- Email: [email protected]
Evaluation of the antihypertensive effect of amlodipine using 24-hour ambulatory blood pressure measurement
CURRENT THERAPEUTIC RESEARCH VOL. 53, NO. 6, JUNE 1993
E V A L U A T I O N OF THE A N T I H Y P E R T E N S I V E E F F E C T OF AMLODIPINE USING 24-HOUR AMBULATORY BLOOD PRESSURE M E A S U R E M E N T ISTEMI NALBANTGIL,BULENTKILI~CIOGLU,REMZI ONDER, AND MEHMETI~LER Faculty of Medicine, Department of Cardiology, Aegean University, Izmir, Turkey
ABSTRACT The antihypertensive effect of amlodipine was investigated in 20 patients (11 men and nine women) with essential hypertension using 24-hour monitoring of ambulatory blood pressure. The patients received placebo initially for I week followed by amlodipine 5 rag/day for 8 weeks. In three patients whose diastolic blood pressure did not fall below 90 mmHg after 4 weeks, the dosage was raised to 10 rag/day. All patients underwent ambulatory blood pressure monitoring at the end of the placebo period and at the end of 8 weeks of active treatment. Blood pressures and heart rate were measured and a physical examination was performed every 2 weeks during the treatment period. By the second week of treatment, systolic and diastolic blood pressures were significantly reduced with amlodipine therapy (P < 0.01). The reduction was more pronounced in the fourth week (P < 0.001). There were no significant changes in heart rate. Ambulatory investigations revealed a significant decrease in both systolic and diastolic blood pressures every hour of the day (P < 0.001). On the other hand, heart rate was significantly reduced only between 8 A~ and 12 noon (P < 0.05). Changes at other hours of the day were not significant. Drugrelated side effects disappeared quickly without the need for tapering off or discontinuing the drug. Amlodipine is an effective and welltolerated drug for the treatment of hypertension. INTRODUCTION
Amlodipine, a new calcium antagonist of the dihydropyridine group, has been successfully used to t r e a t h y p e r t e n s i o n and ischemic h e a r t diseases. 1'2 It is used as a single daily dose because of its long plasma half-life (approximately 35 hours in adults and 48 hours in the elderly). 3 For antih y p er ten s i ve purposes, it can be used as both a single agent and in combination with other antihypertensive drugs, a-7 The purpose of this study was to investigate the antihypertensive effect of a m l o d i p i n e us i ng 24-hour m o n i t o r i n g of a m b u l a t o r y blood pressure. Address correspondence to: Istemi Nalbantgil, M.D., Mithat Papa Cad. 750/5, Izmir 35280, Turkey.
Received for publication on March 23, 1993. Printed in the U.S.A. Reproduction in whole or part is not permitted. 621
0011-393X/93/$3.50
ANTIHYPERTENSIVEEFFECT OF AMLODIPINE
P A T I E N T S AND M E T H O D S
A total of 20 patients (11 men and nine women) ages 41 to 64 years (mean, 54.1 -+ 7.2 years) were enrolled in the study. The hypertensive history of the patients ranged from 1 month to 15 years (average, 62 months). The diagnosis of essential hypertension was confirmed by physical examination, evaluation of serum creatinine and electrolyte values, and urographic analyses. After a 2-week washout period, the diastolic blood pressures of the patients varied between 95 and 110 mmHg. Patients with malignant or accelerated hypertension, those with heart rates <50 beats/min or with advanced conduction abnormalities in their electrocardiographic tracings, and those with grade III or IV hypertensive retinopathies were excluded from the study. All patients signed an informed consent form, and these documents were verified by the Ethical Council of Aegean University. The study design is shown in Figure 1. After a 1-week placebo treatment period, patients underwent their first physical examination. During this examination, blood pressures were measured using arm cuffs and mercury:in-glass sphygmomanometers with patients in a sitting position and after having rested for at least 5 minutes; heart rates were also measured. Measurements were repeated after 2 minutes, and the mean values were taken for both measurements. After thephysical examinations, electrocardiograms and chest roentgenograms were taken, and laboratory blood analyses (hematocrit, hemoglobin, leukocyte count and formula, platelet count, transaminases, serum lactate dehydrogenase, alkaline phosphatase, blood glucose, blood urea, total bilirubin, and serum sodium, potassium, and Chloride) and u r i n a r y analyses were performed. A Spacelabs 200 was used for the 24-hour ambulatory monitoring of blood pressures. Ambulatory measurements were repeated every 20 minutes between 7 AM and 11 PM, and every hour between 11 PM and 7 AM. Thus each patient underwent an average of 56 measurements in 24 hours. Sys-
Weeks
PE
AmBPM Lab PE
6
i
PE
~
3
PE
I~
5
AmBPM Lab PE
PE
~ ~
7
~
Amlodipine 10 mg Placebo, Amlodipine5 mg I
I
Once a day
DBP >90 mmHg DBP <90 mmHg
Once a day
Amlodipine 5mg Once a day
F i g u r e 1. S t u d y design. PE = physical e x a m i n a t i o n ; A m B P M = a m b u l a t o r y blood p r e s s u r e monitoring; Lab = l a b o r a t o r y tests; DBP = diastolic blood pressure.
622
I. NALBANTGIL ET ALl
tolic, diastolic, and mean blood pressures and heart rates were assessed during each hour. In addition to these values, the highest: and lowest systolic and diastolic blood pressures were recorded for a 24-hour period. The number of times that systolic blood pressures were measured >140 mmHg and diastolic pressures >90 mmHg in, 24 hours were expressed as percentages. After the placebo treatment, patients were given amlodipine 5 mg/day and were instructed to take the drug between 8 AM and 9:30 AM. Blood pressures, heart rate, and body weight were measured at each physical examination, which took place every 2 weeks. Or~ the day tha t the physical examination was performed, the patients took their medications after the exam was completed. At the fourth week of treatment, the dosage of amlodipine was increased to 10 mg/day in patients whose diastolic blood pressures did not fall <90 mmHg. At the end of the eighth week, laboratorY analyses and ambulatory blood pressure analyses were repeated in addition to the physical examination.
