Br. J. clin. Pharmac.

(1982), 14, 71S-76S

LONG-TERM EXPERIENCE WITH CAPTOPRIL IN SEVERE

HYPERTENSION
J. HAVELKA,' H.J. BOERLIN,' A. STUDER,1 P. GREMINGER,l W. TENSCHERT,'
T. LUESCHER,' W. SIEGENTHALER,l W. VElTER,' P. WALGER2 & H. VETTER2
'Department of Internal Medicine, University Hospital Zurich, Switzerland
and
2Medizinische Universitats-Poliklinik, Munster, Federal Republic of Germany

1 The long-term effect of the converting-enzyme inhibitor captopril was investigated in 76 patients
with various forms of severe hypertension, most cases being resistant to a standardised triple therapy
(100 mg hydrochlorothiazide or 80-500 mg frusemide; 320 mg propranolol; and 200 mg hydralazine).
2 In each of the three groups examined (essential, renovascular, and renal parenchymatous hyper-
tension) captopril led to a prompt and sustained reduction in systolic and diastolic blood pressure. Up
to an observation time of 21/2 years patients with renovascular hypertension showed a more pro-
nounced fall in mean diastolic blood pressures than those with essential hypertension. About 90% of
all patients required a diuretic and a substantial percentage of patients needed propranolol as a third
drug.
3 The most frequent side effects were skin manifestations, taste disturbances, dizziness, and
non-productive cough. Serious adverse effects were rare and included one case of leucopenia and one
of the nephrotic syndrome, both of them reversed after withdrawal of captopril. Further analysis
showed that side effects occurred mainly in patients with impaired kidney function receiving relatively
high dosages of captopril (> 200 mg/day).
4 Our results show that captopril is a very potent blood-pressure-lowering agent in severe hyper-
tension, especially in cases with renovascular hypertension.

