CURRENT THERAPEUTIC RESEARCH VOL. 52, NO. 6, DECEMBER 1992

EFFECTS OF A COMBINATION OF ATENOLOL AND NIFEDIPINE ON AMBULATORY AND OFFICE BLOOD PRESSURE AND

HEART RATE

NGUYEN PHONG CHAU, 1 XAVIER CHANUDET, 2 AND GI~RARD NGUYEN 3

1URBB, INSERM U263, Paris, 2Service de Pathologie Cardiovasculaire, H6pital Bdgin, St. Mandd, and 3H6pital Avicenne, Bobigny, France

ABSTRACT

Beta-blockers and vasodilators both reduce blood pressure (BP) but have opposite effects on the adrenergic and ren in-angio tens in systems. A low-dose combina t ion of these two classes of drugs might control high blood pressure wi thout affecting the adrenergic and hormona l s ta tus of the patients. In a double-blind study, we investigated the effects of a once-daily dose of atenolol 50 mg plus slow-release nifed- ipine 20 mg. Pa t i en t s with diastolic blood pressures between 90 and 110 mmHg received ei ther atenolol plus nifedipine (A + N) (n -- 31) or placebo (n = 26). Ambula tory 24-hour BP and hear t rate were mea- sured before and 1 month after t rea tment . The effects of the drugs were assessed at four different periods of the day. After 1 month of t rea tment , ambula tory ABP was s ignif icant ly lower in the A + N group, compared with the placebo group, throughout the day (P -- 0.03 to P < 0.0001); the effect was greatest between 10 AM and 5 PM (P < 0.0001). Hear t rate was s ignif icant ly lower in the A + N group dur ing the day but not dur ing the night. In the placebo group, office BP was s ignif icant ly decreased, but ambula tory BP decreased only in those pat ients with high ini t ia l BP readings.

INTRODUCTION

The roles of nifedipine and atenolol in the management of angina pectoris and high blood pressure (BP) have been well documented. 1'2 Nifedipine is a calcium antagonist with strong vasodilatory effects on coronary arteries and peripheral vessels. 3'4 Nifedipine dosing is 20 mg, usually twice daily. Atenolol is a cardioselective beta-blocker with a long half-lifeS; its usual dosing is 100 mg once daily. Although both drugs are potent antihyper- tensive agents, they have different mechanisms of action. In particular, these two drugs have opposite effects on the adrenergic and renin- angiotensin systems. 6 Therefore, a combination of atenolol and nifedipine (using a reduced dose for both) might reduce BP without unnecessarily disturbing the adrenergic and hormonal status of the patient.

Address correspondence to: Prof. N.P. Chau, URBB, Universit6 Paris 7, tour 53, 2 place Jussieu, 75251 Paris Cedex, France. Received for publication on August 17, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted.

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N. P. CHAU ET AL.

We investigated the effects on BP and heart rate (HR) of a combina- tion of 50 mg of atenolol and 20 mg of nifedipine SR (sustained-release formulation). Our aim was to assess whether, in addition to an expected balanced effect on the adrenergic system, the combination would have a sustained effect on blood pressure, thereby permitting once-daily dosing. To evaluate the duration of this effect, we measured ambulatory BP during the day and night using validated monitoring systems.

PATIENTS AND METHODS

Pat ients of both sexes, ages 18 to 70 years, were eligible for this double- blind, placebo-controlled study. All participants provided writ ten informed consent after receiving a full description of the procedures.

After completing a 2-week washout period, eligible patients were ran- domly assigned to receive a combination of atenolol 50 mg plus nifedipine SR 20 mg (A + N) or matching a placebo. In both groups, the capsule was administered in the morning. Only patients with diastolic blood pressures (DBP) between 90 and 110 mmHg were included in the study. Clinical and laboratory examinations were performed in all subjects, and patients with secondary hypertension were excluded.

Office BP was measured in the supine position after 10 minutes of rest. At least three measurements were performed on three different occasions, and the mean value of the readings was used. Ambulatory BP was moni- tored by a validated Spacelabs (Spacelabs Inc., Redmond, Washington) or Diasys system (Novacor Inc., Rueil-Malmaison, France). 7's The devices were programmed for at least three measurements per hour between 8 AM and 10 PM and at least one measurement per hour between 10 PM and 8 AM. Office and ambulatory BP were measured before randomization and after 1 month of treatment. The same monitor was used in each patient before and after treatment.