Statistical Analysis Blood pressures, heart rate, and body weight measured every 2 weeks were evaluated as six different measurements (before and after placebo and at the end of the second, fourth, sixth, and eighth weeks) and laboratory analyses were evaluated as two different measurements (after placebo and at the end of the eighth week) using Student's paired t test (two tailed). Ambulatory blood pressure values were evaluated as one number for each hour. The numbers corresponding to every hour before and after treatment were compared with each other using Student's paired t test. RESULTS
The mean age of the 11 male patients was 56.6 +- 6.1 years and that of the nine female patients was 51.4 -+ 7.7 years. The male patients had a history of hypertension ranging from 1 month to 15 years (average, 69.5 months), and their body weights ranged from 59 to 87 kg (mean, 75.4 + 8.6 kg). The female patients had a history of hypertension ranging from 1 month to 12 years (average, 53.5 months), and their body weights ranged from 58 to 74 kg (mean, 66.9 +- 5.0 kg). Three patients received amlodipine 10 mg/day during the last 4 weeks of the study because their diastolic blood pressures were >90 mmHg. The remaining 17 patients received amlodipine 5 mg/day throughout the study. The systolic and diastolic blood pressure values measured with a sphygmomanometer between 8:30 AM and 10:30 AM are summarized in Table I and Figure 2. Statistical analyses showed a significant reduction in both 623
ANTIHYPERTENSIVE EFFECT OF AMLODIPINE
Table I. Blood pressure, heart rate, and body weight after the washout and placebo periods and after 2, 4, 6, and 8 weeks of amlodipine treatment. Amlodipine Treatment Washout Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats/min) Body weight (kg)
Placebo
Week 2
Week 4
Week 6
Week 8
162.0 --- 7.5
163.2 +_ 9.2
145.8 _+ 6.2*
136.2 _+ 7.71
132.5 +- 7.5t
130.0 _+ 7.01
101.8 ~ 5.5
100.7 + 5.9
91.6 -+ 4.0*
85.5 -+ 5.0*
82.4 -+ 5.1i-
79.9 -+ 4.7t
78.5 +- 8.7 71.1 -+ 8.1
79.0 -+ 8.0 71.3 +- 8.1
72.4 _+ 4.5 71.1 -+ 7.9
71.9 -- 7.2 71.0 -+ 7.8
71.5 + 7.5 71.0 -+ 7.4
70.2 -+ 8.0 70.8 +- 7.7
* P < 0.01. 1 P < 0.001.
systolic and diastolic blood pressures starting from the second week (P < 0.01). This reduction was more pronounced in the fourth week (P < 0.001), and blood pressures continued to decrease slightly in the following weeks. There was an insignificant decrease in the heart rate, while body weight remained unchanged (Table I).
HEART RATE
t t
75
(beats/rain) 65
t
1
t
180_
160BLOOD PRESSURE (mmHg) 140-
T
! I | !
120-
100.
i
"1"-
I
I
80-
60 washout placebo
I
I
I
week 2
week 4
week 6
"'i
week 8
Figure 2. Blood pressure and heart rate changes after the washout and placebo periods and after 2, 4, 6, and 8 weeks of amlodipine treatment. 624
I. N A L B A N T G I L ET AL.
Hourly changes in systolic and diastolic blood pressures and h e a r t rate obtained after 1 week of placebo and 8 weeks of amlodipine t r e a t m e n t are shown in Table II. Pre- and posttreatment highest and lowest systolic and diastolic blood pressures and the number of times systolic blood pressures were measured > 140 m m H g and diastolic pressures >90 m m H g expressed in percentages are given in Table III. There was a significant reduction at every hour in both systolic and diastolic blood pressures, while heart rates showed a significant decrease between 8 AM and 12 noon (P < 0.05) (Figure 3). Changes in heart rate at the other hours of the day were not significant. The rate of systolic blood pressure >140 m m H g was 63.6 +- 4.8% before t r e a t m e n t and 15.0 -+ 3.2% after treatment. The rate of diastolic blood pressure >90 m m H g was 57.3 -+ 5.6% before t r e a t m e n t and 9.9 -+ 3.2% after treatment. In ambulatory measurements, the highest daily measured systolic blood pressure dropped from 187.5 +- 4.9 m m H g to 152.0 - 3.0 m m H g after t r e a t m e n t and diastolic blood pressure from 126.7 +- 3.0 mmHg to 101.1 -+ 3.3 mmHg. Drug- and placebo-induced side effects and the doses at which these side effects were detected are shown in Table IV. None of these adverse effects required discontinuation of the drug. The side effects usually disappeared spontaneously within 2 to 7 days. No significant changes were
Table II. Changesin systolicand diastolicbloodpressures and heart rate over24 hours before and after amlodipinetreatment. Systolic Blood Pressure (mmHg) Before 6 AM 7 AM 8 AM 9 AM 10 AM 11 AM 12 PM 1 PM 2 PM 3 PM 4 PM 5 PM 6 PM 7 PM 8 PM 9 PM 10 PM 11 PM 12AM 1 AM 2 AM 3AM 4AM 5A M
138.3 .+ 22.8 145.0 ± 20.9 147.6 --+ 25.1 152.2 ± 12.2 151.4 --+ 18.0 163.0 ± 19.7 154.6 ± 19.8 159.0 4- 15.1 161.9 --+ 19.7 158,5 ± 25.8 158.8 --+ 24.7 157.4 ± 20.4 165.1 ± 24.2 162.8 ± 23.5 157.0 ± 24.2 155.6 ± 26.0 151,7 .+ 24.9 146,1 ± 18.1 141.1 --+ 21.8 137.6 ± 19.9 134.4 --+ 17.0 131.4±15.1 132.3±15,7 137.5 ± 14.6
After 112.1 117.0 122.9 123.9 128.5 129.9 129.1 126.5 128.0 130.4 128.9 133.1 131.7 129.4 128.2 121.3 119.2 121.7 114.3 116.2 110,8 111.5 110.6 115.4
.+ 12.4t .+ 12.9t --+ 12,2t "+ 12.4t -+ 17.0t "+ 11.4t "+ 12.7t --+ 13.6t "+ 13.8t ± 12.4t .+ 13.7t .+ 10.7t ± 10.9t --+ 13.0t .+ 13.4t --+ 13.1t .+ 12.5t -+ 15.2t --+ 11,2t "+ 13.9t ± 12,0t -+ 11.6t ± 9.0t -+ 15.2t
Diastolic Blood Pressure (mmHg) Before 84.0 ± 17,5 89.0 -+ 14.9 92.1 "+ 13.5 95.2 "+ 14.3 96.3 "+ 15.5 106.3 "+ 13.9 97.2 --+ 13.6 97.5 ± 14.5 100.9 --+ 15.0 96.9 "+ 16.7 95.8 --+ 15.1 100.8 --+ 16.6 99.9 -+ 15.6 101.6 -+ 17.4 101.5 -+ 17.0 95.6 ± 17.6 91.4 .+ 16,7 91.6 -+ 17.3 84,8 --+ 16.5 82.4 .+ 17.3 78.4 --+ 11.4 78.2--+11.2 81.7"+13.9 83.7 +- 12.3
* P < 0.05. t P < 0.01.