Introduction
Recently, the effectiveness of the angiotensin-
converting-enzyme inhibitor captopril has been
shown in the treatment of moderate and severe
refractory hypertension in a variety of studies
(Ferguson et al., 1977, 1980; Zweifler et al., 1979;
Brunner et al., 1979; Heel et al., 1980; Case et al.,
1978; Gavras etal., 1979; Johnston etal., 1979; Bravo
et al., 1979). Nevertheless, only a few studies have
been published on the long-term effect of captopril,
especially in patients with severe hypertension resis-
tant to conventional antihypertensive therapy
(Atkinson et al., 1980; Case et al., 1982; Havelka et
al., 1982; Raine & Ledingham, 1982; Studer et al.,
1981; McCaa et al., 1979). Here we describe our
experience with captopril in patients with hyper-
tension resistant to a conventional standard triple
therapy, who were controlled up to 21/2 years.
Methods
Patients
Seventy six patients (46 men, 30 women, mean age
48.9 + 10.7) were investigated. The mean obser-
0306-5251/82/100071-06 $01.00
vation time was 18.9 + 13.1 months. The patients
were subdivided into three different groups:
The first group comprised 36 patients (25 men, 11
women, mean age 50.0 + 9.4) with essential hyper-
tension who were treated with captopril with a mean
observation period of 16.3 + 12.3 months. The
second consisted of 22 patients (11 men, 11 women,
mean age 48.0 ± 11.5) with renovascular hyper-
tension proved by angiography. These patients were
treated over a mean period of 19.8 ± 13.4 months. In
the third group 18 patients (10 men, 8 women, mean
age 47.9 + 12.3) with renal parenchymal hyper-
tension were treated for a mean of 21.9 ± 14.0
months.
Study protocol
Before starting the captopril treatment 69 of the 76
patients were treated for two weeks with a standard
triple therapy consisting of a diuretic (hydrochloro-
thiazide 100 mg/day or in patients with impaired
kidney function (serum creatinine levels > 150
,umol/l) frusemide (18 to 500 mg/day); propranolol
(320 mg/day); and hydralazine (200 mg/day). If after
two weeks of treatment diastolic blood pressures did
© The Macmillan Press Ltd 1982
72S J. HAVELKA ETAL.
not fall below 105 mmHg and systolic values below
180 mmHg this standard therapy was withdrawn and
captopril was started. Seven patients (two with
essential, two with renovascular, and three with renal
parenchymatous hypertension) entered this study
without pretreatment with standard triple therapy. In
all of these cases systolic pressures were higher than
200 mg or diastolic pressures higher than 115 mm Hg.
If diastolic blood pressure had not fallen below 95
mm Hg after one week of captopril treatment a
diuretic (hydrochlorothiazide or frusemide) was
added. If supine diastolic pressure still did not return
to normal propranolol was added as a third drug.
A second indication for adding a diuretic was fluid
retention (two cases). In two cases propranolol was
given because of tachycardia (pulse rate greater than
100 beats/min). During the first four weeks the
patients were seen twice a week in our outpatient
clinic. After this period visits were scheduled at one
to two week intervals and later, in patients without
complications after four months of captopril treat-
ment, at monthly intervals. Afterwards, the un-
complicated patients were seen every second or every
third month. Blood pressure was measured after 10
minutes of rest in the supine position with a
Gelman-Hawksley Random Zero Sphygmomano-
meter.
The t test and regression analysis were used for
statistical calculations.
Results
Blood pressure
Throughout the observed period of 30 months a
significant and sustained reduction (p < 0.05 to <
0.001) in mean systolic and diastolic blood pressure
was observed in each of the three groups (Figure 1).
Among the three groups there was a more
pronounced response to captopril in patients with
renovascular hypertension compared with those in
essential hypertension as indicated by consistently
lower mean diastolic blood pressure values. These
differences reach statistical significance at 1, 12, 18,
and 30 months. The patients with renal
parenchymatous hypertension also showed
consistently lower mean diastolic blood pressure
values than those with essential hypertension
(significant at months 1 and 13). None of the 76
patients developed clinical symptoms of hypotension
both after the initial dose of 25 mg captopril and
throughout the study.
Drugs
Dosages The mean daily dose of captopril ranged
from 250 to 338 mg/day in patients with essential
hypertension and 243 to 266 mg/day in patients with
renovascular hypertension. The lowest mean dosages
were used in patients with renal parenchymal disease
(184 to 246 mg/day). Throughout the period of
observation, the latter required a higher mean daily
dose of frusemide than the others (Table 1). With this
exception, there were no significant differences in
mean doses of hydrochlorothiazide or propranolol
between the three groups.
Combinations Throughout the 30 months about
90% of patients received a diuretic as a second drug;
38-62% required propranolol as a third drug (Table
1).
Laboratory findings After the start of captopril
treatment slight but statistically insignificant
increases in serum creatinine and serum potassium
values were observed in each of the three groups
(Table 2). Individual analysis of changes in serum
potassium values revealed than in nine (11. 8%) of the
76 patients an increase of more than 1.0 mmol was
observed. In none of 76 patients did serum potassium
concentrations exceed 6.0 mmol/l.
Throughout the study mean serum creatinine
values were significantly higher in patients with renal
parenchymatous hypertension than in those with
essential or renovascular hypertension. Mean serum
sodium concentrations remained unchanged during
the study (Table 2).
Side effects
Thirty six side effects occurred in 26 patients, most of
them during the first twelve months of captopril
treatment. In 12 patients two or more adverse effects
were observed; and 15 different side effects were
observed. Thus in the total group the incidence of
adverse effects during captopril therapy was 34.2%.
Group specific analysis showed that the incidence
of side effects was higher in patients with renal
parenchymal (44.4%) or renovascular (40.9%)
hypertension than in those with essential hyper-
tension (25.0%). The dose of captopril at the time of
onset of adverse effects ranged from 75 to 450 mg/day
(mean 256 + 139 mg/day).
Taste disturbances, skin manifestations, and cough
Taste disturbances and skin manifestations were the
most frequent side effects. Taste loss occurred in
eight (10.5%) patients. In five patients these taste
disturbances disappeared within two to five weeks
without changing the medication, and in three
patients after withdrawal of captopril. Skin eruption,
pruritus and exanthema were observed in nine
patients (11.8%), but only two required topical or
systemic application of antihistamines. Chronic
unproductive cough developed in four (5.3%) out of
 LONG-TERM EXPERIENCE WITH CAPTOPRIL IN SEVERE HYPERTENSION 73S

18
. 36

18 11 vi
362 15 1
E
241 18 13m14t
P ~~~~~~~10
19

150
II.T
-0
0
0
[-

STT 1 6 12 18 24 30 months
Figure 1 Systolic and diastolic blood pressure after two weeks of standard triple therapy (STI) and in response to
captopril (month 1 to 30) in patients with severe essential (light bars), renovascular (black bars), and renal
parenchymal (hatched bars) hypertension.
Statistically significant differences: * P < 0.05; ** P < 0.025; P < 0.005.