Statistical Analysis

During the first examination of the ambulatory BP data, all readings with a pulse pressure (PP) < 20 mmHg and systolic blood pressure (SBP) > 180 mmHg or with a PP > 160 mmHg (PP = SBP - DBP) were dis- carded. The number of rejected readings was less than 5%. Hourly means for BP and HR were also calculated. To determine whether the effect of t rea tment was maintained over 24 hours, we divided the day into four periods: period 1 = 10 PM to 6 AM, period 2 = 6 AM to 10 AM, period 3 = 10 AM to 5 PM, and period 4 = 5 PM to 10 PM. Period 1 was considered the at rest nighttime, period 2 the waking time, period 3 the working time, and period 4 the t ime of returning home and family activities.

An unpaired Student 's t test was used to verify the comparability of

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EFFECT OF ATENOLOL + NIFEDIPINE ON AMBULATORY BP

the two groups at the time of study entry. The effects of the drug combi- nation were assessed by comparing the data in the A + N and placebo groups after 1 month of treatment. The change in BP was defined as the difference between BP observed 1 month after t rea tment and BP observed before treatment. Predictors of the responses were obtained by linear re- gression of the responses versus the patients' characteristics at study en- try. To evaluate the role of the monitoring device, a two-factor analysis of variance was performed (one factor was the t reatment group and the other was the monitoring device). Calculations were performed using the Systat computer packages (Systat Inc, Evanston, Illinois) and a Macintosh II computer.

RESULTS

Of the 57 patients enrolled in the study, 31 patients (21 men, 10 women) received the combination A + N, and 26 patients (18 men, 8 women) received placebo. Ambulatory BP was measured by the Spacelabs system in 32 patients and by the Diasys system in 25. In the total sample, the mean age was 51 +- 11 years; the mean SBP and DBP were 163 -+ 12 and 98 - 7 mmHg, respectively. Before treatment, both groups were compa- rable in all measured variables (Table I).

In a preliminary analysis, a two-factor analysis of variance showed

Table I. Pretreatment variables in patients receiving atenolol 50 mg plus nifedipine 20 mg (A + N) or placebo. (Values are expressed as mean -+ SD.)

Parameter* A + N (n = 31) Placebo (n = 26)

Age (yr) 50 -+ 12 54 - 11 Weight (kg) 73 -+ 9 74 -+ 8

Office SBP 162 -+ 11 163 -+ 13 Office DBP 98 - 7 99 -+ 7 Office HR 73 _+ 10 72 _+ 10

SBP1 131 _ 14 130 _+ 17 SBP2 149 -- 14 146 -- 21 SBP3 153 - 6 152 __ 19 SBP4 150 - 1 7 152 _+ 19

DBP1 81 -- 12 83 + 10 DBP2 94 -+ 13 96 _+ 14 OBP3 97 - 14 99 + 13 DBP4 92 - 12 96 +_ 13

HR1 71 _+ 9 70 -+ 9 HR2 81 +_ 11 80 -+ 9 HR3 86+-11 87_+11 HR4 84 - 10 84 _+ 11

SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = be'art rate. * BP is expressed in mmHg and HR in beats/rain. The numbers 1 to 4 designate ambulatory BP measure- ments dunng periods 1 to 4 of the day; period 1 = 10 PM to 6 AM, period 2 = 6 AM to 10 AM, period 3 = 10 AM to 5 PM, period 4 = 5 PM to 10 PM.

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N. P. CHAU ET AL.

that the measurement device (Spacelabs or Diasys) had no effect on BP readings. Subsequently, readings from the two devices were grouped to- gether, and the device factor was ignored.

The potent effect of A + N on BP and HR was observed after 1 month of treatment (Figure 1). Office BP and HR were significantly lower in the A + N group compared with the placebo group (P = 0.028 to P = 0.002) (Table II). Ambulatory BP was also lower in the A + N group, and the difference was significant during all four periods of the day (P = 0.03 to P < 0.0001). The effect of A + N was greatest during period 3 (P < 0.0001), that is, during the period of full activity for the patients. The effect of A + N on ambulatory HR was significant in periods 2 and 3 (P = 0.01 and P = 0.001, respectively). During period 4, the effect was at the limit of statis- tical significance (P = 0.05). No effect on HR was observed during the night.

