- Email: [email protected]
Combination therapy with amlodipine and captopril for resistant systemic hypertension
Combination Therapy with Amlodipine and Captopril for Resistant Systemic Hypertension Derek Maclean,
lhisstudywasconductedtoassess the therapeutic utility of combinbtg amiodipine with captoprli in patients with moderate-to-severe hypertension. Patients had hypertension of WHO grades Hii, with initial mean sitthtg and standig diastolic: blood pressure of 100-ii9 mm Hg (phase V) after 24 weeks on placebo, and had remained uncontroiied (diioik biood pressure >95 mm Hg) desptte a further 4 weeks on lowdose captoprii. Twenty-nine patii entered the computer-randomized, double-blind, piacebocontroiied, l-way crossover comparison of either amkdipine 10 mg once daily or matching placebo added to continued therapy with captoprii 25 mg twice daily for 4 weeks. Patients then acted as their own control and received the atternative amlodipbie/piacebo treatment plus their continued captoprii therapy for another 4 weeks. Oncedaiiy amiodipine was shown to be effective when combined with captoprii. Mean baseline supine systoik biood pressure decreased from 167 to 149 mm Hg and standhtg systopc biood pressure from 167 to 144 mm Hg. Mean supine diastolic biood pressure decreased from 105 to 92 mm Hg, and standing diioiii biood pressure decreased from 110 to 96 mm Hg. The placebo-corrected amiodipine differences in mean changes from captoprii baseline were - l6/ - 12.2 mm Hg for supine and -2O.U - lL9 mm Hg for standing systoik and diastolic blood pressures, respecttteiy (p
From the Department of Clinical Pharmacology, Ninewells Hospital, Dundee, Scotland, United Kingdom. Details reported are reproduced with the permission of the Journal of Human Hypertension. Address for reprints: Derek Maclean, MB, FRCP, Department of Clinical Pharmacology, Ninewells Hospital, Dundee DDl 9SY, Scotland, United Kingdom.
MB
chemical and hematom parameters were noted. (Am J Cardioi 1994;73:66A-WA)
C
ombined therapy with a calcium antagonist and an angiotensin-converting enzyme (ACE) inhibitor has been shown to be effective in the treatment of severe hypertension.1,2 It has been suggested that this combination may be advantageous in patients with more severe hypertension, whose blood pressure levels may be controlled without the need for larger doses of diuretic.3 Since the treatment of patients with moderate-to-severe hypertension may be associated with clinically unacceptable side effects, there remains a need to find effective low dose combinations with low side-effect profiles. Amlodipine, a novel 1,4-dihydropyridine calcium antagonist with high oral bioavailability and a long plasma halflife,4 has been shown to be an effective antihypertensive agent when administered alone at a dosage range of 2.5-10 mg once daily.5,6 In this study, the therapeutic utility of combining amlodipine 10 mg once daily with the ACE inhibitor captopril25 mg twice daily in hypertensive patients uncontrolled on low-dose captopril alone was assessed. This article is a brief review of the study, whose results have been reported previously in greater detail.’ ME7HOD9
inciusion criteria: Males and females aged 18-65 years were entered into the study if their mean diastolic blood pressure (DBP), both sitting and standing (WHO grades I-III), was between 100 and 119 mm Hg (Korotkoff phase V) after 4 weeks on placebo or > 95 mm Hg on captopril therapy. Patients were either newly diagnosed with hypertension or were experiencing poor blood pressure control or tolerability problems with previous antihypertensive therapy. Exciusion criteria: Patients were excluded from the study if they had clinically significant impairment of hepatic or renal function (serum creatinine > 120 kmol/liter or liver enzymes > 10%
A SUPPLEMENT:
SECOND-GENERATION
CALCIUM
ANTAGONISTS
5!jA
DBP
DBP
110-119 mm Hg
>95 mm Hg
1 -4
-2
1 Captopril 25 mg bid
0
4
8
screenings were performed at baseline and at each visit and included hemoglobin and hematocrit, red blood cell count, white blood cell count and differential, and platelet count. Urinalysis and electrocardiogram also were performed at baseline and at each subsequent visit.
