto de Medicina y Dermatología, Hospital Clinic (IDIBAPS), University of Barcelona, Barcelona, Spain

Correspondence and requests for reprints to Dr Antonio Coca, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain. Tel: +34 93 227 57 59; fax: +34 93 227 57 24; e-mail:

Stroke is the third most-frequent cause of death after cancer and heart disease in developed countries, and is one of the most common reasons for developing cognitive impairment and vascular dementia [1]. High blood pressure is a major risk factor for stroke, and a continuous relationship between blood pressure and the occurrence of stroke [2,3] has been well established. However, evidence from hypertension treatment trials has shown that relatively small reductions of blood pressure [5–6 mmHg in diastolic blood pressure (DBP), 10–12 mmHg in systolic blood pressure (SBP) over 3–5 years] reduce the risk of stroke by more than one-third [4].

In addition, high blood pressure levels after stroke increase the risk of recurrent stroke [5] and recent trials indicate that reduction of blood pressure with combined antihypertensive therapy is beneficial in reducing stroke recurrence [6]. The UK transient ischaemic attack (TIA) aspirin trial data demonstrated a direct and continuous relationship between blood pressure (both SBP and DBP) and recurrent stroke in patients with previous minor stroke or TIA [5]. In that study, a lowering of DBP of approximately 5 mmHg was associated with a reduction in stroke by one-third. In the PROGRESS trial [6], patients who were treated with a combination of the angiotensin-converting enzyme inhibitor (ACEI), perindopril, and the diuretic, indapamide, showed a significantly higher reduction of stroke recurrence than patients who were treated with the ACEI in monotherapy. This may be explained by the combination inducing a greater reduction of blood pressure. In a systematic review, Rashid et al. [7] recently demonstrated that evidence from randomized controlled trials supports the use of antihypertensive agents in lowering blood pressure for the prevention of vascular events in patients with previous stroke or TIA. In their meta-analysis, vascular prevention was associated positively with the magnitude by which blood pressure was reduced [7]. Antihypertensive treatment and blood pressure control have also shown a lower incidence of the progression of silent cerebral infarction [8].

However, the issue of lowering blood pressure after a cerebrovascular event has been controversial for some years because blood pressure reduction might worsen cerebral perfusion when autoregulation remains chronically damaged, or when there is severe carotid artery stenosis. Some studies have suggested that lowering blood pressure does not always have favourable effects on stroke recurrence, and that a J-shaped relationship between blood pressure and recurrent stroke could be observed in patients with a recent history of ischaemic stroke [9,10]. In cross-sectional studies, Kario et al. [11] and Watanabe et al. [12] hypothesized that an excessive nocturnal dip might have caused silent cerebrovascular lesions in elderly hypertensives. Kario et al. [11] showed that, in addition to a nondipping circadian blood pressure pattern, patients who were defined as extreme dippers (nocturnal reduction of SBP ≥ 20% of waking SBP) had advanced silent cerebrovascular damage. In a group of 575 older Japanese hypertensive patients followed for an average of 3.4 years, Kario et al. [13] also showed a J-shaped relationship between dipping status and stroke incidence (extreme dippers 12%, dippers 6.1%, nondippers 7.6%, reverse dippers 22%). By contrast, other studies have shown that a reduced nocturnal blood pressure dip may have an adverse effect on the development of silent ischaemic lesions and symptomatic stroke in patients with a history of symptomatic lacunar infarcts [14].

Thus, a number of studies suggest that either a reduced (non-dipper or reverse dipper) or excessive nocturnal fall of blood pressure (extreme dipper) could be damaging for the brain, meaning that the issue of how physicians should manage blood pressure after stroke is still unclear. There is no doubt that hypertensive patients who have suffered a stroke should reduce their blood pressure at the same time as preserving the physiological circadian pattern of blood pressure or dipper profile (nocturnal reduction of blood pressure between 10% and 20% of waking blood pressure). It is important to note that a reduced day/night ratio, the so-called non-dipping pattern (nocturnal reduction of blood pressure < 10% of waking blood pressure), following acute stroke is related to an altered autonomic regulation, leading to pathological activation of the sympathetic nervous system [15,16]. This may occur also in normotensive patients and could be one of the possible explanations for the beneficial effects of blood pressure reduction observed in normotensive patients with previous stroke [6]. In a recent issue of the journal, Fujiwara et al. [17] described a correlation between nocturnal reduction of blood pressure and regional cerebral blood flow in the carotid artery area in patients with ischaemic stroke. In their study, which was performed in 47 hypertensive patients with previous ischaemic stroke (more than 1 month before entering the study) who received antihypertensive treatment, regional cerebral blood flow measured by single-photon emission computed tomography was directly dependent on the magnitude of the nocturnal blood pressure fall. These patients had a mean daytime ambulatory blood pressure of 134/83 mmHg and a mean nighttime ambulatory blood pressure of 127/78 mmHg. The authors concluded that antihypertensive treatment promoting nocturnal blood pressure dipping induces a protective effect on cerebral circulation among patients with ischaemic stroke.

To maintain a constant blood flow, an autoregulatory mechanism of the vascular resistance is activated at the cerebral level in response to variations in systemic blood pressure. Hypertension and atherosclerosis associated with ageing cause adaptive cerebral vascular changes, leading to a shift in the lower limit of autoregulation towards high pressure, with impaired tolerance to bood pressure decreases. The shift appears to be proportional to the severity of the hypertension. The curve shifts back to lower levels after effective antihypertensive treatment [18]. The recurrence of ischaemic stroke occurs when the level of blood pressure is less than the lower limit of autoregulation of cerebral blood flow. Whether cerebral hypoperfusion due to systemic hypotension can induce brain damage remains uncertain. A recent study in 535 patients with previous stroke, followed for 4 years, found a stroke recurrence risk of 2.4 [95% confidence interval (CI) 1.38–4.27] in patients with DBP ≥ 80 mmHg compared to those with DBP < 80 mmHg. The risk for patients with SBP ≥ 140 mmHg was also 2.4 (95% CI 1.39–4.15) compared to those with SBP < 140 mmHg [19]. In the PROGRESS study [6], mean blood pressure at entry was 136/79 mmHg in non-hypertensive patients and mean blood pressure reduction among those treated with combination therapy was 12.3 mmHg for SBP and 5.0 mmHg for DBP. There was a significant reduction in the recurrence of stroke in both hypertensive and non-hypertensive patients who received combination therapy and who had the greatest lowering of blood pressure. Although the study by Fujiwara et al. [17] supports the idea of ‘the lower the better’, excessive nocturnal blood pressure fall (extreme dippers) is probably best avoided. This underlines the importance of the time of day when the antihypertensive medication is given to patients with previous stroke from the perspective of chronotherapy. When treating hypertensive patients, the objective is to reduce blood pressure at the same time as preserving the physiological dipper circadian pattern, which is particularly important in those patients who have suffered a stroke. For this purpose, ambulatory blood pressure monitoring should be routinely performed in hypertensive survivors of stroke to determine the number and doses of antihypertensive drugs. The time of day when these drugs should be given should depend on the circadian pattern, thereby avoiding the non-dipper, riser and extreme dipper circadian profiles induced by treatment.

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