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1 AJH 1999;12: Differential Effects of Morning and Evening Dosing of Nisoldipine ER on Circadian Blood Pressure and Heart Rate William B. White, George A. Mansoor, Thomas G. Pickering, Donald G. Vidt, Howard G. Hutchinson, Roger B. Johnson, and Robert Noveck The time of administration of once-daily antihypertensive agents may have a significant impact on blood pressure control during awake and sleep periods. Using 24-h ambulatory monitoring, we compared the effects of morning and evening dosing of the long-acting dihydropyridine calcium channel blocker, nisoldipine extended-release (ER), on circadian blood pressure (BP) and heart rate in patients with mild-to-moderate hypertension. After completing a 3-week placebo run-in period, 85 patients were randomized to morning versus evening nisoldipine ER treatment at a fixed 20-mg dose. Patients were treated for 4 weeks, followed by crossover to the alternate dosing regimen for 4 additional weeks. Twenty-four hour ambulatory monitoring was performed at baseline and at 4 and 8 weeks after randomization. Awake and sleep times were determined by electronic activity recorders (Actigraphy). Similar least-squares ( SE) mean changes from baseline in 24-h BP (systolic BP/diastolic BP: 11.9/ /0.5 v 11.6/ /0.5 mm Hg) and heart rate (1.0/ /0.4 beats/min) occurred with morning and evening administration, respectively. A significantly greater effect on awake diastolic BP (systolic BP/diastolic BP: 12.6/ /0.4 v 11.3/ /0.4 mm Hg; P.16/.01) was observed with morning dosing compared with evening dosing. In addition, small increases in sleep and early morning heart rate were seen with evening compared with morning administration of nisoldipine (sleep, v beats/min; P <.001; early morning, v beats/min; P.002). These differential effects on awake BP and sleep heart rate were also observed in patients who had normal (dippers) and elevated (nondippers) BP values during sleep. Appropriate evaluation of the efficacy and safety of long-acting antihypertensive agents is essential when evening administration is being considered. In the present study, the timing of nisoldipine ER administration had no effect on mean changes in BP and heart rate over a 24-h period. However, nisoldipine ER had some differential effects during sleep and awake periods with morning relative to evening dosing. Am J Hypertens 1999;12: American Journal of Hypertension, Ltd. KEY WORDS: Hypertension, ambulatory blood pressure monitoring, circadian rhythm, nisoldipine ER, morning and evening administration. Received August 21, Accepted January 5, From the University of Connecticut School of Medicine, Farmington, Connecticut (WBW, GAM); Cornell University Medical College, New York Hospital, New York, New York (TGP); Cleveland Clinic, Cleveland, Ohio (DGV); Medical Affairs Department, Zeneca Pharmaceuticals, Wilmington, Delaware (HGH, RBJ); and Tulane School of Medicine, New Orleans, Louisiana (RN). Support was provided by the National Institutes of Health General Clinical Research Grant MOI-RR and by grants from Zeneca Pharmaceuticals and the Patrick and Catherine Weldon Donaghue Medical Research Foundation. Address correspondence and reprint requests to William B. White, MD, Professor of Medicine and Chief, Section of Hypertension and Clinical Pharmacology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT by the American Journal of Hypertension, Ltd /99/$20.00 Published by Elsevier Science, Inc. PII S (99)

2 AJH AUGUST 1999 VOL. 12, NO. 8, PART 1 MORNING V EVENING DOSING OF NISOLDIPINE 807 The effects of time of dosing on the pharmacodynamics of long-acting, once-daily antihypertensive drugs are an important consideration for antihypertensive therapeutics. 1 Studies using ambulatory monitoring of blood pressure (BP) and heart rate have shown that altering the dosing time of antihypertensive agents may have a clinically meaningful effect on nocturnal BP. 2 4 In addition, some agents given once or twice daily may not provide adequate BP control, and the antihypertensive effect of some agents may taper by the end of a 24-h period. 3,5 Thus, it is appropriate to perform studies with once-daily hypertensive therapies to evaluate the effects of dosing time on circadian BP and heart rate. Nisoldipine is a potent vascular-selective dihydropyridine calcium antagonist used in the treatment of hypertension. To optimize the drug s time-effect profile over the 24-h dosing period, nisoldipine was developed in a coat-core, extended-release (ER) formulation. 