The reduction in office BP in the A + N group was not related to the initial office BP values (Figure 2). The ambulatory BP responses, however, were significantly correlated with the initial ambulatory BP values during all t ime periods (P values from 0.019 to 0.0003). As an example, Figure 2 displays the SBP and DBP responses during working hours versus the initial SBP and DBP values.

In the placebo group, there was a significant decrease in office SBP (from 163 +- 13 mmHg to 149 +-- 14 mmHg; P < 0.002) and office DBP (from 99 -+ 7 mmHg to 95 -+ 11 mmHg; P < 0.034), but no change in HR (72

SBP (mmHg)

i 1 i

0 6 12 18 24 time (h)

DBP (mmHg) 120-

100-

8 0

60 , , ,

6 12 18 24 time (h)

HR (b/min) 100.

90-

80.

70.

60.

50.

6 12 18 24 time (h)

n Before treatment

* After treatment

F igure 1. M e a n -+ S E blood pressure and hear t rate (HR) before and I month after t r e a t m e n t w i th atenolol 50 m g + nifedipine 20 m g (A + N) once daily. SBP = systo l ic blood pressure; D B P = diastol ic blood pressure.

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EFFECT OF ATENOLOL + NIFEDIPINE ON AMBULATORY BP

Table II. Blood pressure and heart rate (HR) in patients receiving atenolol 50 mg plus ni- fedipiue 20 mg (A + N) or placebo after 1 month of treatment. (Values are ex- pressed as mean ± SD.)

Parameter* A + N Placebo Difference P Value

Office SBP 140 ± 15 149 ± 14 - 9 0.028 Office DBP 85 ± 11 95 ± 11 - 8 0.012 Office HR 70 ± 8 74 ± 12 - 9 0.002

SBP1 122 ± 15 131 ± 17 - 9 0.025 SBP2 131 ± 16 145 ± 23 - 1 4 0.009 SBP3 129 ± 16 150 ± 18 -21 0.0001 SBP4 136 ± 16 150 ± 18 - 1 4 0.003

DBP1 75 ± 11 85 ± 13 - 1 0 0.005 DBP2 85 ± 13 95 ± 13 - 1 0 0.006 DBP3 82 ± 13 96 ± 13 - 1 4 0.0001 DBP4 86 ± 13 97 ± 14 -11 0.003

HR1 65 ± 11 69 ± 8 - 4 NS HR2 72 ± 10 80 ± 13 - 8 0.011 HR3 73 ± 13 85 ± 10 - 1 2 0.001 HR4 75 ± 12 82 ± 11 - 7 0.05

SBP = systolic blood pressure; DBP = diastolic blood pressure; NS = not significant. * BP is expressed mmHg and heart rate in beats/rain. The numbers 1 to 4 designate ambulatory BP measurements during periods 1 to 4 of the day; period 1 = 10 PM to 6 AM, period 2 = 6 AM to 10 AM, period 3 = 10 AM to 5 PM, period 4 = 5 PM to 10 PM.

+ 10 beats/min before and 74 -+ 12 beats/min after treatment). The reduc- tion in office SBP in the placebo group was not correlated with age or weight but was significantly correlated with the initial office SBP values (r = 0.57; P = 0.003). Likewise, the reduction in office DBP with placebo was not correlated with age or weight but was significantly correlated with the initial office DBP value (r = 0.43; P = 0.03).

In contrast to the office BP, ambulatory BP and HR remained un- changed in the placebo group (Figure 3), except in patients with high initial daytime BP readings. In the 13 patients in the A + N group with high initial ambulatory SBP during working hours, the ambulatory SBP during work of 165 -+ 15 mmHg at entry was reduced to 161 -+ 15 after 1 month of placebo t reatment (P < 0.016). Similarly, in the 13 patients with high initial DBP during working hours, the DBP during the same time period was 109 -+ 9 mmHg before and 104 -+ 7 mmHg after placebo (P < 0.03). Thus a placebo effect on ambulatory BP does exist in these subjects, although the effect was small (a reduction of 4 to 5 mmHg). A comparison of BP and HR before and after placebo t rea tment (by paired t test) indi- cated no significant change during any period of the day.