Table 1 Mean daily dose of captopril, hydrochlorothiazide, or frusemide and propranolol (+ s.d.) in three groups of patients
studied. Percentages of patients receiving captopril alone, captopril and diuretic, and captopril, diuretic, and propranolol are also
shown.
Captopril (%)
Month Captopril Hydrochlorothiazide Frusemide Propranolol with with
Dose (mg) No Dose (mg) No Dose (mg) No Dose (mg) No Alone Diuretic Propranolol
Essential hypertension
1 250 166 36 70±23 16 128±75 13 178±90 7 19 81 19
6 336 160 24 64 18 9 158±85 13 182±72 12 8 92 50
12 338 127 19 75 29 7 173 74 11 184 76 11 5 95 58
18 332 138 19 63 23 8 144 78 10 200 78 11 5 95 58
24 315 146 14 48 16 6 183 166 7 170±63 8 7 93 57
30 288 162 8 42 14 3 157 150 4 160±0 5 13 87 62
Renovascular hypertension
1 266± 141 22 69±26 8 91 26 11 120±57 2 14 86 9
6 262 ± 141 18 70 ± 21 5 113 86 9 187 122 4 22 78 22
12 262± 168 16 57±24 7 122±64 7 150 124 4 13 87 25
18 258± 141 13 50± 18 5 136±64 7 187 122 3 8 92 23
24 259 ± 150 11 55 ± 11 5 148 64 5 240 139 3 9 91 27
30 243± 190 7 50±0 5 178±64 3 173 140 3 14 86 43
Renal parenchymatous hypertension
1 213 ± 117 18 50 0 3 203 116 13 24 _88 5 11 89 28
6 218 ± 150 15 50 18 5 203 72 9 120 57 5 7 93 33
12 246 ± 156 11 58 14 3 222 69 6 88 44 3 18 82 27
18 241 ± 140 11 63 53 3 202 85 6 120 46 4 18 82 36
24 223 ± 148 10 63 18 2 193±94 6 120±46 4 20 80 40
30 184± 124 8 100±0 1 181 100 5 133±46 3 25 75 38
74S J. HAVELKA ETAL.
Table 2 Mean serum creatinine, serum potassium and serum sodium
( s.d.) before and at the end of the captopril therapy.
Creatinine
('Umol/l)
Hypertension Before After Before After Before After
Essential 126 132 3.7 3.8
FM63 ±+79 ±0.5 ±0.5 ±3 ±3
Renovascular * 124 * 149 3.6 4.0
591 +741 07 04 3
Renal ±0 4.1 4.4
parenchymatous ± 208 ± 307 ± 0.9 ± 0.8 ± 3
Statistically significant differences: * P < 0.005; ** P < 0.001.
76 patients during treatment with captopril. In one
case, captopril had to be withdrawn after two months
of persistent cough. This was followed by disap-
pearance of the symptom within three weeks.
Haematological side effects One woman developed
a slight normocytic (mean corpuscular volume 8.5
AM: ), normochromic (mean corpuscular haemo-
globin 30.4 pg, mean corpuscular haemoglobin
concentration 33.9 g/dl) anaemia (red blood cell
count 3.37 x 1022/1 haemoglobin 10.2 g/dl) while
taking 400 mg captopril for eight months. The dose of
captopril could not be reduced because there was no
other way of controlling her hypertension. She was
given the drug for another 16 months and repeated
blood cell counts still showed the slight anaemia,
except for a short remission at 15 months. One
woman with renal insufficiency (serum creatinine
values 345 ,mol/l at the beginning of the study and
592 ,tmol/l at the onset of side effect) developed
leucopenia with a white blood cell count of 2.3 x 109/l
(absolute granulocyte count 520) eight weeks after
introducing captopril. At that time the dose of
captopril was 450 mg/day. Two weeks after the
withdrawal of captopril the white blood cell count
returned to normal. Re-exposure of the patient to a
reduced dose of captopril (75 mg/day) again caused
leucopenia (2.9 x 109/l). Captopril treatment was
again stopped and white blood cell counts promptly
returned to normal. Finally, this patient was again
re-exposed to a small dose of captopril (12.5 mg twice
daily) and over one year the white blood cell counts
remained normal. The present dose of captopril is 50
mg/day.
Renal side effects A nephrotic syndrome developed
in one woman with renal parenchymal disease
(serum creatinine at the time of onset was 300 ,umol/l,
captopril dosage 450 mg/day) 10 months after the
