Therapeutic effects of evening administration of guanabenz and clonidine on morning hypertension

The circadian variation in blood pressure in humans has been well established since the first chronic intra-arterial recordings were made in the late 1970s [1]. It is well known that many factors, such as physical activity and periods of rest, strongly influence the diurnal blood pressure pattern, as well as circadian variation in autonomic and hormonal systems. The importance of this circadian pattern has been brought to the fore by the now very extensive literature that has developed over the last two decades showing that cardiovascular events, such as stroke, transient ischaemic attacks, myocardial infarction and sudden cardiac death, occur most frequently during the morning hours, coinciding with the rapid rise in blood pressure and heart rate [2–5]. Stroke is one- to three-fold more likely in the morning [5], whereas the Framingham study showed that the incidence of sudden death was nearly two-fold more likely than at any other time [6]. It has been suggested that the circadian variation in haemodynamic, autonomic and hormonal systems that underlie the morning surge in blood pressure, a hypercoagulable state and a greater tendency for cardiac dysrhythmias, all synchronize to create an environment that predisposes to higher incidences of cardiovascular events [7]. This scenario, combined with long-standing cardiac or vascular hypertrophy, may form part of the explanation for the excessive cardiovascular events observed in the morning. However, there have been few, if any, studies directly examining this hypothesis. For example, it is not known whether the rate of rise, the level reached during the morning, or the night to morning blood pressure or heart rate difference, is the critical factor. Furthermore, it has yet to be established that the morning surge in blood pressure or heart rate is even correlated with excess cardiovascular events. Clearly, the mechanisms and risk factors underlying the morning blood pressure surge need to be fully and systematically investigated. Perhaps the most important issue is whether appropriate therapeutic prevention of the morning blood pressure surge can be developed and, if so, will this be beneficial in reducing cardiovascular events? Is the early morning surge in blood pressure a possible target for therapy? The information in this area is limited partly due to there being no established approaches for attenuating the morning elevation in blood pressure. Insufficient duration of action of antihypertensive drugs has been suggested as one reason for the peak in blood pressure in the morning in treated hypertensives [8], and a number of attempts have been made to better target therapy to this high-risk period of the day. DeQuattro and colleagues found that twice daily doses of labetolol decreased 24-h systolic blood pressure and reduced the morning systolic blood pressure but did not affect diastolic blood pressure or heart rate [9]. Two very recent studies have compared COER-verapamil with an angiotensin-converting enzyme inhibitor and showed that only verapamil attenuated the elevated morning blood pressure [10,11] but are in contrast to an earlier report suggesting that verapamil had no effect on the morning blood pressure rise [12]. These studies offer no real insight into the mechanism underlying the rate of rise in blood pressure. In this issue of the journal, Hashimoto et al. [13] focus on this problem directly. The authors examined the effect of evening administration of clonidine and guanabenz in hypertensive patients evaluated using a home-based blood pressure measurement. The aim of their study was to determine whether these drugs affected morning hypertension with bedtime administration. Patients were recruited to have morning hypertension and were assigned to either the guanabenz or the clonidine group. Blood pressure was assessed by self-monitored equipment in the home environment. The study showed that both drugs effectively lowered morning blood pressure and, in a subgroup of subjects, that the drugs were effective in reducing high evening blood pressure [13]. From these studies, there is evidence that morning hypertension can be prevented by the timed administration of appropriate therapy. The known mechanism of action of these drugs is to inhibit the sympathetic nervous system, suggesting that much of the rise in blood pressure in the waking hours is due to activation of the sympathetic nervous system, as supported by other studies. For example, Panza et al. [14] showed that circadian variation in vascular tone is related to α-adrenoceptor sympathetic vasoconstrictor activity because the α-adrenoceptor antagonist phentolamine had its greatest vasodilatory effect in the morning. A once daily dose of the α1-adrenoceptor antagonist doxazosin given at night was shown to reduce blood pressure, particularly in the morning [15]. Thus, taken together, it appears that targeting the sympathetic nervous system may be an appropriate way of specifically preventing the high levels of blood pressure that can occur in the early morning after waking. Some points of the article by Hashimoto et al. [13] are worthy of discussion. First, most patients were taking other antihypertensive agents, clouding the study considerably in pure scientific terms. It is not known whether there was a significant interaction between any of these treatments, or what would happen if untreated hypertensive patients were studied. However, this may be appropriate because the authors have recognized that treating patients to achieve a particular 24-h level of blood pressure is not always successful in terms of reducing the morning surge in blood pressure. Thus, the current results are most relevant to those patients already on therapy but without adequate control of morning blood pressure. The second consideration is that only evening administration of a single dose was examined, and