625
After 67,0 73,2 73,5 71.9 77.3 77.6 76.5 78.0 76.2 77.5 80,4 80.6 82.3 80.2 79.7 73.4 71.4 71.5 69.6 65.5 62.9 62.1 62.6 65.9
.+ 10.0t -+ 11.3t --+ 11.2t "+ 9.2t "+ 11.2t -+ 10,0t "4" 11.8t ± 9.6t --+ 10.9t --+ 10.8t ± 8.0* -+ 11.6t ± 11.9t -+ 11.6t ± 9.8t --+ 11.7t -+ 10.8t -+ 8.9t "+ 12.9t "+ 11.9t ± 9.6t .+ 9.6t ± 9.7t -+ 10.0t
Heart Rate (beats/min) Before
Alter
70.2 .+ 10.9 72.4 +- 10.4 79.7 --+ 11.3 84.5 --+ 12.3 88.6 --+ 10.4 92.0 "+ 14.8 82.2 "+ 11.2 83.6 --+ 11.3 86.7 "+ 11.8 83.9 ± 11.0 83.6 -+ 13.9 82.9 ± 13.8 87.8 ± 14.3 85.4 .+ 17.7 81.9 --+ 11.8 83.9 --+ 13.4 82.2 .+ 14.1 79.3 -+ 14.6 75.8 -+ 12.5 71.3 ± 11.3 70.6 --+ 10.2 69.7"+11.9 69.6.+10.1 68.8 -+ 10.5
71.9 --+ 9.4 73.3 + 18.0 71.8 .+ 17.6" 72.2 --+ 10.7" 74.3 --+ 11.0" 74.4 "+ 12.6" 78.6 -+ 16,1 78.3 "+ 13.3 81.0 "+ 16.4 81.9 --+ 16.1 83.1 .+ 17.2 82.7 .+ 14.1 82.9 .+ 14.2 82.9 -+ 23.5 78.3 --+ 14.0 78.8 .+ 14.3 77.5 -+ 15.2 73.0 --+ 14.9 71.7 .+ 9.8 72.7 --+ 12.9 65.0 .+ 8.9 65.5±7.5 63.5-+7.7 69.8 -+ 7.4
ANTIHYPERTENSIVE EFFECT OF AMLODIPINE
T a b l e IlL M a x i m u m a n d m i n i m u m a m b u l a t o r y systolic a n d diastolic blood p r e s s u r e s before a n d a f t e r a m l 0 d i p i n e t r e a t m e n t a n d p e r c e n t a g e of systolic blood p r e s s u r e s (SBP) > 140 m m H g a n d diastolic blood p r e s s u r e s (DBP) > 9 0 m m H g in all m e a s u r e m e n t s .
Maximum SBP (mmHg) Minimum SBP (mmHg) Maximum DBP (mmHg) Minimum DBP (mmHg) SBP >140 mmHg o(°/o) DBP >90 mmHg (%)
Before Treatment
After Treatment
P
187.5 _+ 4.9 119.3 -+ 3.5 126.7 -+ 3.0 67.0 + 2.8 63.6 _+ 4.8 57.3 _+ 5.6
152.0 +_ 3.0 97.1 --- 1.9 101.1 +_ 3.3 51.4 _+ 1.5 15.0 _+ 3.2 9.9 _+ 3.2
0.001 0.001 0.001 0.01 0.001 0.001
found in the electrocardiogram and laboratory analyses repeated at the end of the eighth week. DISCUSSION
Both systolic and diastolic blood pressures were significantly reduced after 2 weeks of treatment with amlodipine 5 mg/day. At the end of the fourth week, diastolic blood pressures fell below 90 mmHg in 17 of the 20 patients. In the remaining three patients, whose dosage was increased to 10 mg/day, diastolic blood pressures fell below 90 mmHg after 4 weeks of 1oo HEART RATE (beats/min)
80
{~(}
~--a~
o _~ ~llC
-
180 BLOOD PRESSURE (mmHg)
16o
140 -
/~,f~_.
....
J"~..,~.
,,I
1 20
~ f
"-u
D
il JIl~
.... U- ~ " ~ ' 1 ~ - - U - . . - - D -
-41
.~.-+l~--i~
-II.
-Q/11
U " rY'~'Q--U ~-I~-. 0 "-U
60 --
- I 7
I 9
I II
I 13
I 15
I 17
I 19
I" 21
'I 23
.I !
I 3
I 5
TIME OF DAY (hr) F i g u r e 3. D a i l y c h a n g e s in systolic a n d diastolic blood p r e s s u r e s a n d h e a r t r a t e o b t a i n e d w i t h a m b u l a t o r y t e c h n i q u e s before (@) a n d a f t e r (t3) a m l o d i p i n e t r e a t m e n t .
626
I. NALBANTGIL ET AL.
Table IV. Side effects.