DISCUSSION

Vasodilators and beta-blocking agents have a concomitant effect on BP

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N. P. C H A U E T A L .

ASBPoffice(mmHg) A

40 7 [] 20 -{ (R = 0.15, NS)

0-[ ~ [] o

-2O

:::1 ; 140 150 160 170 180 190

SBPoffice (mmHg)

ADBPoffice (mmHg)

D O O 121 fl

o N o o

° ~ I o o o o

o []

(R = 0.02, NS) o

80 90 100 1 l0

DBPoffice (mmHg)

B

i

120

ASBP3 (mmHg) ADBP3 (mmHg)

20] (R=0.55o, p<0.01) C ~ ? (R=0.54, p<0.01) D

0 ~ . ~ . . ~ ~ o 0 _ ~ o ~ [] o o

_ 0t []

::1 ...... °o:o ::00t i ° 120 130 140 150 160 170 180 190 70 80 90 100 l l0 120 130 140

SBP3 (mmHg) DBP3 (mmHg)

Figure 2. Change in office blood pressure (panels A and B) and ambulatory blood pressure (panels C and D) in patients receiving atenolol 50 mg + nifedipine 20 mg. SBP3, DBP3 = systolic and diastolic blood pressure measured during period 3 (10 AM to 5 PM); NS = not significant.

and opposite effects on the sympathetic and renin-angiotensin systems. Thus a combination of these two drug classes may be useful in treating hypertension. Combinations of vasodilators and beta-blockers have been shown to protect the heart from excessive adrenergic stimulation and are well tolerated, even by patients with coronary artery disease, e-l l These findings justify the use of a combination atenolol plus nifedipine.

The beta-blocker atenolol decreases office HR and BP, and several reports have demonstrated that this drug reduces plasma renin activ- ity. 12-14 This inhibitory effect is significantly correlated with the reduc- tion in BP and is exerted irrespectively of a patient's renal function. 12 In contrast, Lederballe Pedersen et a115 have shown that 10 to 20 mg of the calcium antagonist nifedipine increases HR, plasma norepinephrine lev- els, and plasma renin activity. Although the acute rise in sympathetic activity may be attenuated during chronic treatment, it still remains a determinant of plasma renin activity. Guazzi et al 3 have reported an acute increase in cardiac output and HR with 10 mg of sublingual nifedipine. In a double-blind, placebo-controlled study, Subramanian et a116 have shown that 20 mg of nifedipine three times daily increased HR.

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EFFECT OF ATENOLOL + NIFEDIPINE ON AMBULATORY BP

SBP (mmHg) HR (b/rain) 100

12oj

901 50l , , , , 0 6 12 18 24 0 6 12 18 24

time (h) time (h)

DBP (mmHg)

1201

lOOJ ~ a Before Placebo ~,._ * After Placebo

80] ~

601 . . . . 0 6 12 18 24

time (h)

F igure 3. Mean -+ SE blood pressure and h e a r t ra te (HR) before and 1 m o n t h af ter t r e a t m e n t w i th placebo once daily. SBP = systolic blood pressure ; DBP = diastolic blood pressure .

When prescribed alone, calcium channel blockers such as nifedipine generally require twice-daily dosing to normalize BP in patients with es- tablished hypertension. By combining 50 mg of atenolol with 20 mg of nifedipine SR, BP should decrease significantly for a 24-hour period with only small disturbances in HR and hormonal status.

In previous studies with calcium antagonists, a significant response in office BP was not always confirmed by a significant response in ambula- tory BP. Nitrendipine, for example, significantly reduced office BP, but its effect on ambulatory BP during working hours was not significantF The beta-blocker betaxolol and the calcium antagonist verapamil both reduced office BP, but only betaxolol decreased ambulatory BP. is The calcium channel blocker nicardipine reduced both office and ambulatory BP. 19

The effect of atenolol on office BP is well known. However, its effects on ambulatory BP are less well defined. In a one-group study of six subjects (without a placebo-control group), Millar-Craig et al 2° showed that 100 to 200 mg of atenolol given in the morning (8:30 or 11 AM) reduced intra- arterial BP, but only during the day. In contrast, HR was reduced during the entire 24 hours. In another study, 21 100 to 200 mg of atenolol was given at 8 AM for approximately 41/2 months to 12 subjects with essentia ! hyper- tension. In this study, intra-arterial BP was reduced for most of the day (except from 10 PM to 2 AM for SBP and from 7 to 8 AM for DBP), while HR was significantly reduced for almost the entire 24-hour period.