6 After oral administration of nisoldipine ER, drug concentration increases for 6 to 12 h, and then a plateau is maintained for up to 24 h. 6,7 The elimination half-life of nisoldipine ER ranges from 7 to 12 h. Nisoldipine ER provides 24-h antihypertensive efficacy when administered in the morning, typically in a fasting state. 8 To investigate whether time of administration influences the 24-h efficacy of nisoldipine ER, we performed a double-blind, crossover study using ambulatory monitoring of BP and heart rate in patients with essential hypertension. MATERIALS AND METHODS Study Patients The study protocol and consent forms were approved by the institutional review boards of the various centers, and all patients provided written informed consent. Men and women, 21 years of age or older, with stage I or II hypertension defined by the criteria of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) were eligible for the study. 9 Patients were included if the average of three seated office DBP measurements after 5 min of rest was 90 and 109 mm Hg at the end of the singleblind, placebo run-in period. Key exclusion criteria were any known form of secondary hypertension, systolic BP 200 mm Hg or diastolic BP 110 mm Hg; bradycardia (heart rate 45 beats/min) or tachycardia (heart rate 100 beats/ min), stroke or myocardial infarction in the previous 6 months, congestive heart failure (left ventricular ejection fraction 40%), clinically significant hepatic or renal disease, uncontrolled diabetes mellitus, life-style factors such as night-shift work or regular naps during the daytime, or history of allergy or intolerance to study medications. Study Design The study had a randomized, doubleblind, crossover design that included a 3-week, singleblind, placebo run-in phase and an 8-week doubleblind active treatment phase (Figure 1). Patients who successfully completed the baseline screening period entered the run-in period and received placebo in the FIGURE 1. The study design was double-blind, double-dummy, and crossover; ambulatory BP recordings were performed at the end of placebo baseline and after 4 and 8 weeks of double-blind morning or evening nisoldipine ER treatment.

3 808 WHITE ET AL AJH AUGUST 1999 VOL. 12, NO. 8, PART 1 morning and evening. After completing the run-in period, patients were randomly assigned to receive morning or evening administration of 20 mg nisoldipine ER for 4 weeks. The actual treatment given to each patient was determined at each center by a randomization schedule, and patients were allocated to treatment in balanced blocks. Patients in one group received nisoldipine ER in the morning (between 7 am and 9 am) and matching placebo in the evening (between 9 pm and 11 pm), whereas those in the other group received matching placebo in the morning and nisoldipine ER in the evening. After receiving 4 weeks of active therapy, the patients then received nisoldipine ER by the alternate dosing schedule for 4 weeks. Patients were instructed to fast for 1 h before and after taking study medication, and to take their medication at the same time each day, regardless of scheduled office visits or ambulatory BP monitoring. The effects of nisoldipine ER after morning and evening administration were assessed by determining changes in 24-h ambulatory BP and heart rate and office BP and heart rate. Ambulatory Blood Pressure Recordings Twentyfour hour ambulatory BP and heart rate were measured with SpaceLabs monitors (Redmond, WA). 10 Ambulatory BP was measured 24 h before randomization and 24 h before the last day of treatment during the two active treatment periods. Patients were fitted with a monitor on the same arm used for office BP determinations, with cuff size adapted to the arm circumference. All monitors were compared against a standard mercury sphygmomanometer to ensure that office diastolic BP and ambulatory BP were in agreement ( 7 mm Hg). BP and heart rate were recorded every 15 min over the 24-h period. Successful monitoring occurred when 80% of readings were valid over the monitoring period, including a minimum of two valid readings/h (with an allowance for a maximum of two nonconsecutive h of missing data) and at least 4hofvalid measurements after patients awakened in the morning. If these criteria were not satisfied, the monitoring study could be repeated. The time of dosing of medication, sleep, and awakening were recorded on diary cards. A Mini Motionlogger Actigraph (Ambulatory Monitoring Inc., Ardsley, NY), a wristwatch-sized device that records motion, was attached to the wrist of the other arm and used to determine sleep and awake times. 