Amlodipine
:Placebo
Amlodipine 5 mg (n = 20) Headache Dry mouth Fatigue
2 1 1
1
Amlodipine 10 mg (n = 3) Headache Fatigue
1 1
treatment. The blood-pressure-lowering effect of the drug was seen in the first 2 weeks, and in the following weeks both systolic and diastolic blood pressures showed a significant but slower decrease. In the 24-hour ambulatory measurements, the changes found in both systolic and diastolic blood pressures were in accordance with the circadian r h y t h m found in normotensive people, s In ambulatory m e a s u r e m e n t s t a k e n after the placebo period, the systolic blood pressure was > 140 m m H g in 63.6 - 4.8% of all measurements; this rate fell to 15.0 -+ 3.2% after t r e a t m e n t with amlodipine (P < 0.001). Diastolic blood pressures were >90 m m H g in 57.3 --- 5.6% of all measurements after placebo and fell to 9.9 -+ 3.2% after amlodipine (P < 0.001). The highest systolic blood pressures fell from 187.5 -+ 4.9 m m H g to 152.0 + 3.0 m m H g and diastolic pressures from 119.9 +- 3.5 m m H g to 97.1 -+ 1.9 mmHg. These findings agree with those of other studies. 9-12 The 24-hour monitoring of heart rate revealed no difference between heart rates obtained with placebo and with amlodipine during the period from noon to evening. Heart rates did not increase after drug intake, and there was a marked difference between placebo and the drug between 8 AM and 12 noon. This effect of the drug has not been reported in previous studies using 24-hour ambulatory measurements. 11'12 Ischemic events (symptomatic or silent ischemia, myocardial infarction, and sudden death), cardiac mortality outside the hospital, and strokes show a circadian r h y t h m that peaks between 8 AM and 12 noon. 13-15 Blood pressures and heart rate also peak at these hours. 16 Ischemic events possibly could be reduced by decreasing these morning rises in blood pressure and heart rate with various drugs. While some investigators claim that beta-receptor blockers could be effective in this respect, 17 others have concluded that beta-receptor blockers are insufficient.is According to our findings, amlodipine prevents the morning peaks in blood pressure and heart rate seen in hypertensive patients. Previous studies 1°'19 using a sphygmomanometer have reported that amlodipine does not cause tachyphylaxis. The changes in heart rate seen in our patients could be due to changes in blood pressure. The relationship 627
ANTIHYPERTENSIVEEFFECTOF AMLODIPINE
between blood pressure and heart rate has been previously demonstrated in other studies. 2° Based on our findings, the increases in heart rate and blood pressure seen in the morning, which are considered unfavorable, are decreased by amlodipine. Amlodipine was generally well tolerated by the patients. Side effects spontaneously disappeared in a few days without the need for tapering off or discontinuing the drug. Because amlodipine 10 mg/day was used only in three patients, we cannot definitely state that side effects are dose related. There were no significant changes in the body weight of patients before or after treatment. The drug caused no significant changes in blood biochemistry. In conclusion, amlodipine was found to be an effective and welltolerated drug for the treatment of hypertension. In addition to decreasing the morning peaks in blood pressure, it also favorably affects heart rate. References:
1. Burges RA, Dodd MG. Amlodipine. Cardiovasc Drug Rev 1990; 8:25-44. 2. Murdoch D, Heel RC. Amlodipine. Drugs 1991; 41:478-505. 3. Elliott HL, Meredith PA, Reid JL, Faulkner JK. A comparison of the disposition of single oral doses of amlodipine in young and elderly patients. J Cardiovasc Pharmacol 1988; 12(Suppl 7):564-566. 4. Baez MA, Weidler DJ. Antihypertensive effect of amlodipine in hypertensive patients. J Hypertens 1986; 4(Suppl 5):$458-$460. 5. Chrysant SG, Chrysant C, Trus J, Hitckcoch A. Antihypertensive effectiveness of amlodipine in combination with hydrochlorothiazide. A m J Hypertens 1989; 2:537-541. 6. Davies J, Jensen H, Garsdal P. A double-blind comparison of amlodipine and placebo added to open enalapril in patients with moderate to severe essential hypertension. J Cardiovasc Pharmacol 1991; 17(Suppl 1):S16-S18. 7. Frick MH, McGibney D, Tyler HM. A dose-response study of amlodipine in mild to moderate hypertension. J Intern Med 1989; 225:101-105. 8. Cesana G, DeVito G, Ferrario M, et al. Ambulatory blood pressure normalcy: The PAMELA study. J Hypertens 1991; 9(Suppl 3):S17-$23. 9. Webster J, Robb OJ, Jeffers A, et al. Once daily amlodipine in the treatment of mild to moderate hypertension. Br J Pharmacol 1987; 27:713-719. 10. Julius S. Amlodipine in hypertension: An overview of the clinical dossier. J Cardiovasc Pharmacol 1988; 12(Suppl 7):$27-$33. 11. Raftery EB, Heber ME, Brigdan G, A1-Khawaja I. 24-hour blood pressure control with the once-daily calcium channel antagonist, amlodipine. J Cardiovasc Pharmacol 1991; 17(Suppl 1):$8-S12. 12. Mraczek WJ, Burris JF, Allenby KS. Effect of amlodipine on 24 hour ambulatory blood pressure in hypertensive patients. J Cardiovasc Pharmacol 1991; 17(Suppl 1):$13-S15. 13. Muller JE, Ludmer PL, Willich SN, et al. Circadian variation in the frequency of sudden cardiac death. Circulation 1987; 75:131-138. 628
I. NALBANTGILETAL.
14. Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. New Engl J Med 1985; 131:1315-1322. 15. Marshall J. Diurnal variation in occurrence of strokes. Stroke 1987; 8:230-231. 16. Gottlieb SO. Circadian patterns of myocardial ischemia. Pathophysiologic and therapeutic considerations. J Cardiovasc Pharmacol 1988; 12(Suppl 7):S18-$21. 17. Cruickshank JM. Antihypertensive drugs and cardioprotection. Blood Pressure 1992; l(Suppl 1):47-57. 18. Taylor CR, Hodge EM, White DA. The circadian rhythm of angina pectoris. J Cardiovasc Pharmacol 1991; 17(Suppl 1):$43-$45. 19. Webster J, Robb OJ, Jaffers TA, et al. Once-daily amlodipine in the treatment of mild to moderate hypertension. J Cardiovasc Pharmacol 1988; 12(Suppl 7):$72-$75. 20. Mancia G, Ferrari A, Gregorini L, et al. Blood pressure and heart variability in normotensive and hypertensive human beings. Circ Res 1983; 53:96-104.