start of captopril. Urinary protein excretion was then
9.1 g/24 h. Captopril was immediately withdrawn and
Potassium Sodium.
(mmol/l) (mmol/l)
140 139
140 139
4
141 140
±3
the proteinuria gradually decreased and disappeared
within six months.
Other side effects Fluid retention with a rapid in-
crease in body weight was seen in two patients, which
was managed by adding a diuretic. Sinus tachycardia
was observed in two patients which required
additional therapy with propranolol. Two patients
had Raynaud's phenomenon while receiving
captopril without simultaneous treatment with
propranolol. Three patients complained of slight
dizziness, which did not require a dose reduction of
captopril. One woman patient with impaired kidney
function (serum creatinine 309 pmol/l, captopril
dosage 75 g/day) developed oral ulcerations after 29
months of treatment. These ulcers disappeared
within two weeks under local symptomatic therapy.
Finally, one episode each of the following adverse
effects was noticed: arthralgia, gastrointestinal dis-
comfort, hair loss, and supraventricular extra-
systoles. The last disappeared when captopril was
withdrawn because of insufficient blood pressure
control.
Discussion
The results of this study showed that captopril had a
prompt and sustained effect in patients with various
forms of severe hypertension, the vast majority of
patients being resistant to previous treatment with a
standard triple therapy. In each of the three groups
examined (essential, renovascular, and renal
parenchymatous hypertension) the effect of captopril
persisted up to 21/2 years. Others have described
similar results in these types of patients, although
most periods of observation have been shorter
(Brunner et al., 1979; Case et al., 1982; Ferguson et
al., 1980; McCaa et al., 1979; Zweifler et al., 1979).
As already described (Havelka et al., 1982; Studer et
al., 1981), the reduction in blood pressure was more
 LONG-TERM EXPERIENCE WITH CAPTOPRIL IN SEVERE HYPERTENSION
pronounced in patients with renovascular than in
those with essential hypertension.
It is now generally accepted that the antihyper-
tensive effect of captopril can be potentiated by
simultaneous application of a diuretic (Atkinson et
al., 1980; Ferguson et al., 1980; White etal., 1980). It
is thus not astonishing that nearly 90% of our patients
required a diuretic as a second drug. Finally, in this
study, as in others (Case et al., 1982; Ferguson et al.,
1980), a (3-blocker had to be given as a third drug in a
substantial proportion of patients to maintain a good
blood pressure control. Several investigators
(Atkinson et al., 1980; Case et al., 1978) have
described appreciable and symptomatic hypotension
in response to an initial dose of captopril. Such
episodes were never seen in our 76 patients although
most of them had been pretreated with a diuretic.
In patients with severe hypertension a drastic
reduction in blood pressure is generally associated
with an increase in serum creatinine values. The
simultaneous rise in serum potassium may be caused
both by the decrease in kidney function and by a
suppression of adrenal aldosterone release (Havelka
et al., 1982; Studer et al., 1981). In this study an
increase in serum potassium concentrations of more
than 1.0 mmol/l was observed in nine (11.8%) of the
76 patients during captopril therapy, though absolute
values never exceeded 6.0 ,umol/l.
The frequency and type of side effects agree with
those reported in other studies (Brunner et al., 1979;
Ferguson et al., 1980; Forslund et al., 1981; Gavras et
al., 1979, 1981; Grossman et al., 1980; Prins et al.,
1979; Rosendorff et al., 1980; Seedat 1979, 1980;
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