Combination Therapy with Amlodipine and
Captopril for Resistant Systemic Hypertension
Derek Maclean,
lhisstudywasconductedtoassess the thera-
peutic utility of combinbtg amiodipine with capto-
prli in patients with moderate-to-severe hyper-
tension. 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 low-
dose captoprii. Twenty-nine patii entered the
computer-randomized, double-blind, piacebo-
controiied, 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 contin-
ued captoprii therapy for another 4 weeks. Once-
daiiy 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 sys-
toik and diastolic blood pressures, respecttteiy
(p <O.OOl for ail 4 measurements). The most
common side effects encountered with amlo-
dipine were flushing and pedal edema. The combi-
nation of amiodipine and captoprii was well toier-
ated, and no patient discontinued therapy. No
significant treatment-reiated effects on bk-
From the Department of Clinical Pharmacology, Ninewells Hospi-
tal, Dundee, Scotland, United Kingdom. Details reported are
reproduced with the permission of the Journal of Human Hyperten-
sion.
Address for reprints: Derek Maclean, MB, FRCP, Department
of Clinical Pharmacology, Ninewells Hospital, Dundee DDl 9SY,
Scotland, United Kingdom.
A SUPPLEMENT:
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 hyper-
tension, whose blood pressure levels may be con-
trolled without the need for larger doses of di-
uretic.3 Since the treatment of patients with
moderate-to-severe hypertension may be associ-
ated with clinically unacceptable side effects, there
remains a need to find effective low dose combina-
tions with low side-effect profiles. Amlodipine, a
novel 1,4-dihydropyridine calcium antagonist with
high oral bioavailability and a long plasma half-
life,4 has been shown to be an effective antihyper-
tensive 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 pre-
vious antihypertensive therapy.
Exciusion criteria: Patients were excluded from
the study if they had clinically significant impair-
ment of hepatic or renal function (serum creati-
nine > 120 kmol/liter or liver enzymes > 10%
SECOND-GENERATION CALCIUM ANTAGONISTS 5!jA
 DBP DBP
110-119 >95
mm Hg mm Hg
1 1
Captopril 25 mg bid
-4 -2 0 4
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 sphygmo-
manometer. Recordings were obtained approxi-
mately 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 per-
formed at baseline and at each visit (aspartate
aminotransferase, gamma glutamyltransferase, bili-
rubin, alkaline phosphatase, total protein and albu-
min, glucose, blood urea nitrogen, creatinine, so-
dium, potassium, and calcium). Hematologic
Supine
BaselineTreatment BaselineTreatment
Amlodipine Placebo
* P<O.ooi.
56A THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73
screenings were performed at baseline and at each
visit and included hemoglobin and hematocrit, red
blood cell count, white blood cell count and differ-
ential, and platelet count. Urinalysis and electrocar-
I diogram also were performed at baseline and at
8 12 each subsequent visit.
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 cross-
over comparison phase. Patients received amlo-
dipine 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 double-
blind 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-treat-
ment crossover design. Both primary efficacy analy-
sis and intention to treat analysis were performed.
Only the results of the primary efficacy analysis are
reported here.
Standing
Fl6uR5 2.6lood pressure responseJt0
amlodlpine vs placebo In patients on
IJaw low4loso captopltl therapy.
Amlodlplne then placebo, n = W; pla-
cebotlmnamlodlplned,n = l4.
BasslineTreatment BaselineTreatmenl
Amlodipine Placebo
JANUARY 27, 1994
 TABLE I Supine and Standing Heart Rates: Changes From Baseline to End of Each Double-Blind Period
End of Mean Difference (95% Cl)
Baseline Period in Changes Between Treatment Significance
Treatment n (mean) (mean) Groups (amlodipme. placebo) of Comparisons

Supine heart rate (beatsimin)

1st period Amlodlpine 13 83.1 85.0
Placebo 14 84.2 85.7
2.9 (-0.1, 6.1) p = 0.0477
2nd period Amlodipine 14 84.2 86.5
Placebo 13 83.1 79.7
Standing heart rate (beats/min)
1st period Amlodlplne 13 86.7 88.3
Placebo 14 88.2 91.1
3.2 (-0.8, 7.4) p = 0.1121
2nd period Amlodlpine 14 88.2 90.9
Placebo 13 86.7 81.4
Adapted with permission from J Hum Hypertens.’

RESULTS randomized to receive placebo then amlodipine

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 ex-
cluded 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 amlo-
dipine, 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 base-
line: -18/-12.2 mm Hg for supine and -20.11
- 11.9 mm Hg for standing SBP and DBP, respec-
tively (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
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 double-
blind phase of the study are shown in Table II. The
most common side effects associated with amlo-
dipine 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, hemato-
logic, or ECG changes were noted, and no abnor-
malities 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
The study design did not permit assessment of
Treatment-Related During Double-Blind Phase whether the beneficial changes in blood pressure
Captopril + Placebo Captopril + Amlodipine could have been obtained by therapy with amlo-
(n = 29) (n = 29) dipine alone, nor whether captopril modulates the
Ankle swelling 0 5 vasodilatory adverse-event profile of the calcium
Flushing 0 4 antagonist. The short-term therapeutic utility of
Fatigue 0 3
Dizziness 2 2 the combination of amlodipine plus captopril in
Headache 1 1 patients with moderate to severe hypertension is
Palpitations 1 1
Nausea 1 0 high, and longer-term studies of the efficacy and
Nervousness 0 1 tolerability of this combination are warranted.
Insomnia 0 1
Itchy eyes 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 gener-
ally 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 low-
dose captopril twice daily in patients with moder-
ately severe essential hypertension. In Europe,
captopril is licensed for twice-daily dosing for the
treatment of hypertension.8 The addition of amlo-
dipine 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 vaso-
dilator-type adverse events, no patient discontin-
ued therapy.
REFERENCES
l. White WB, Viadero JJ, Lane TJ, PodeslaS. Effects of combination therapy
with captopril and nifedipine in severe or resistant hypertension.C&z Phanna-
co1Z-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;70:279-
284.
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 moderate-@severeessentialhypertension..I 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.

SSA THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73 JANUARY 27, 1994