629
E V A L U A T I O N OF THE A N T I H Y P E R T E N S I V E E F F E C T OF AMLODIPINE USING 24-HOUR AMBULATORY BLOOD PRESSURE M E A S U R E M E N T ISTEMI NALBANTGIL,BULENTKILI~CIOGLU,REMZI ONDER, AND MEHMETI~LER Faculty of Medicine, Department of Cardiology, Aegean University, Izmir, Turkey
ABSTRACT The antihypertensive effect of amlodipine was investigated in 20 patients (11 men and nine women) with essential hypertension using 24-hour monitoring of ambulatory blood pressure. The patients received placebo initially for I week followed by amlodipine 5 rag/day for 8 weeks. In three patients whose diastolic blood pressure did not fall below 90 mmHg after 4 weeks, the dosage was raised to 10 rag/day. All patients underwent ambulatory blood pressure monitoring at the end of the placebo period and at the end of 8 weeks of active treatment. Blood pressures and heart rate were measured and a physical examination was performed every 2 weeks during the treatment period. By the second week of treatment, systolic and diastolic blood pressures were significantly reduced with amlodipine therapy (P < 0.01). The reduction was more pronounced in the fourth week (P < 0.001). There were no significant changes in heart rate. Ambulatory investigations revealed a significant decrease in both systolic and diastolic blood pressures every hour of the day (P < 0.001). On the other hand, heart rate was significantly reduced only between 8 A~ and 12 noon (P < 0.05). Changes at other hours of the day were not significant. Drugrelated side effects disappeared quickly without the need for tapering off or discontinuing the drug. Amlodipine is an effective and welltolerated drug for the treatment of hypertension. INTRODUCTION
Amlodipine, a new calcium antagonist of the dihydropyridine group, has been successfully used to t r e a t h y p e r t e n s i o n and ischemic h e a r t diseases. 1'2 It is used as a single daily dose because of its long plasma half-life (approximately 35 hours in adults and 48 hours in the elderly). 3 For antih y p er ten s i ve purposes, it can be used as both a single agent and in combination with other antihypertensive drugs, a-7 The purpose of this study was to investigate the antihypertensive effect of a m l o d i p i n e us i ng 24-hour m o n i t o r i n g of a m b u l a t o r y blood pressure. Address correspondence to: Istemi Nalbantgil, M.D., Mithat Papa Cad. 750/5, Izmir 35280, Turkey.
Received for publication on March 23, 1993. Printed in the U.S.A. Reproduction in whole or part is not permitted. 621
0011-393X/93/$3.50
ANTIHYPERTENSIVEEFFECT OF AMLODIPINE
P A T I E N T S AND M E T H O D S
A total of 20 patients (11 men and nine women) ages 41 to 64 years (mean, 54.1 -+ 7.2 years) were enrolled in the study. The hypertensive history of the patients ranged from 1 month to 15 years (average, 62 months). The diagnosis of essential hypertension was confirmed by physical examination, evaluation of serum creatinine and electrolyte values, and urographic analyses. After a 2-week washout period, the diastolic blood pressures of the patients varied between 95 and 110 mmHg. Patients with malignant or accelerated hypertension, those with heart rates <50 beats/min or with advanced conduction abnormalities in their electrocardiographic tracings, and those with grade III or IV hypertensive retinopathies were excluded from the study. All patients signed an informed consent form, and these documents were verified by the Ethical Council of Aegean University. The study design is shown in Figure 1. After a 1-week placebo treatment period, patients underwent their first physical examination. During this examination, blood pressures were measured using arm cuffs and mercury:in-glass sphygmomanometers with patients in a sitting position and after having rested for at least 5 minutes; heart rates were also measured. Measurements were repeated after 2 minutes, and the mean values were taken for both measurements. After thephysical examinations, electrocardiograms and chest roentgenograms were taken, and laboratory blood analyses (hematocrit, hemoglobin, leukocyte count and formula, platelet count, transaminases, serum lactate dehydrogenase, alkaline phosphatase, blood glucose, blood urea, total bilirubin, and serum sodium, potassium, and Chloride) and u r i n a r y analyses were performed. A Spacelabs 200 was used for the 24-hour ambulatory monitoring of blood pressures. Ambulatory measurements were repeated every 20 minutes between 7 AM and 11 PM, and every hour between 11 PM and 7 AM. Thus each patient underwent an average of 56 measurements in 24 hours. Sys-
Weeks
PE
AmBPM Lab PE
6
i
PE
~
3
PE
I~
5
AmBPM Lab PE
PE
~ ~
7
~
Amlodipine 10 mg Placebo, Amlodipine5 mg I
I
Once a day
DBP >90 mmHg DBP <90 mmHg
Once a day
Amlodipine 5mg Once a day
F i g u r e 1. S t u d y design. PE = physical e x a m i n a t i o n ; A m B P M = a m b u l a t o r y blood p r e s s u r e monitoring; Lab = l a b o r a t o r y tests; DBP = diastolic blood pressure.
622
I. NALBANTGIL ET ALl
tolic, diastolic, and mean blood pressures and heart rates were assessed during each hour. In addition to these values, the highest: and lowest systolic and diastolic blood pressures were recorded for a 24-hour period. The number of times that systolic blood pressures were measured >140 mmHg and diastolic pressures >90 mmHg in, 24 hours were expressed as percentages. After the placebo treatment, patients were given amlodipine 5 mg/day and were instructed to take the drug between 8 AM and 9:30 AM. Blood pressures, heart rate, and body weight were measured at each physical examination, which took place every 2 weeks. Or~ the day tha t the physical examination was performed, the patients took their medications after the exam was completed. At the fourth week of treatment, the dosage of amlodipine was increased to 10 mg/day in patients whose diastolic blood pressures did not fall <90 mmHg. At the end of the eighth week, laboratorY analyses and ambulatory blood pressure analyses were repeated in addition to the physical examination.
