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- vation time was 18.9 + 13.1 months. The patients
converting-enzyme inhibitor captopril has been were subdivided into three different groups:
shown in the treatment of moderate and severe The first group comprised 36 patients (25 men, 11
refractory hypertension in a variety of studies women, mean age 50.0 + 9.4) with essential hyper-
(Ferguson et al., 1977, 1980; Zweifler et al., 1979; tension who were treated with captopril with a mean
Brunner et al., 1979; Heel et al., 1980; Case et al., observation period of 16.3 + 12.3 months. The
1978; Gavras etal., 1979; Johnston etal., 1979; Bravo second consisted of 22 patients (11 men, 11 women,
et al., 1979). Nevertheless, only a few studies have mean age 48.0 ± 11.5) with renovascular hyper-
been published on the long-term effect of captopril, tension proved by angiography. These patients were
especially in patients with severe hypertension resis- treated over a mean period of 19.8 ± 13.4 months. In
tant to conventional antihypertensive therapy the third group 18 patients (10 men, 8 women, mean
(Atkinson et al., 1980; Case et al., 1982; Havelka et age 47.9 + 12.3) with renal parenchymal hyper-
al., 1982; Raine & Ledingham, 1982; Studer et al., tension were treated for a mean of 21.9 ± 14.0
1981; McCaa et al., 1979). Here we describe our months.
experience with captopril in patients with hyper-
tension resistant to a conventional standard triple Study protocol
therapy, who were controlled up to 21/2 years.
Before starting the captopril treatment 69 of the 76
patients were treated for two weeks with a standard
Methods triple therapy consisting of a diuretic (hydrochloro-
thiazide 100 mg/day or in patients with impaired
Patients kidney function (serum creatinine levels > 150
,umol/l) frusemide (18 to 500 mg/day); propranolol
Seventy six patients (46 men, 30 women, mean age (320 mg/day); and hydralazine (200 mg/day). If after
48.9 + 10.7) were investigated. The mean obser- two weeks of treatment diastolic blood pressures did
0306-5251/82/100071-06 $01.00 © The Macmillan Press Ltd 1982
72S J. HAVELKA ETAL.

not fall below 105 mmHg and systolic values below hypertension and 243 to 266 mg/day in patients with
180 mmHg this standard therapy was withdrawn and renovascular hypertension. The lowest mean dosages
captopril was started. Seven patients (two with were used in patients with renal parenchymal disease
essential, two with renovascular, and three with renal (184 to 246 mg/day). Throughout the period of
parenchymatous hypertension) entered this study observation, the latter required a higher mean daily
without pretreatment with standard triple therapy. In dose of frusemide than the others (Table 1). With this
all of these cases systolic pressures were higher than exception, there were no significant differences in
200 mg or diastolic pressures higher than 115 mm Hg. mean doses of hydrochlorothiazide or propranolol
If diastolic blood pressure had not fallen below 95 between the three groups.
mm Hg after one week of captopril treatment a
diuretic (hydrochlorothiazide or frusemide) was Combinations Throughout the 30 months about
added. If supine diastolic pressure still did not return 90% of patients received a diuretic as a second drug;
to normal propranolol was added as a third drug. 38-62% required propranolol as a third drug (Table
A second indication for adding a diuretic was fluid 1).
retention (two cases). In two cases propranolol was
given because of tachycardia (pulse rate greater than Laboratory findings After the start of captopril
100 beats/min). During the first four weeks the treatment slight but statistically insignificant
patients were seen twice a week in our outpatient increases in serum creatinine and serum potassium
clinic. After this period visits were scheduled at one values were observed in each of the three groups
to two week intervals and later, in patients without (Table 2). Individual analysis of changes in serum
complications after four months of captopril treat- potassium values revealed than in nine (11. 8%) of the
ment, at monthly intervals. Afterwards, the un- 76 patients an increase of more than 1.0 mmol was
complicated patients were seen every second or every observed. In none of 76 patients did serum potassium
third month. Blood pressure was measured after 10 concentrations exceed 6.0 mmol/l.
minutes of rest in the supine position with a Throughout the study mean serum creatinine
Gelman-Hawksley Random Zero Sphygmomano- values were significantly higher in patients with renal
meter. parenchymatous hypertension than in those with
The t test and regression analysis were used for essential or renovascular hypertension. Mean serum
statistical calculations. sodium concentrations remained unchanged during
the study (Table 2).