11 It provides an objective determination of sleep times by a built-in algorithm, or by use of an event marker button activated by a patient when retiring or awakening. Each activity monitor was synchronized with the ambulatory BP monitor time at the start of recording. Patients were instructed to activate the recorder before sleeping and after awakening. The times TABLE 1. BASELINE CHARACTERISTICS OF PATIENTS Gender, n (%) Women 32 (43) Men 43 (57) Mean age, years (SD) 57.8 (9.1) Race, n (%) White 46 (61) Black 26 (35) Hispanic 2 (3) Asian 1 (1) Mean weight, kg (SD) Women 77.3 (14.0) Men 85.4 (15.5) Office blood pressure Systolic BP, mm Hg (SD) (13.9) Diastolic BP, mm Hg (SD) 97.3 (5.0) Heart rate, beats/min (SD) 75.5 (10.0) determined from these Actigraph recordings were the primary data used for sleep and awake BP and heart rate analyses, and diary card information was used when activity monitor data could not be interpreted. It has been demonstrated that more precise values are obtained for both mean sleep BP and sleep BP loads when actual times of wakefulness and sleep are used rather than arbitrary times of daytime and nighttime. 12 In addition, electronic activity improves the ability to obtain objective and precise times of wakefulness and sleep, 13 which is of relevance in a study that assesses the chronobiologic impact of antihypertensive drug dosing times. Statistical Analyses The primary objective was to evaluate whether 24-h BP changes with nisoldipine ER were independent of the time of nisoldipine administration, such that the mean reductions in diastolic 24-h ambulatory BP were equivalent for both morning and evening dosing. On the basis of a maximum difference in response between dosing schedules acceptable for clinical equivalence of 3.4 mm Hg, with a.05 level of significance and 80% testing power, the total sample size required was 60 patients. The sample size was based on an estimated within-subject standard deviation of 6.3 mm Hg for 24-h diastolic ambulatory BP. 14 An analysis of variance (ANOVA) model for a crossover design was used to demonstrate equivalence between the two treatment regimens for the primary endpoint. 15 The model included terms for sequence group, patient within sequence group, period, and treatment. The test for unequal carryover effect was performed by testing for the effect of sequence group using the patients within sequence group mean square as the denominator of the F-ratio, whereas period and treatment were tested using the within-patient residual mean square as the denomina-

4 AJH AUGUST 1999 VOL. 12, NO. 8, PART 1 MORNING V EVENING DOSING OF NISOLDIPINE 809 TABLE 2. BASELINE CHARACTERISTICS OF DIPPERS AND NONDIPPERS Systolic Criteria Dippers (n 39) Nondippers (n 36) Diastolic Criteria Dippers Nondippers (n 56) (n 19) Gender, n (%) Women 14 (36) 18 (50) 24 (43) 8 (42) Men 25 (64) 18 (50) 32 (57) 11 (58) Mean age, years (SD) 57.7 (10.1) 58.0 (8.0) 57.2 (9.8) 59.7 (6.8) Race, n (%) White 29 (74) 17 (47) 37 (66) 9 (47) Black 8 (21) 18 (50) 16 (29) 10 (53) Other 2 (5) 1 (3) 3 (5) 0 (0) tor. 15 A 90% confidence interval, which was equivalent to using two one-sided tests, each with a significance level of.05, was generated from the ANOVA model to assess treatment equivalence. This primary analysis included all randomized patients who had evaluable 24-h ABP data at baseline and after the two treatment phases. Secondary objectives were to evaluate the mean change from baseline in systolic 24-h ABP; in systolic and diastolic ABP during awake, sleep, and early morning periods (4 h after awakening); and systolic and diastolic ABP in dippers and nondippers. Dippers were defined as patients whose mean systolic BP decreased by 10% during sleep compared with awake BP values. Nondippers were patients whose sleep systolic BP declined by 10%. 