Statistical Analysis Blood pressures, heart rate, and body weight measured every 2 weeks were evaluated as six different measurements (before and after placebo and at the end of the second, fourth, sixth, and eighth weeks) and laboratory analyses were evaluated as two different measurements (after placebo and at the end of the eighth week) using Student's paired t test (two tailed). Ambulatory blood pressure values were evaluated as one number for each hour. The numbers corresponding to every hour before and after treatment were compared with each other using Student's paired t test. RESULTS
The mean age of the 11 male patients was 56.6 +- 6.1 years and that of the nine female patients was 51.4 -+ 7.7 years. The male patients had a history of hypertension ranging from 1 month to 15 years (average, 69.5 months), and their body weights ranged from 59 to 87 kg (mean, 75.4 + 8.6 kg). The female patients had a history of hypertension ranging from 1 month to 12 years (average, 53.5 months), and their body weights ranged from 58 to 74 kg (mean, 66.9 +- 5.0 kg). Three patients received amlodipine 10 mg/day during the last 4 weeks of the study because their diastolic blood pressures were >90 mmHg. The remaining 17 patients received amlodipine 5 mg/day throughout the study. The systolic and diastolic blood pressure values measured with a sphygmomanometer between 8:30 AM and 10:30 AM are summarized in Table I and Figure 2. Statistical analyses showed a significant reduction in both 623
ANTIHYPERTENSIVE EFFECT OF AMLODIPINE
Table I. Blood pressure, heart rate, and body weight after the washout and placebo periods and after 2, 4, 6, and 8 weeks of amlodipine treatment. Amlodipine Treatment Washout Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Heart rate (beats/min) Body weight (kg)
Placebo
Week 2
Week 4
Week 6
Week 8
162.0 --- 7.5
163.2 +_ 9.2
145.8 _+ 6.2*
136.2 _+ 7.71
132.5 +- 7.5t
130.0 _+ 7.01
101.8 ~ 5.5
100.7 + 5.9
91.6 -+ 4.0*
85.5 -+ 5.0*
82.4 -+ 5.1i-
79.9 -+ 4.7t
78.5 +- 8.7 71.1 -+ 8.1
79.0 -+ 8.0 71.3 +- 8.1
72.4 _+ 4.5 71.1 -+ 7.9
71.9 -- 7.2 71.0 -+ 7.8
71.5 + 7.5 71.0 -+ 7.4
70.2 -+ 8.0 70.8 +- 7.7
* P < 0.01. 1 P < 0.001.
systolic and diastolic blood pressures starting from the second week (P < 0.01). This reduction was more pronounced in the fourth week (P < 0.001), and blood pressures continued to decrease slightly in the following weeks. There was an insignificant decrease in the heart rate, while body weight remained unchanged (Table I).
HEART RATE
t t
75
(beats/rain) 65
t
1
t
180_
160BLOOD PRESSURE (mmHg) 140-
T
! I | !
120-
100.
i
"1"-
I
I
80-
60 washout placebo
I
I
I
week 2
week 4
week 6
"'i
week 8
Figure 2. Blood pressure and heart rate changes after the washout and placebo periods and after 2, 4, 6, and 8 weeks of amlodipine treatment. 624
I. N A L B A N T G I L ET AL.
Hourly changes in systolic and diastolic blood pressures and h e a r t rate obtained after 1 week of placebo and 8 weeks of amlodipine t r e a t m e n t are shown in Table II. Pre- and posttreatment highest and lowest systolic and diastolic blood pressures and the number of times systolic blood pressures were measured > 140 m m H g and diastolic pressures >90 m m H g expressed in percentages are given in Table III. There was a significant reduction at every hour in both systolic and diastolic blood pressures, while heart rates showed a significant decrease between 8 AM and 12 noon (P < 0.05) (Figure 3). Changes in heart rate at the other hours of the day were not significant. The rate of systolic blood pressure >140 m m H g was 63.6 +- 4.8% before t r e a t m e n t and 15.0 -+ 3.2% after treatment. The rate of diastolic blood pressure >90 m m H g was 57.3 -+ 5.6% before t r e a t m e n t and 9.9 -+ 3.2% after treatment. In ambulatory measurements, the highest daily measured systolic blood pressure dropped from 187.5 +- 4.9 m m H g to 152.0 - 3.0 m m H g after t r e a t m e n t and diastolic blood pressure from 126.7 +- 3.0 mmHg to 101.1 -+ 3.3 mmHg. Drug- and placebo-induced side effects and the doses at which these side effects were detected are shown in Table IV. None of these adverse effects required discontinuation of the drug. The side effects usually disappeared spontaneously within 2 to 7 days. No significant changes were
Table II. Changesin systolicand diastolicbloodpressures and heart rate over24 hours before and after amlodipinetreatment. Systolic Blood Pressure (mmHg) Before 6 AM 7 AM 8 AM 9 AM 10 AM 11 AM 12 PM 1 PM 2 PM 3 PM 4 PM 5 PM 6 PM 7 PM 8 PM 9 PM 10 PM 11 PM 12AM 1 AM 2 AM 3AM 4AM 5A M
138.3 .+ 22.8 145.0 ± 20.9 147.6 --+ 25.1 152.2 ± 12.2 151.4 --+ 18.0 163.0 ± 19.7 154.6 ± 19.8 159.0 4- 15.1 161.9 --+ 19.7 158,5 ± 25.8 158.8 --+ 24.7 157.4 ± 20.4 165.1 ± 24.2 162.8 ± 23.5 157.0 ± 24.2 155.6 ± 26.0 151,7 .+ 24.9 146,1 ± 18.1 141.1 --+ 21.8 137.6 ± 19.9 134.4 --+ 17.0 131.4±15.1 132.3±15,7 137.5 ± 14.6
After 112.1 117.0 122.9 123.9 128.5 129.9 129.1 126.5 128.0 130.4 128.9 133.1 131.7 129.4 128.2 121.3 119.2 121.7 114.3 116.2 110,8 111.5 110.6 115.4
.+ 12.4t .+ 12.9t --+ 12,2t "+ 12.4t -+ 17.0t "+ 11.4t "+ 12.7t --+ 13.6t "+ 13.8t ± 12.4t .+ 13.7t .+ 10.7t ± 10.9t --+ 13.0t .+ 13.4t --+ 13.1t .+ 12.5t -+ 15.2t --+ 11,2t "+ 13.9t ± 12,0t -+ 11.6t ± 9.0t -+ 15.2t
Diastolic Blood Pressure (mmHg) Before 84.0 ± 17,5 89.0 -+ 14.9 92.1 "+ 13.5 95.2 "+ 14.3 96.3 "+ 15.5 106.3 "+ 13.9 97.2 --+ 13.6 97.5 ± 14.5 100.9 --+ 15.0 96.9 "+ 16.7 95.8 --+ 15.1 100.8 --+ 16.6 99.9 -+ 15.6 101.6 -+ 17.4 101.5 -+ 17.0 95.6 ± 17.6 91.4 .+ 16,7 91.6 -+ 17.3 84,8 --+ 16.5 82.4 .+ 17.3 78.4 --+ 11.4 78.2--+11.2 81.7"+13.9 83.7 +- 12.3
* P < 0.05. t P < 0.01.