I 12
amlodlpbwlOmgoncedaUyorpkeboaddedtocaptoprll 25n@twkedaUyInpatkntswtthD5P>55mmH&
above normal); myocardial infarction or stroke within the past 6 months; severe angina pectoris; allergy or intolerance to ACE inhibitors or calcium antagonists; intermittent, unstable, or accelerated hypertension; poor attendance or compliance; or concomitant use of other drugs (e.g., cimetidine or indomethacin). Women of childbearing potential also were excluded. Methods: Supine and standing systolic blood pressure (SBP) and DBP (phase V) readings were obtained using a Hawksley Random Zero sphygmomanometer. Recordings were obtained approximately 12 hours after the previous dose of captopril and 24 hours after the previous dose of amlodipine. Side effects, both volunteered and observed, were recorded, as were any intercurrent illnesses. Side effects were graded as mild, moderate, or severe by the assessing physician, who also judged their possible relation to the blinded therapy. No leading questions were asked. Routine biochemical screenings were performed at baseline and at each visit (aspartate aminotransferase, gamma glutamyltransferase, bilirubin, alkaline phosphatase, total protein and albumin, glucose, blood urea nitrogen, creatinine, sodium, potassium, and calcium). Hematologic Supine
STUDY DESIGN AND ANALYSIS The study design is shown in Figure 1. Patients whose DBP was between 100 and 119 mm Hg after 2-4 weeks on placebo entered the open captopril phase. Patients received captopril 25 mg twice daily plus placebo capsules matching amlodipine for 4 weeks. Patients whose standing and sitting average DBP was > 95 mm Hg were then entered into the randomized, double-blind, 2-way crossover comparison phase. Patients received amlodipine 10 mg once daily or matching placebo plus captopril25 mg twice daily for 4 weeks. All patients then acted as their own control and received the alternative amlodipine or placebo therapy plus continued captopril for 4 weeks, irrespective of blood pressure values noted at the time of the changeover. Twenty-nine patients (mean blood pressure 167 + 3/104 +- 1 mm Hg supine; 168 + 4/ 110 2 1 mm Hg standing) entered the doubleblind crossover phase of the study. Baseline blood pressure values were taken to be the means of 3 measurements obtained at the end of captopril monotherapy, before the start of double-blind therapy. These baseline means were subtracted from the means of 3 measurements recorded at the end of each period of double-blind treatment. Blood pressure changes from baseline values were analyzed using a standard analysis of variance model appropriate for a 2-period, 2-treatment crossover design. Both primary efficacy analysis and intention to treat analysis were performed. Only the results of the primary efficacy analysis are reported here.
Standing
2.6lood pressure responseJt0 amlodlpine vs placebo In patients on IJaw low4loso captopltl therapy. Amlodlplne then placebo, n = W; placebotlmnamlodlplned,n = l4. Fl6uR5
BaselineTreatment BaselineTreatment Amlodipine Placebo
BasslineTreatment BaselineTreatmenl Amlodipine Placebo
* P
56A
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73
JANUARY 27, 1994
TABLE I Supine and Standing Heart Rates: Changes From Baseline to End of Each Double-Blind Period
Supine heart rate (beatsimin) 1st period
2nd period Standing heart rate (beats/min) 1st period
2nd period Adapted with permission
End of Period (mean)
Treatment
n
Baseline (mean)
Amlodlpine Placebo
13 14
83.1 84.2
85.0 85.7
Amlodipine Placebo
14 13
84.2 83.1
86.5 79.7
Amlodlplne Placebo
13 14
86.7 88.2
88.3 91.1
Amlodlpine Placebo
14 13
88.2 86.7
90.9 81.4
Mean Difference (95% Cl) in Changes Between Treatment Groups (amlodipme. placebo)
Significance of Comparisons
2.9 (-0.1,
6.1)
p = 0.0477
3.2 (-0.8,
7.4)
p = 0.1121
from J Hum Hypertens.’