16 Dippers and nondippers were also defined by a second criterion that used diastolic BP changes instead of systolic BP changes during the sleep and awake periods. The secondary efficacy endpoints were analyzed in the same manner as the primary endpoint, and patients included in the analyses of the secondary endpoints had to meet the same requirements as for patients included in the primary analysis. Systolic BP, diastolic BP, and heart rate during the early morning were calculated by averaging all BP and heart rate data points from the 4-h period after the awake times determined by Actigraphs. Comparisons of the dipper and nondipper subgroups were done separately for morning and evening administration. These comparisons were done using an ANOVA model with terms for period and dipper classification. RESULTS Demography and Pretreatment Characteristics Eighty-five patients were randomized to treatment with morning or evening administration of nisoldipine. Seventy-five patients were evaluable after completing the two active treatment periods (Table 1). Ten patients were withdrawn from the study after randomization: eight for adverse events (most commonly peripheral edema and headache) and two were lost to follow-up. Demographic characteristics of dippers and nondippers are displayed for both systolic and diastolic BP criteria (Table 2). According to systolic BP and diastolic BP criteria, about 25 35% of white hypertensives were nondippers, whereas 40 70% of black hypertensives were nondippers. TABLE 3. AMBULATORY BP AND HEART RATE ACCORDING TO DOSING TIME (N 75) Hour Baseline (Mean SD) Morning Dosing LS Mean Change (Mean SE) Evening Dosing LS Mean Change (Mean SE) Difference ( SE) (90% CI) P value Systolic BP ( ).66 Awake ( ).16 Sleep ( ).13 Early morning* ( ).11 Diastolic BP ( ).16 Awake ( ).01 Sleep ( ).25 Early morning ( ).54 Heart Rate ( ).23 Awake ( ).89 Sleep ( ).001 Early morning ( ).002 * Average of first 4 h postawakening. LS, least-squares; SD, standard deviation; SE, standard error; CI, confidence interval.

5 810 WHITE ET AL AJH AUGUST 1999 VOL. 12, NO. 8, PART 1 FIGURE 2. Effect of morning versus evening dosing of nisoldipine ER on SBP over 24 hours. The uppermost panel displays SBP levels for baseline and for the two dosing times, whereas the lower panel shows the changes in SBP from baseline for the two dosing times. Efficacy There were no differences in least-squares (LS) mean ( SE) changes in 24-h BP or heart rate according to dosing time (Table 3). The differences in the LS mean ( SE) change from baseline in ambulatory systolic and diastolic BP and heart rate (morning minus evening administration) were mm Hg, mm Hg, and beats/min, with 90% confidence intervals of 1.9 to 1.1 mm Hg, 2.0 to 0.2 mm Hg, and 1.8 to 0.3 beats/min, respectively. The effects of morning and evening administration of nisoldipine ER on 24-h ambulatory systolic and diastolic BP profiles are shown in Figures 2 and 3. BP was lowered with both morning and evening administration of nisoldipine ER throughout the monitoring period, and there was equivalent mean 24-h BP reduction without affecting 24-h average heart rate (Table 3). As shown in Figure 4, 24-h heart rate profiles were similar after morning and evening administration. An evaluation of the sleep and awake periods revealed differential BP and heart rate effects for morning compared with evening dosing (Table 3). During the awake period, the antihypertensive effect of nisoldipine was greater after morning compared with evening administration (P.16 for systolic BP and P.01 for diastolic BP). Similarly, there was a trend for reductions in BP during sleep to be greater with nighttime compared with morning dosing. Both during sleep and in the early morning period, evening dosing of nisoldipine was associated with 2- to 3-beats/min increases in heart rate, compared with morning dosing. During the awake period, there were no differences in heart rate responses for morning compared with evening administration. The effects of morning and evening dosing of nisoldipine ER in systolic dippers and nondippers are shown in Table 4. Similar to the results in the overall population, the LS mean changes in 24-h BP and heart rate did not differ significantly between the two dosing regimens for these two groups. However, in both groups, reductions in awake BP were greater with morning dosing, and heart rate tended to increase during sleep with evening dosing. Independent of the time of administration, average reductions in BP over 24 h for nondippers treated with nisoldipine ER tended to be greater than those for