625
After 67,0 73,2 73,5 71.9 77.3 77.6 76.5 78.0 76.2 77.5 80,4 80.6 82.3 80.2 79.7 73.4 71.4 71.5 69.6 65.5 62.9 62.1 62.6 65.9
.+ 10.0t -+ 11.3t --+ 11.2t "+ 9.2t "+ 11.2t -+ 10,0t "4" 11.8t ± 9.6t --+ 10.9t --+ 10.8t ± 8.0* -+ 11.6t ± 11.9t -+ 11.6t ± 9.8t --+ 11.7t -+ 10.8t -+ 8.9t "+ 12.9t "+ 11.9t ± 9.6t .+ 9.6t ± 9.7t -+ 10.0t
Heart Rate (beats/min) Before
Alter
70.2 .+ 10.9 72.4 +- 10.4 79.7 --+ 11.3 84.5 --+ 12.3 88.6 --+ 10.4 92.0 "+ 14.8 82.2 "+ 11.2 83.6 --+ 11.3 86.7 "+ 11.8 83.9 ± 11.0 83.6 -+ 13.9 82.9 ± 13.8 87.8 ± 14.3 85.4 .+ 17.7 81.9 --+ 11.8 83.9 --+ 13.4 82.2 .+ 14.1 79.3 -+ 14.6 75.8 -+ 12.5 71.3 ± 11.3 70.6 --+ 10.2 69.7"+11.9 69.6.+10.1 68.8 -+ 10.5
71.9 --+ 9.4 73.3 + 18.0 71.8 .+ 17.6" 72.2 --+ 10.7" 74.3 --+ 11.0" 74.4 "+ 12.6" 78.6 -+ 16,1 78.3 "+ 13.3 81.0 "+ 16.4 81.9 --+ 16.1 83.1 .+ 17.2 82.7 .+ 14.1 82.9 .+ 14.2 82.9 -+ 23.5 78.3 --+ 14.0 78.8 .+ 14.3 77.5 -+ 15.2 73.0 --+ 14.9 71.7 .+ 9.8 72.7 --+ 12.9 65.0 .+ 8.9 65.5±7.5 63.5-+7.7 69.8 -+ 7.4
ANTIHYPERTENSIVE EFFECT OF AMLODIPINE
T a b l e IlL M a x i m u m a n d m i n i m u m a m b u l a t o r y systolic a n d diastolic blood p r e s s u r e s before a n d a f t e r a m l 0 d i p i n e t r e a t m e n t a n d p e r c e n t a g e of systolic blood p r e s s u r e s (SBP) > 140 m m H g a n d diastolic blood p r e s s u r e s (DBP) > 9 0 m m H g in all m e a s u r e m e n t s .
Maximum SBP (mmHg) Minimum SBP (mmHg) Maximum DBP (mmHg) Minimum DBP (mmHg) SBP >140 mmHg o(°/o) DBP >90 mmHg (%)
Before Treatment
After Treatment
P
187.5 _+ 4.9 119.3 -+ 3.5 126.7 -+ 3.0 67.0 + 2.8 63.6 _+ 4.8 57.3 _+ 5.6
152.0 +_ 3.0 97.1 --- 1.9 101.1 +_ 3.3 51.4 _+ 1.5 15.0 _+ 3.2 9.9 _+ 3.2
0.001 0.001 0.001 0.01 0.001 0.001
found in the electrocardiogram and laboratory analyses repeated at the end of the eighth week. DISCUSSION
Both systolic and diastolic blood pressures were significantly reduced after 2 weeks of treatment with amlodipine 5 mg/day. At the end of the fourth week, diastolic blood pressures fell below 90 mmHg in 17 of the 20 patients. In the remaining three patients, whose dosage was increased to 10 mg/day, diastolic blood pressures fell below 90 mmHg after 4 weeks of 1oo HEART RATE (beats/min)
80
{~(}
~--a~
o _~ ~llC
-
180 BLOOD PRESSURE (mmHg)
16o
140 -
/~,f~_.
....
J"~..,~.
,,I
1 20
~ f
"-u
D
il JIl~
.... U- ~ " ~ ' 1 ~ - - U - . . - - D -
-41
.~.-+l~--i~
-II.
-Q/11
U " rY'~'Q--U ~-I~-. 0 "-U
60 --
- I 7
I 9
I II
I 13
I 15
I 17
I 19
I" 21
'I 23
.I !
I 3
I 5
TIME OF DAY (hr) F i g u r e 3. D a i l y c h a n g e s in systolic a n d diastolic blood p r e s s u r e s a n d h e a r t r a t e o b t a i n e d w i t h a m b u l a t o r y t e c h n i q u e s before (@) a n d a f t e r (t3) a m l o d i p i n e t r e a t m e n t .
626
I. NALBANTGIL ET AL.
Table IV. Side effects.