RESULTS Of the 29 patients who entered the double-blind portion of the study, 18 had received previous antihypertensive therapy: 4 patients had received an ACE inhibitor, 9 patients a calcium antagonist, 1 patient a thiazide diuretic, and 15 patients a P-adrenoceptor antagonist. Two patients were excluded from the primary efficacy analysis because blood pressure readings were not taken within the 9- to 15hour postdose window for blood pressure recording that is appropriate for captopril. The blood pressure responses to treatment are shown in Figure 2. In patients receiving amlodipine, mean baseline supine SBP decreased from 167 to 149 mm Hg and standing SBP from 167 to 144 mm Hg; mean supine DBP decreased from 105 to 92 mm Hg and standing DBP from 110 to 96 mm Hg. Figure 3 shows the amlodipine-minus-placebo differences in mean changes from captopril baseline: -18/-12.2 mm Hg for supine and -20.11 - 11.9 mm Hg for standing SBP and DBP, respectively (p < 0.001 for all 4 measurements). The 95% confidence intervals for supine SBP (mm Hg) were from -25.5 to - 10.3 and for supine DBP (mm Hg) from -15.9 to -8.5; for standing SBP (mm Hg) they were from -28.0 to -12.4 and for standing DBP (mm Hg) from - 15.8 to -8.0. A total of 19 patients in the amlodipine group achieved supine DBP < 95 mm Hg, compared with only 3 in the placebo group; 9 patients in the amlodipine group achieved supine DBP ~90 mm Hg, compared with only 1 patient in the placebo group. No clinically important differences in heart rate (Table I) were seen in either treatment group. Prior to treatment, mean weight for the patients randomized to receive amlodipine then placebo plus captopril were 82.6 kg (males) and 63.5 kg (females); the corresponding values for patients
randomized to receive placebo then amlodipine plus captopril were 83.7 kg (males) and 69.9 kg (females). No significant weight changes occurred during therapy; the mean difference in body weight changes from baseline between the treatment groups was -0.3 kg (95% confidence interval -0.8, +0.4; p = 0.5220). All reported adverse events defined as possibly treatment-related occurring during the doubleblind phase of the study are shown in Table II. The most common side effects associated with amlodipine therapy were flushing and pedal edema. The ankle swelling was not associated with weight gain, and in all but 1 patient, these effects were mild to moderate. None of the patients discontinued therapy because of any side effects during the double-blind crossover portion of the study. No significant treatment-related biochemical, hematologic, or ECG changes were noted, and no abnormalities were detected on urinalysis. None of the patients reported cough, hoarseness, or rhinitis, possibly because the captopril dosage was low.
Supine
Standing
O
:p-F
fjj--F
Systolic
Diastolic
Systolic
Diastolic
* P co.oo1.
FIGURE 3.5lwd pressure reductton from baseline after amlodipine therapy: placebo subtracted changes. Amk dipine than placebo, n = 13; placebo then amlodlpine, n=l4.
A SUPPLEMENT:
SECOND-GENERATION
CALCIUM
ANTAGONISTS
57A
TABLE II All Reported Adverse Events Defined as Possibly Treatment-Related During Double-Blind Phase
Ankle swelling Flushing Fatigue Dizziness Headache Palpitations Nausea Nervousness Insomnia Itchy eyes
Captopril + Placebo (n = 29)
Captopril + Amlodipine (n = 29)
0 0 0 2 1 1 1 0 0 1
5 4 3 2 1 1 0 1 1 0
DISCUSSION Amlodipine has been shown to provide effective blood-pressure control throughout the 24-hour dosing period when given once daily and is generally well tolerated.6 Captopril is also generally well tolerated.3 The results of this study demonstrate that amlodipine 10 mg once daily is an effective antihypertensive drug when combined with lowdose captopril twice daily in patients with moderately severe essential hypertension. In Europe, captopril is licensed for twice-daily dosing for the treatment of hypertension.8 The addition of amlodipine to the captopril regimen was effective in lowering blood pressure in patients on background low-dose captopril. In addition, amlodipine plus captopril was associated with a low side-effect profile. Although a few patients experienced vasodilator-type adverse events, no patient discontinued therapy.