To assess the BP response in our study, we evaluated BP during four periods of the day. Our time periods were somewhat arbitrary, but we

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N. P. CHAU ET AL.

believe that they reflect the likely division of activities for most of our subjects. Having patients keep a diary of daily activities is a better proce- dure for identifying "at work" and "at rest" BP, and we have used this method in previous studies. However, the annotations of the subjects, even in a standardized form, were of inequal quality and the results could not be analyzed statistically. Our present study clearly demonstrated a signifi- cant effect of atenolol 50 mg plus nifedipine 20 mg on office and ambula- tory BP. The effect on ambulatory BP was maintained over 24 hours and was most significant during working hours. The combination also de- creased HR, but only between 10 AM and 5 PM. Thus the A + N combina- tion was able to protect the patients during activities or stressful situa- tions but did not unduly decrease HR.

In contrast to office BP, ambulatory BP does not change in patients given placebo, 22-2a although contradictory data have been reported. 25 Our data suggested that, in the group as a whole, ambulatory BP remained unchanged after placebo. However, a detailed analysis showed that ambu- latory BP did respond to placebo in patients with a high initial daytime BP. Some authors have suggested eliminating the placebo group when assessing the effect of antihypertensive drugs. Our data suggest that, with- out a control group, the effect of the drug might be overestimated in pa- tients with high ambulatory BP values before treatment.

Many researchers prefer to use automatic BP monitoring rather than measuring BP in the physician's office. Avoiding the white coat effect (blood pressure increases in the presence of a physician) is an important argument in favor of automatic measurements. 26 Due to the regression to the mean, repeated BP determinations are more reliable than occasional determinations. The so-called law of initial value is also a factor. 27 Most biologic responses to treatment are negatively correlated with the initial value of the parameter. In our study, ambulatory BP responses at all periods of the day were significantly related to the initial BP values. How- ever, while office BP responses with placebo followed the law of initial values, they did not do so with the A + N combination. This inconsistency provides additional support for the use of ambulatory BP, rather than office BP, for assessing the effects of antihypertensive drugs.

In conclusion, our results demonstrated that the combination of aten- olol 50 mg plus nifedipine 20 mg decreases BP throughout the day. This combination lowers HR during the day without depressing HR at night. Our data also suggested that ambulatory BP responds to placebo in pa- tients with sustained daytime hypertension before treatment.

References:

1. Cruickshank JM. Reduced total mortal i ty and death from myocardial infarction and stroke in moderate/severe hypertensives t reated with Tenormin (atenolol). Drugs Exp Clin Res 1990; 16:133-136.

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EFFECT OF ATENOLOL + NIFEDIPINE ON AMBULATORY BP

2. Lederball Pedersen O, Mikkelsen E. Acute and chronic effects of nifedipine in arterial hypertension. Eur J Clin Pharmacol 1978; 14:375-381.

3. Guazzi M, Olivari MT, Polese A, et al. Nifedipine, a new antihypertensive with rapid action. Clin Pharmacol Ther 1977; 22:528-532.

4. Robinson BF, Dobb RJ, Kelsey GR. Effect ofnifedepine on resistance vessels, arteries and veins in man. Br J Clin Pharmacol 1980; 10:433-438.

5. Harry JO, Young J. The duration of action of atenolol in man. Br J Clin Pharmaco11977; 4:387-391.

6. Koch-Weser J. Vasodilator drugs in the treatment of hypertension. Arch Intern Med 1974; 133:1017-1027.

7. De Gaudemaris R, Battistella P, Siche JP, et al. Mesure de la pression art~rielle en ambulatoire. Evaluation d'un nouvel appareil automatique syst~me Spacelabs. In: Mal- lion JM, Safar M, eds. La mesure ambulatoire de la pression art~rielle-proc~dd Spacelabs. Grenoble, France: Squibb Medical Systems, 1985:25-32.

