Changes of Nocturnal Blood Pressure Dipping Status in Hypertensives by Nighttime Dosing of a-Adrenergic Blocker, Doxazosin Results from the HALT Study

Abnormal nocturnal blood pressure (BP) dipping status may be partly determined by nocturnal sympathetic activity. We studied the effect of nighttime dosing of an a1-adrenergic blocker, doxazosin, on the BP dipping status of 118 hypertensives, all of whom underwent 24-hour ambulatory BP monitoring before and after treatment. The mean nighttime/daytime ratio of systolic BP was increased (0.91 after therapy versus 0.89 at baseline, P,0.05). The patients were initially divided into 4 groups on the basis of their dipping status at the baseline assessment: 18 (15%) were extreme dippers, with a nighttime systolic BP fall of at least 20% of daytime BP; 46 (39%) were dippers (fall between 10% and 20%); 48 (41%) were nondippers (fall between 0% and 10%); and 6 (5%) were risers (nocturnal increase of systolic BP). A shift in dipping status toward less nocturnal BP dipping was observed after doxazosin therapy (P,0.05). Dipping status was determined by nighttime more than by daytime BP, and this was not explained by differences in the number of daytime and nighttime readings. The effects of doxazosin on the mean nocturnal systolic BP changes were an increase of 4.3 mm Hg in extreme dippers and decreases of 0.7 mm Hg in dippers, 12 mm Hg in nondippers, and 18 mm Hg in risers; the reduction was only significant in the latter 2 groups (both P,0.01). To estimate the effects of regression to the mean on the changes in dipping status, we also defined dipping status with the average of the BPs before and after doxazosin and found no difference in the degree of nighttime BP reduction among each group. The reduction of daytime BP was now significantly greater in the subgroups with less dipping: 6.4 mm Hg for extreme dippers and 16 mm Hg for risers (P,0.05). In conclusion, nighttime dosing with doxazosin markedly affects the nocturnal BP dipping status of hypertensives, but the apparently greater reduction in nighttime pressure in nondippers and risers may be, at least partly, due to the effect of regression to the mean. The most important determinants of the effect of doxazosin were the absolute BP levels, both day and night, rather than dipping status per se. (Hypertension. 2000;35:787-794.) Key word: blood pressure monitoring n adrenergic receptor blocking n circadian rhythm n prospective studies One of the most interesting features revealed by ambulatory blood pressure (BP) monitoring (ABPM) is the diurnal variation of BP.1 Most normotensive and hypertensive individuals show a decrease of BP of '10% during the night (the so-called dipping pattern), but there are others in whom the BP decrease may be reduced (nondippers)2– 6 or exaggerated (extreme dippers).7,8 These different patterns are increasingly thought to be of clinical relevance because there is evidence from a large prospective study6 that hypertensive patients who are nondippers are at greater risk of cardiovascular morbidity than dippers. There is also evidence that extreme dippers are at increased risk of ischemic stroke, possibly as a result of the excessive nocturnal BP fall.9 Another clinically relevant group is patients with renal failure, in whom nondipping is associated with microalbuminuria (an early marker of renal damage).4 One prospective study4 has found that nondipping is an independent risk factor for progression of renal disease. Thus, it is reasonable to suppose that deviations from the normal dipping pattern in either direction can have pathological significance, although for different reasons. Nondippers experience a greater “BP load” over 24 hours than dippers with the same daytime BP and, hence, may be more likely to develop target organ damage. On the other hand, extreme dippers might be more susceptible to ischemic episodes that result from low BP, especially in high-risk hypertensive patients with predisposing arterial stenosis (eg, elderly hypertensives7 and patients with carotid artery disease10 or coronary artery disease8) when antihypertensive therapy lowers nocturnal BP further. Received August 24, 1999; first decision September 16, 1999; revision accepted November 4, 1999. From the Hypertension Center (K.K., J.E.S., T.G.P.), Weill Medical College of Cornell University The New York Presbyterian Hospital, New York, and the Department of Psychiatry (J.E.S.), SUNY Stony Brook, NY. This study was supported, in part, by a grant from Pfizer Pharmaceuticals. Correspondence to Dr. Kazuomi Kario, MD, PhD, FACC, or Thomas G. Pickering, MD, DPhil, Hypertension Center, Department of Medicine, Weill Medical College of Cornell University, 1300 York Ave, New York, NY, 10021. E-mail [email protected] or [email protected] © 2000 American Heart Association, Inc. Hypertension is available at http://www.hypertensionaha.org 787 by gest on A uust 5, 2017 http://hyhajournals.org/ D ow nladed from The mechanisms of dipping are complex. Although both demographic factors (eg, older age and black race) and medical conditions (renal disease, diabetes, Cushing disease, etc) are associated with nondipping, lifestyle and behavioral factors are also important.11–13 Thus, both the level of physical activity during the day and the duration and quality of sleep during the night will influence the observed diurnal BP changes.14 The underlying physiological mechanisms are also likely to be complex. The nocturnal decrease of BP is in part determined by changes in sympathetic nerve activity. Thus both plasma and urine catecholamines are lower during the night than during the day,15 and direct recordings from muscle sympathetic nerves have also shown a decreased level of activity during slow-wave (but not REM) sleep.16 In previous studies that assessed heart rate variability, abnormal dipping status (nondippers and extreme dippers) was also partly determined by the abnormal variation of sympathovagal balance during the sleep and awake periods.17,18 Recently, there have been several papers on the differential effects of antihypertensive medications on the diurnal variation of ambulatory BP (ABP) levels in hypertensives with different nocturnal dipping status.19–25 Doxazosin, an a1adrenergic blocker, may suppress the a1-adrenergicdependent BP level selectively, suppressing nighttime BP levels only in hypertensive nondippers but not in hypertensive dippers.19 However, there is no report of nighttime dosing of doxazosin on nocturnal BP in extreme dippers, and most previous studies have not evaluated the possible effects of regression to the mean. In this substudy of the Hypertension and Lipid Trial (HALT),26,27 we have investigated the effect of nighttime dosing of doxazosin on the BP dipping status of hypertensive subgroups with different nocturnal BP