SSA
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73
The study design did not permit assessment of whether the beneficial changes in blood pressure could have been obtained by therapy with amlodipine alone, nor whether captopril modulates the vasodilatory adverse-event profile of the calcium antagonist. The short-term therapeutic utility of the combination of amlodipine plus captopril in patients with moderate to severe hypertension is high, and longer-term studies of the efficacy and tolerability of this combination are warranted.
REFERENCES l. White WB, Viadero JJ, Lane TJ, PodeslaS. Effects of combination therapy with captopril and nifedipine in severe or resistant hypertension.C&z Phannaco1Z-her1986;39:4%48. 2. Guazzi MD, De&are N, GaIli C, et al. Calcium-channel blockade with nifedipine and angiotensin converting-enzymeinhibition with captopril in the therapy of patients with severe primary hypertension.Circulation 1984;70:279284. 3. MacGregor GA. Sodium balance and calcium antagonistsin hypertension. In: Epstein M, Loutzenhiser R, eds. Calcium Antagonists and the Kidney. Philadelphia: Hanley & Belfus, 1990:213-224. 4. Faulkner JK, McGibney D, Chasseaud LF, Perry JL, Taylor IW. The pharmacokiietics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily. Br J Clin Phannacol1986,22:21-25
8. Dodd MG, Ma&m I. Anti-hypertensive effects of amlodipine, a novel diiydropyridine calcium channel blocker. Br J Phammol1985;85(suppl):335P. 6. Webster J, Robb OJ, Jeffers TA, Scott AK, Petrie JC, Towler HM. Once daily amlodipine in the treatment of mild to moderate hypertension. Br J Phannacol1987;24:71>719.
7. Maclean D, Mitchell ET, Wilcox RG, Walker P, Tyler HM. Amkxiipine and captopril in [email protected] Hum Hyp&m 1988.2: 127-132. 8. Drayer JIM, Weber MA. Monotherapy of essential hypertension with a converting-enzymeinhibitor. ,Yy~en.&~ 1983;5(suppl3):108-113.
JANUARY 27, 1994
lhisstudywasconductedtoassess the therapeutic utility of combinbtg amiodipine with captoprli in patients with moderate-to-severe hypertension. Patients had hypertension of WHO grades Hii, with initial mean sitthtg and standig diastolic: blood pressure of 100-ii9 mm Hg (phase V) after 24 weeks on placebo, and had remained uncontroiied (diioik biood pressure >95 mm Hg) desptte a further 4 weeks on lowdose captoprii. Twenty-nine patii entered the computer-randomized, double-blind, piacebocontroiied, l-way crossover comparison of either amkdipine 10 mg once daily or matching placebo added to continued therapy with captoprii 25 mg twice daily for 4 weeks. Patients then acted as their own control and received the atternative amlodipbie/piacebo treatment plus their continued captoprii therapy for another 4 weeks. Oncedaiiy amiodipine was shown to be effective when combined with captoprii. Mean baseline supine systoik biood pressure decreased from 167 to 149 mm Hg and standhtg systopc biood pressure from 167 to 144 mm Hg. Mean supine diastolic biood pressure decreased from 105 to 92 mm Hg, and standing diioiii biood pressure decreased from 110 to 96 mm Hg. The placebo-corrected amiodipine differences in mean changes from captoprii baseline were - l6/ - 12.2 mm Hg for supine and -2O.U - lL9 mm Hg for standing systoik and diastolic blood pressures, respecttteiy (p
From the Department of Clinical Pharmacology, Ninewells Hospital, Dundee, Scotland, United Kingdom. Details reported are reproduced with the permission of the Journal of Human Hypertension. Address for reprints: Derek Maclean, MB, FRCP, Department of Clinical Pharmacology, Ninewells Hospital, Dundee DDl 9SY, Scotland, United Kingdom.