8. O'Brien E, O'Malley K. Twenty-four-hour ambulatory blood pressure monitoring: A re- view of validation data. J Hypertens 1990; 8 (Suppl 6):S11-S16.

9. Gilmore E, Weil J, Chidsey C. Treatment of essential hypertension with a new vasodi- lator in combination with beta-adrenergic blockade. New Engl J Med 1970; 282:521-527.

10. Zacest R, Gilmore E, Koch-Weser J. Treatment of essential hypertension with combined vasodilation and beta-adrenergic blockade. New Engl J Med 1972; 286:617-622.

11. Gottlieb TB, Katz FH, Chidsey CA. Combined therapy with vasodilator drugs and beta- adrenergic blockade in hypertension: A comparative study of minoxidil and hydralazine. Circulation 1972; 45:571-582.

12. Zech PY, Labeeuw M, Pozet N, et al. Response to atenolol in arterial hypertension in relation to renal function, pharmacokinetics and renin activity. Postgrad Med J 1977; 53 (Suppl 3):134-141.

13. Amery A, Lunen P, Fagard R, Reybrouck T. Atenolol and plasma renin concentration in hypertensive patients. Postgrad Med J 1977; 53 (Suppl 3):116-119.

14. Dreslinski G, Messerli FH, Dunn FG, et al. Hemodynamics biochemical and reflexive changes produced by atenolol in hypertension. Circulation 1982; 65:1365-1368.

15. Lederballe Pedersen O, Mikkelsen E, Christensen NJ, et al. Effect of nifedipine on plasma renin, aldosterone and catecholamines in arterial hypertension. Eur J Clin Phar- macol 1979; 15:235-240.

16. Subramanian VB, Bowles MJ, Khurmi NS, et al. Rationale for the choice of calcium antagonists in chronic stable angina. An objective double-blind placebo controlled com- parison of nifedipine and verapamil. Am J Cardiol 1982; 50:1173-1179.

17. White WB, Smith VE, Mc Cabe EJ, Mieran MK. Effect of chronic nitrendipine on casual (office) and 24-hour ambulatory blood pressure. Clin Pharmacol Ther 1985, 38:60-64.

18. Waeber G, Beck G, Waeber B, et al. Comparison of betaxolol with verapamil in hyper- tensive patients: Discrepancy between office and ambulatory blood pressure. J Hypertens 1986; 8:239-245.

19. Broadhurst PA, Bridgen G, Heber M. Twenty-four-hour ambulatory blood pressure pro- file of a new, sustained-release preparation of nifedipine. Cardiovasc Drugs Ther 1990; 4:435-438.

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20. Millar-Craig MW, Kenny D, Mann S, et al. Effect of once-daily atenolol on ambulatory blood pressure. BMJ 1979; 1:237-238.

21. Floras JS, Vann Jones J, Fox P, et al. Effect of long-term, once daily administration of atenolol on ambulatory blood pressure of hypertensive patients. J Cardiovasc Pharmacol 1981; 3:958-964.

22. Gould BA, Mann S, Davies AB, et al. Does placebo lower blood pressure? Lancet 1981; 2:1377-1381.

23. Dupont AG, Van der Niiepen P, Six RO. Placebo does not lower ambulatory blood pres- sure. Br J Clin Pharmacol 1987; 24:106-109.

24. Conway J, Johnston J, Coats A, et al. The use of blood pressure monitoring to improve the accuracy and reduce the number of subjects in clinical trials of antihypertensive agents. J Hypertens 1988; 6:111-116.

25. Bellet M, Pagny YL, Chatellier G, et al. Evaluation of slow-release nicardipine in essen- tial hypertension by casual and ambulatory blood pressure measurement. Effects of acute versus chronic administration. J Hypertens 1987; 5:599-604.

26. Mancia G, Bertinieri G, Grassi G, et al. Effects of blood pressure measurements by the doctor on patient's blood pressure and heart rate. Lancet 1983; 2:695-698.

27. Wilder J. The law of initial value. Z Neurol Psychiatr 1931; 137:317-330.

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