thus it is difficult to assess whether this treatment is optimal or could be refined further. The third aspect worthy of consideration is the methodology used to assess blood pressure. Home blood pressure recordings systems are inexpensive and quite effective but with known operator weaknesses [16]. The very low cost factor does enable studies to be performed with very large numbers, which would be difficult and expensive to carry out with ambulatory blood pressure monitors. The study by Hashimoto et al. [13] may have been improved by ambulatory monitoring in order to more fully show the time course of the effect of clonidine and guanabenz. On the other hand, they were able to study two groups of patients three times. Thus, if used with caution, they may have a place in clinical research as an adjunct, rather than a replacement, for ambulatory blood pressure monitors. How to assess the morning surge in blood pressure? One of the main problems in this area is that, until now, there has been no accepted way of measuring the rate of rise in blood pressure or heart rate after waking. There is no consensus concerning the correct measurement to study or target with therapy. The usual analytical approach involves aggregation of multiple measurements to provide mean 24-h, mean day and mean night measurements on the basis of fixed clock times or synchronizing records relative to the time of waking. Thus, these data are segmented into a higher blood pressure period, approximating the daytime awake period and a low blood pressure period corresponding to a night-time sleep period. The difference in these two values constitutes the major circadian variation in blood pressure and has been used to evaluate the morning increase in blood pressure [17]. However, this approach is limited, and an objective mathematical model may better elucidate important components of the blood pressure and heart rate curve that may be related to the high risk associated with diurnal variation. Previous mathematical approaches include the Minnesota Cosinor method, which assumes that the high and low blood pressure periods have the same length and that the diurnal pattern follows a smooth symmetrical sine wave [18]. Fourier analysis, which constitutes the super position of multiple cosine functions of different amplitude and frequency, has also been tried but is overly complex [19]. The square wave model involves the estimation of the daytime and night-time plateau with a vertical transition between the two periods, and is mathematically a better fit than the Cosinor method [20]. However, the assumption of an abrupt transition from day to night is clearly not the case. To date, there is no simple method available to determine the rate of increase in blood pressure and heart rate in the morning separately from the decrease in blood pressure and heart rate in the evening. We have proposed a method which will measure the rate of rise in blood pressure and heart rate in the early morning period [21]. We found that hypertensives have a higher rate of rise in blood pressure than normotensives. Thus, there are now appearing methodologies that enable us to accurately measure the morning blood pressure surge from all angles. Is early morning surge in blood pressure a long-term risk factor for patients? This is perhaps the burning question. Clearly, the answer remains unknown. This area recently was given excellent coverage in a review by Weber [7] who states that, while a direct link has yet to be established, it can be postulated that the early morning surge in blood pressure may be a factor in precipitating events. Although there have been a number of very large outcome studies related to determining cardiovascular risk, such as the HOPE study [22], none have included assessment of the morning surge in blood pressure. Conversely, the outcome study (CONVINCE) was the first to determine primary prevention of cardiovascular events using a formulation of verapamil (COER-verapamil), which has its highest plasma concentrations during the early morning hours when cardiovascular risk is the greatest. This trial did not have an ambulatory component and, unfortunately, was stopped prematurely for economic reasons [23]. Thus, there is a clear need to establish whether there is a link between the early morning blood pressure surge and outcome. The study by Hashimoto et al. [13] offers a simple therapeutic option of a well-established therapy to answer this question. A long-term clinical trial giving clonidine in the evening in those patients with poorly treated morning blood pressure and measuring outcome might appear to be the next logical step, although such a study would need to be set up very carefully given the numerous interactive factors, appropriate controls, and so on. There is also the very important ethical issue of an awareness of not treating the morning surge in blood pressure very effectively in some patients. A more cautious approach might be to test this idea in an animal model first. With a clearer understanding of the mechanisms underlying the morning risk, a more appropriate clinical trial can be designed. Conclusion The most important aspect of the study by Hashimoto et al. [13] is the demonstration that a relatively simple treatment with established antihypertensive drugs (guanabenz and clonidine) given at night can selectively lower morning blood pressure in patients already receiving therapy who have poor hypertension control in the morning. The study is an important stepping stone toward unravelling the causes and mechanisms underlying the excess cardiovascular events that occur at this time. The authors propose a simple way of treating the morning blood pressure rise in a relatively safe way and point the finger in the direction of the sympathetic nervous system which these drugs specifically target. In the long term, an exciting prospect would be to optimize antihypertensive therapy to minimize the risk of cardiovascular events.