MB
chemical and hematom parameters were noted. (Am J Cardioi 1994;73:66A-WA)
C
ombined therapy with a calcium antagonist and an angiotensin-converting enzyme (ACE) inhibitor has been shown to be effective in the treatment of severe hypertension.1,2 It has been suggested that this combination may be advantageous in patients with more severe hypertension, whose blood pressure levels may be controlled without the need for larger doses of diuretic.3 Since the treatment of patients with moderate-to-severe hypertension may be associated with clinically unacceptable side effects, there remains a need to find effective low dose combinations with low side-effect profiles. Amlodipine, a novel 1,4-dihydropyridine calcium antagonist with high oral bioavailability and a long plasma halflife,4 has been shown to be an effective antihypertensive agent when administered alone at a dosage range of 2.5-10 mg once daily.5,6 In this study, the therapeutic utility of combining amlodipine 10 mg once daily with the ACE inhibitor captopril25 mg twice daily in hypertensive patients uncontrolled on low-dose captopril alone was assessed. This article is a brief review of the study, whose results have been reported previously in greater detail.’ ME7HOD9
inciusion criteria: Males and females aged 18-65 years were entered into the study if their mean diastolic blood pressure (DBP), both sitting and standing (WHO grades I-III), was between 100 and 119 mm Hg (Korotkoff phase V) after 4 weeks on placebo or > 95 mm Hg on captopril therapy. Patients were either newly diagnosed with hypertension or were experiencing poor blood pressure control or tolerability problems with previous antihypertensive therapy. Exciusion criteria: Patients were excluded from the study if they had clinically significant impairment of hepatic or renal function (serum creatinine > 120 kmol/liter or liver enzymes > 10%
A SUPPLEMENT:
SECOND-GENERATION
CALCIUM
ANTAGONISTS
5!jA
DBP
DBP
110-119 mm Hg
>95 mm Hg
1 -4
-2
1 Captopril 25 mg bid
0
4
8
screenings were performed at baseline and at each visit and included hemoglobin and hematocrit, red blood cell count, white blood cell count and differential, and platelet count. Urinalysis and electrocardiogram also were performed at baseline and at each subsequent visit.
I 12
amlodlpbwlOmgoncedaUyorpkeboaddedtocaptoprll 25n@twkedaUyInpatkntswtthD5P>55mmH&
above normal); myocardial infarction or stroke within the past 6 months; severe angina pectoris; allergy or intolerance to ACE inhibitors or calcium antagonists; intermittent, unstable, or accelerated hypertension; poor attendance or compliance; or concomitant use of other drugs (e.g., cimetidine or indomethacin). Women of childbearing potential also were excluded. Methods: Supine and standing systolic blood pressure (SBP) and DBP (phase V) readings were obtained using a Hawksley Random Zero sphygmomanometer. Recordings were obtained approximately 12 hours after the previous dose of captopril and 24 hours after the previous dose of amlodipine. Side effects, both volunteered and observed, were recorded, as were any intercurrent illnesses. Side effects were graded as mild, moderate, or severe by the assessing physician, who also judged their possible relation to the blinded therapy. No leading questions were asked. Routine biochemical screenings were performed at baseline and at each visit (aspartate aminotransferase, gamma glutamyltransferase, bilirubin, alkaline phosphatase, total protein and albumin, glucose, blood urea nitrogen, creatinine, sodium, potassium, and calcium). Hematologic Supine
STUDY DESIGN AND ANALYSIS The study design is shown in Figure 1. Patients whose DBP was between 100 and 119 mm Hg after 2-4 weeks on placebo entered the open captopril phase. Patients received captopril 25 mg twice daily plus placebo capsules matching amlodipine for 4 weeks. Patients whose standing and sitting average DBP was > 95 mm Hg were then entered into the randomized, double-blind, 2-way crossover comparison phase. Patients received amlodipine 10 mg once daily or matching placebo plus captopril25 mg twice daily for 4 weeks. All patients then acted as their own control and received the alternative amlodipine or placebo therapy plus continued captopril for 4 weeks, irrespective of blood pressure values noted at the time of the changeover. Twenty-nine patients (mean blood pressure 167 + 3/104 +- 1 mm Hg supine; 168 + 4/ 110 2 1 mm Hg standing) entered the doubleblind crossover phase of the study. Baseline blood pressure values were taken to be the means of 3 measurements obtained at the end of captopril monotherapy, before the start of double-blind therapy. These baseline means were subtracted from the means of 3 measurements recorded at the end of each period of double-blind treatment. Blood pressure changes from baseline values were analyzed using a standard analysis of variance model appropriate for a 2-period, 2-treatment crossover design. Both primary efficacy analysis and intention to treat analysis were performed. Only the results of the primary efficacy analysis are reported here.