6 AJH AUGUST 1999 VOL. 12, NO. 8, PART 1 MORNING V EVENING DOSING OF NISOLDIPINE 811 FIGURE 3. Effect of morning versus evening dosing of nisoldipine ER on DBP over 24 hours. The uppermost panel displays DBP levels for baseline and for the two dosing times, whereas the lower panel shows the changes in DBP from baseline for the two dosing times. dippers (Table 4). With morning dosing, the 24-h LS mean ( SE) changes in BP were / mm Hg in nondippers and / mm Hg in dippers (P.17/P.03). With evening dosing, the values were / mm Hg and / mm Hg, respectively (P.09/P.13). Most of these differences are attributable to the much larger reductions in BP during sleep observed in nondippers compared with dippers. Patients were also classified as dippers and nondippers based on a diastolic BP classification similar to the systolic BP classification (Table 2). All diastolic nondippers were systolic nondippers. Despite the classification change, the overall results were similar to the results for the systolic dippers and nondippers (data not shown). DISCUSSION Principal Findings Our data demonstrate that nisoldipine ER has similar overall mean effects on 24-h BP and heart rate when administered in the morning and evening. However, differential effects were observed for awake and sleep periods with the different times of administration. These could be characterized as small reductions in awake diastolic BP after morning dosing compared with evening dosing and small increases in sleep and early morning heart rate after evening dosing compared with morning dosing. Finally, patients who were characterized as nondippers at baseline tended to have larger reductions in sleep BP compared with those patients characterized at baseline as dippers, regardless of time of dosing of nisoldipine ER. Effects of Timing of Dosing of Antihypertensive Therapy on Ambulatory BP: Sample Size Considerations Recently, investigators have begun to evaluate the effects of antihypertensive drugs on the circadian rhythms of blood pressure as they relate to drug pharmacokinetics at steady state, alteration of drug disposition by various delivery systems, and timing of drug dosing. 17,18 Although a fairly large number of studies have been performed to assess the impact of timing of dosing of therapy, most have had small sample sizes, open-label design, short treatment periods, or may not have used a crossover design that

7 812 WHITE ET AL AJH AUGUST 1999 VOL. 12, NO. 8, PART 1 FIGURE 4. Effect of morning versus evening dosing of nisoldipine ER on heart rate over 24 hours. The uppermost panel displays the heart rate values for baseline and for the two dosing times, whereas the lower panel shows the changes in heart rate from baseline for the two dosing times. allows for reduced error variability. 19 In our study, we prospectively calculated the sample size requirements for the present crossover design and took into consideration the variability of ambulatory BP as well as the desire to be able to detect 3.4-mm Hg differences between the dosing regimens on 24-hour diastolic BP. This power calculation demonstrated that at least 60 patients were required to demonstrate a 3.4-mm Hg difference in ambulatory diastolic BP between groups. A recent review 19 of the chronopharmacology of antihypertensive drugs revealed that 15 studies evaluating the effect of dosing time of several classes of agents on circadian BP rhythms had as few as six and a maximum of 20 total patients. Thus, most studies in this field have been greatly underpowered. Effects of Dosing Time of Antihypertensive Therapy on 24-h BP and Heart Rate Profiles Our study showed that morning dosing of nisoldipine induced lower awake diastolic BP compared with evening dosing (Table 3, Figure 3), whereas evening dosing of nisoldipine ER induced higher sleep heart rates compared with morning dosing (Table 3, Figure 4). These changes, although numerically modest, are likely to be related to the pharmacokinetics of the nisoldipine formulation. 6,8 When the tablet was administered in the morning, the ambulatory BP was lowered to a greater extent in the afternoon than when given in the evening (Figures 2, 3). Furthermore, when nisoldipine was administered in the evening, the ambulatory BP tended to be lower at night than when the drug was given in the morning (Figures 2, 3). Small increases in heart rate were also noted during sleep in patients who received nisoldipine in the evening. This may have occurred because of enhanced baroreflex sensitivity and reflex increases in heart rate that are often seen in the presence of arterial vasodilation during sleep. 20 Other studies comparing the effects of time of administration have been performed with the dihydropyridine calcium antagonists, nifedipine gastrointestinal therapeutic system (GITS), 21 and amlodipine. 22 In the nifedipine trial, patients were studied using 30 mg at either 10 am or 10 pm. 22 The treatment periods