Amlodipine
:Placebo
Amlodipine 5 mg (n = 20) Headache Dry mouth Fatigue
2 1 1
1
Amlodipine 10 mg (n = 3) Headache Fatigue
1 1
treatment. The blood-pressure-lowering effect of the drug was seen in the first 2 weeks, and in the following weeks both systolic and diastolic blood pressures showed a significant but slower decrease. In the 24-hour ambulatory measurements, the changes found in both systolic and diastolic blood pressures were in accordance with the circadian r h y t h m found in normotensive people, s In ambulatory m e a s u r e m e n t s t a k e n after the placebo period, the systolic blood pressure was > 140 m m H g in 63.6 - 4.8% of all measurements; this rate fell to 15.0 -+ 3.2% after t r e a t m e n t with amlodipine (P < 0.001). Diastolic blood pressures were >90 m m H g in 57.3 --- 5.6% of all measurements after placebo and fell to 9.9 -+ 3.2% after amlodipine (P < 0.001). The highest systolic blood pressures fell from 187.5 -+ 4.9 m m H g to 152.0 + 3.0 m m H g and diastolic pressures from 119.9 +- 3.5 m m H g to 97.1 -+ 1.9 mmHg. These findings agree with those of other studies. 9-12 The 24-hour monitoring of heart rate revealed no difference between heart rates obtained with placebo and with amlodipine during the period from noon to evening. Heart rates did not increase after drug intake, and there was a marked difference between placebo and the drug between 8 AM and 12 noon. This effect of the drug has not been reported in previous studies using 24-hour ambulatory measurements. 11'12 Ischemic events (symptomatic or silent ischemia, myocardial infarction, and sudden death), cardiac mortality outside the hospital, and strokes show a circadian r h y t h m that peaks between 8 AM and 12 noon. 13-15 Blood pressures and heart rate also peak at these hours. 16 Ischemic events possibly could be reduced by decreasing these morning rises in blood pressure and heart rate with various drugs. While some investigators claim that beta-receptor blockers could be effective in this respect, 17 others have concluded that beta-receptor blockers are insufficient.is According to our findings, amlodipine prevents the morning peaks in blood pressure and heart rate seen in hypertensive patients. Previous studies 1°'19 using a sphygmomanometer have reported that amlodipine does not cause tachyphylaxis. The changes in heart rate seen in our patients could be due to changes in blood pressure. The relationship 627
ANTIHYPERTENSIVEEFFECTOF AMLODIPINE
between blood pressure and heart rate has been previously demonstrated in other studies. 2° Based on our findings, the increases in heart rate and blood pressure seen in the morning, which are considered unfavorable, are decreased by amlodipine. Amlodipine was generally well tolerated by the patients. Side effects spontaneously disappeared in a few days without the need for tapering off or discontinuing the drug. Because amlodipine 10 mg/day was used only in three patients, we cannot definitely state that side effects are dose related. There were no significant changes in the body weight of patients before or after treatment. The drug caused no significant changes in blood biochemistry. In conclusion, amlodipine was found to be an effective and welltolerated drug for the treatment of hypertension. In addition to decreasing the morning peaks in blood pressure, it also favorably affects heart rate. References:
1. Burges RA, Dodd MG. Amlodipine. Cardiovasc Drug Rev 1990; 8:25-44. 2. Murdoch D, Heel RC. Amlodipine. Drugs 1991; 41:478-505. 3. Elliott HL, Meredith PA, Reid JL, Faulkner JK. A comparison of the disposition of single oral doses of amlodipine in young and elderly patients. J Cardiovasc Pharmacol 1988; 12(Suppl 7):564-566. 4. Baez MA, Weidler DJ. Antihypertensive effect of amlodipine in hypertensive patients. J Hypertens 1986; 4(Suppl 5):$458-$460. 5. Chrysant SG, Chrysant C, Trus J, Hitckcoch A. Antihypertensive effectiveness of amlodipine in combination with hydrochlorothiazide. A m J Hypertens 1989; 2:537-541. 6. Davies J, Jensen H, Garsdal P. A double-blind comparison of amlodipine and placebo added to open enalapril in patients with moderate to severe essential hypertension. J Cardiovasc Pharmacol 1991; 17(Suppl 1):S16-S18. 7. Frick MH, McGibney D, Tyler HM. A dose-response study of amlodipine in mild to moderate hypertension. J Intern Med 1989; 225:101-105. 8. Cesana G, DeVito G, Ferrario M, et al. Ambulatory blood pressure normalcy: The PAMELA study. J Hypertens 1991; 9(Suppl 3):S17-$23. 9. Webster J, Robb OJ, Jeffers A, et al. Once daily amlodipine in the treatment of mild to moderate hypertension. Br J Pharmacol 1987; 27:713-719. 10. Julius S. Amlodipine in hypertension: An overview of the clinical dossier. J Cardiovasc Pharmacol 1988; 12(Suppl 7):$27-$33. 11. Raftery EB, Heber ME, Brigdan G, A1-Khawaja I. 24-hour blood pressure control with the once-daily calcium channel antagonist, amlodipine. J Cardiovasc Pharmacol 1991; 17(Suppl 1):$8-S12. 12. Mraczek WJ, Burris JF, Allenby KS. Effect of amlodipine on 24 hour ambulatory blood pressure in hypertensive patients. J Cardiovasc Pharmacol 1991; 17(Suppl 1):$13-S15. 13. Muller JE, Ludmer PL, Willich SN, et al. Circadian variation in the frequency of sudden cardiac death. Circulation 1987; 75:131-138. 628
I. NALBANTGILETAL.
14. Muller JE, Stone PH, Turi ZG, et al. Circadian variation in the frequency of onset of acute myocardial infarction. New Engl J Med 1985; 131:1315-1322. 15. Marshall J. Diurnal variation in occurrence of strokes. Stroke 1987; 8:230-231. 16. Gottlieb SO. Circadian patterns of myocardial ischemia. Pathophysiologic and therapeutic considerations. J Cardiovasc Pharmacol 1988; 12(Suppl 7):S18-$21. 17. Cruickshank JM. Antihypertensive drugs and cardioprotection. Blood Pressure 1992; l(Suppl 1):47-57. 18. Taylor CR, Hodge EM, White DA. The circadian rhythm of angina pectoris. J Cardiovasc Pharmacol 1991; 17(Suppl 1):$43-$45. 19. Webster J, Robb OJ, Jaffers TA, et al. Once-daily amlodipine in the treatment of mild to moderate hypertension. J Cardiovasc Pharmacol 1988; 12(Suppl 7):$72-$75. 20. Mancia G, Ferrari A, Gregorini L, et al. Blood pressure and heart variability in normotensive and hypertensive human beings. Circ Res 1983; 53:96-104.
629