Standing
2.6lood pressure responseJt0 amlodlpine vs placebo In patients on IJaw low4loso captopltl therapy. Amlodlplne then placebo, n = W; placebotlmnamlodlplned,n = l4. Fl6uR5
BaselineTreatment BaselineTreatment Amlodipine Placebo
BasslineTreatment BaselineTreatmenl Amlodipine Placebo
* P
56A
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73
JANUARY 27, 1994
TABLE I Supine and Standing Heart Rates: Changes From Baseline to End of Each Double-Blind Period
Supine heart rate (beatsimin) 1st period
2nd period Standing heart rate (beats/min) 1st period
2nd period Adapted with permission
End of Period (mean)
Treatment
n
Baseline (mean)
Amlodlpine Placebo
13 14
83.1 84.2
85.0 85.7
Amlodipine Placebo
14 13
84.2 83.1
86.5 79.7
Amlodlplne Placebo
13 14
86.7 88.2
88.3 91.1
Amlodlpine Placebo
14 13
88.2 86.7
90.9 81.4
Mean Difference (95% Cl) in Changes Between Treatment Groups (amlodipme. placebo)
Significance of Comparisons
2.9 (-0.1,
6.1)
p = 0.0477
3.2 (-0.8,
7.4)
p = 0.1121
from J Hum Hypertens.’
RESULTS Of the 29 patients who entered the double-blind portion of the study, 18 had received previous antihypertensive therapy: 4 patients had received an ACE inhibitor, 9 patients a calcium antagonist, 1 patient a thiazide diuretic, and 15 patients a P-adrenoceptor antagonist. Two patients were excluded from the primary efficacy analysis because blood pressure readings were not taken within the 9- to 15hour postdose window for blood pressure recording that is appropriate for captopril. The blood pressure responses to treatment are shown in Figure 2. In patients receiving amlodipine, mean baseline supine SBP decreased from 167 to 149 mm Hg and standing SBP from 167 to 144 mm Hg; mean supine DBP decreased from 105 to 92 mm Hg and standing DBP from 110 to 96 mm Hg. Figure 3 shows the amlodipine-minus-placebo differences in mean changes from captopril baseline: -18/-12.2 mm Hg for supine and -20.11 - 11.9 mm Hg for standing SBP and DBP, respectively (p < 0.001 for all 4 measurements). The 95% confidence intervals for supine SBP (mm Hg) were from -25.5 to - 10.3 and for supine DBP (mm Hg) from -15.9 to -8.5; for standing SBP (mm Hg) they were from -28.0 to -12.4 and for standing DBP (mm Hg) from - 15.8 to -8.0. A total of 19 patients in the amlodipine group achieved supine DBP < 95 mm Hg, compared with only 3 in the placebo group; 9 patients in the amlodipine group achieved supine DBP ~90 mm Hg, compared with only 1 patient in the placebo group. No clinically important differences in heart rate (Table I) were seen in either treatment group. Prior to treatment, mean weight for the patients randomized to receive amlodipine then placebo plus captopril were 82.6 kg (males) and 63.5 kg (females); the corresponding values for patients
randomized to receive placebo then amlodipine plus captopril were 83.7 kg (males) and 69.9 kg (females). No significant weight changes occurred during therapy; the mean difference in body weight changes from baseline between the treatment groups was -0.3 kg (95% confidence interval -0.8, +0.4; p = 0.5220). All reported adverse events defined as possibly treatment-related occurring during the doubleblind phase of the study are shown in Table II. The most common side effects associated with amlodipine therapy were flushing and pedal edema. The ankle swelling was not associated with weight gain, and in all but 1 patient, these effects were mild to moderate. None of the patients discontinued therapy because of any side effects during the double-blind crossover portion of the study. No significant treatment-related biochemical, hematologic, or ECG changes were noted, and no abnormalities were detected on urinalysis. None of the patients reported cough, hoarseness, or rhinitis, possibly because the captopril dosage was low.