8 AJH AUGUST 1999 VOL. 12, NO. 8, PART 1 MORNING V EVENING DOSING OF NISOLDIPINE 813 TABLE 4. AMBULATORY BP AND HEART RATE IN DIPPERS AND NONDIPPERS* Parameter Hour Baseline (Mean SD) Morning Dosing LS Mean D (Mean SE) Evening Dosing LS Mean D (Mean SE) P Value Dippers (n 39) Systolic BP Awake Sleep Diastolic BP Awake Sleep Heart rate Awake Sleep Nondippers (N 36) Systolic BP Awake Sleep Diastolic BP Awake Sleep Heart rate Awake Sleep * Dippers defined as a sleep systolic BP decline 10% compared with awake systolic BP. All others are classified as nondippers. Abbreviations same as Table 3. were 1 and 2 weeks, respectively. Nifedipine GITS did induce a 3- to 5-beats/min increase in ambulatory heart rate compared with placebo; however, this was not statistically significant, possibly because of the small sample size. Similarly, morning dosing lowered daytime BP slightly more than evening dosing, but this did not achieve statistical significance. Similar to the present study of nisoldipine ER, an evaluation of amlodipine by Mengden and coworkers 22 indicated that morning and evening dosing of the drug had little impact on mean 24-h BP control. However, evening dosing of amlodipine resulted in a significant increase in heart rate compared with baseline (73 7 v 77 10, P.05). Unlike our trial, there were only 20 patients in the comparison of the effect of amlodipine dosing time on 24-h BP and heart rate profiles, and the power of the study to show additional differences comes into question. Circadian Variation of BP and the Effects of Antihypertensive Therapy Recognition of the characteristics of the circadian variation of BP and heart rate has led to increased numbers of clinical trials that evaluate the effects of antihypertensive therapy on early morning, awake, and sleep blood pressures. The circadian pattern of BP typically is characterized by higher values during the awake and active period and lower BP and heart rate during sleep. However, this nocturnal decline in BP is blunted or absent in some hypertensive patients and their cardiovascular risks may be excessive. 16,23 Thus, it has become of interest to determine the effects of antihypertensive drugs on nocturnal BP in nondippers. In our patient population, approximately 25% to 35% of white hypertensives were nondippers, whereas 40% to 70% of black hypertensives were nondippers (Table 2). Both morning and evening dosing of nisoldipine induced substantially greater reductions in sleep BP in nondippers compared with dippers (Table 4). As a group, the nondippers were actually converted to dippers after administration of nisoldipine ER. Similar findings in nondippers versus dippers have been reported with a placebo-controlled trial of COER-verapamil 24 and in an open-label evaluation of amlodipine in older patients from Japan. 25

9 814 WHITE ET AL AJH AUGUST 1999 VOL. 12, NO. 8, PART 1 Conclusions Our data show that overall 24-h BP control is similar when nisoldipine is dosed in the morning versus the evening. Small, differential effects during the awake and sleep periods averaged out to yield reductions in 24-h BP within 1 mm Hg for the morning versus evening administration regimens. These data and those of other chronopharmacology studies show, however, that it is mandatory to perform a well-powered clinical trial using 24-h ambulatory BP monitoring to determine the effects of dosing time on the circadian BP and heart rate. Most longacting antihypertensive drugs were developed for morning dosing or split, twice-daily administration. Although it is likely that many drugs would be as effective and safe when administered at night as during the day, some agents may have substantially different effects on nocturnal BP 4 when given at bedtime versus upon awakening. Thus, unless the antihypertensive agent has been properly studied and safety and efficacy have been fully assessed, dosing before sleep is inadvisable. ACKNOWLEDGMENT We thank Gary Dorrell, MS, ELS and Kendall Wills Sterling, ELS, for editorial assistance. REFERENCES 1. White WB: A chronotherapeutic approach to the management of hypertension. Am J Hypertens 1996;10:29S 33S. 2. Lemmer B: Differential effects of antihypertensive drugs on circadian rhythm in blood pressure from chronobiologic point of view. Blood Press Monitor 1996;1: Pickering TG, Levenstein M, Walmsley P, et al: Nighttime dosing of doxazosin has peak effect on morning ambulatory blood pressure. Results of the HALT study. Am J Hypertens 1994;6: Palatini P, Racioppa A, Raule G, et al: Effect of timing of administration on the plasma ACE inhibitory activity and the antihypertensive effect of quinapril. 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