Supine
Standing
O
:p-F
fjj--F
Systolic
Diastolic
Systolic
Diastolic
* P co.oo1.
FIGURE 3.5lwd pressure reductton from baseline after amlodipine therapy: placebo subtracted changes. Amk dipine than placebo, n = 13; placebo then amlodlpine, n=l4.
A SUPPLEMENT:
SECOND-GENERATION
CALCIUM
ANTAGONISTS
57A
TABLE II All Reported Adverse Events Defined as Possibly Treatment-Related During Double-Blind Phase
Ankle swelling Flushing Fatigue Dizziness Headache Palpitations Nausea Nervousness Insomnia Itchy eyes
Captopril + Placebo (n = 29)
Captopril + Amlodipine (n = 29)
0 0 0 2 1 1 1 0 0 1
5 4 3 2 1 1 0 1 1 0
DISCUSSION Amlodipine has been shown to provide effective blood-pressure control throughout the 24-hour dosing period when given once daily and is generally well tolerated.6 Captopril is also generally well tolerated.3 The results of this study demonstrate that amlodipine 10 mg once daily is an effective antihypertensive drug when combined with lowdose captopril twice daily in patients with moderately severe essential hypertension. In Europe, captopril is licensed for twice-daily dosing for the treatment of hypertension.8 The addition of amlodipine to the captopril regimen was effective in lowering blood pressure in patients on background low-dose captopril. In addition, amlodipine plus captopril was associated with a low side-effect profile. Although a few patients experienced vasodilator-type adverse events, no patient discontinued therapy.
SSA
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73
The study design did not permit assessment of whether the beneficial changes in blood pressure could have been obtained by therapy with amlodipine alone, nor whether captopril modulates the vasodilatory adverse-event profile of the calcium antagonist. The short-term therapeutic utility of the combination of amlodipine plus captopril in patients with moderate to severe hypertension is high, and longer-term studies of the efficacy and tolerability of this combination are warranted.
REFERENCES l. White WB, Viadero JJ, Lane TJ, PodeslaS. Effects of combination therapy with captopril and nifedipine in severe or resistant hypertension.C&z Phannaco1Z-her1986;39:4%48. 2. Guazzi MD, De&are N, GaIli C, et al. Calcium-channel blockade with nifedipine and angiotensin converting-enzymeinhibition with captopril in the therapy of patients with severe primary hypertension.Circulation 1984;70:279284. 3. MacGregor GA. Sodium balance and calcium antagonistsin hypertension. In: Epstein M, Loutzenhiser R, eds. Calcium Antagonists and the Kidney. Philadelphia: Hanley & Belfus, 1990:213-224. 4. Faulkner JK, McGibney D, Chasseaud LF, Perry JL, Taylor IW. The pharmacokiietics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily. Br J Clin Phannacol1986,22:21-25
8. Dodd MG, Ma&m I. Anti-hypertensive effects of amlodipine, a novel diiydropyridine calcium channel blocker. Br J Phammol1985;85(suppl):335P. 6. Webster J, Robb OJ, Jeffers TA, Scott AK, Petrie JC, Towler HM. Once daily amlodipine in the treatment of mild to moderate hypertension. Br J Phannacol1987;24:71>719.
7. Maclean D, Mitchell ET, Wilcox RG, Walker P, Tyler HM. Amkxiipine and captopril in [email protected] Hum Hyp&m 1988.2: 127-132. 8. Drayer JIM, Weber MA. Monotherapy of essential hypertension with a converting-enzymeinhibitor. ,Yy~en.&~ 1983;5(suppl3):108-113.
JANUARY 27, 1994