Results Side effects
Blood pressure Thirty six side effects occurred in 26 patients, most of
them during the first twelve months of captopril
Throughout the observed period of 30 months a treatment. In 12 patients two or more adverse effects
significant and sustained reduction (p < 0.05 to < were observed; and 15 different side effects were
0.001) in mean systolic and diastolic blood pressure observed. Thus in the total group the incidence of
was observed in each of the three groups (Figure 1). adverse effects during captopril therapy was 34.2%.
Among the three groups there was a more Group specific analysis showed that the incidence
pronounced response to captopril in patients with of side effects was higher in patients with renal
renovascular hypertension compared with those in parenchymal (44.4%) or renovascular (40.9%)
essential hypertension as indicated by consistently hypertension than in those with essential hyper-
lower mean diastolic blood pressure values. These tension (25.0%). The dose of captopril at the time of
differences reach statistical significance at 1, 12, 18, onset of adverse effects ranged from 75 to 450 mg/day
and 30 months. The patients with renal (mean 256 + 139 mg/day).
parenchymatous hypertension also showed
consistently lower mean diastolic blood pressure Taste disturbances, skin manifestations, and cough
values than those with essential hypertension Taste disturbances and skin manifestations were the
(significant at months 1 and 13). None of the 76 most frequent side effects. Taste loss occurred in
patients developed clinical symptoms of hypotension eight (10.5%) patients. In five patients these taste
both after the initial dose of 25 mg captopril and disturbances disappeared within two to five weeks
throughout the study. without changing the medication, and in three
patients after withdrawal of captopril. Skin eruption,
Drugs pruritus and exanthema were observed in nine
patients (11.8%), but only two required topical or
Dosages The mean daily dose of captopril ranged systemic application of antihistamines. Chronic
from 250 to 338 mg/day in patients with essential 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 Potassium Sodium.
('Umol/l) (mmol/l) (mmol/l)
Hypertension Before After Before After Before After
Essential 126 132 3.7 3.8 140 139
FM63 ±+79 ±0.5 ±0.5 ±3 ±3
Renovascular * 124 * 149 3.6 4.0 140 139
591 +741 07 04 3 4
Renal ±0 4.1 4.4 141 140
parenchymatous ± 208 ± 307 ± 0.9 ± 0.8 ± 3 ±3
Statistically significant differences: * P < 0.005; ** P < 0.001.

76 patients during treatment with captopril. In one the proteinuria gradually decreased and disappeared
case, captopril had to be withdrawn after two months within six months.
of persistent cough. This was followed by disap-
pearance of the symptom within three weeks. Other side effects Fluid retention with a rapid in-
crease in body weight was seen in two patients, which
Haematological side effects One woman developed was managed by adding a diuretic. Sinus tachycardia
a slight normocytic (mean corpuscular volume 8.5 was observed in two patients which required
AM: ), normochromic (mean corpuscular haemo- additional therapy with propranolol. Two patients
globin 30.4 pg, mean corpuscular haemoglobin had Raynaud's phenomenon while receiving
concentration 33.9 g/dl) anaemia (red blood cell captopril without simultaneous treatment with
count 3.37 x 1022/1 haemoglobin 10.2 g/dl) while propranolol. Three patients complained of slight
taking 400 mg captopril for eight months. The dose of dizziness, which did not require a dose reduction of
captopril could not be reduced because there was no captopril. One woman patient with impaired kidney
other way of controlling her hypertension. She was function (serum creatinine 309 pmol/l, captopril
given the drug for another 16 months and repeated dosage 75 g/day) developed oral ulcerations after 29
blood cell counts still showed the slight anaemia, months of treatment. These ulcers disappeared
except for a short remission at 15 months. One within two weeks under local symptomatic therapy.
woman with renal insufficiency (serum creatinine Finally, one episode each of the following adverse
values 345 ,mol/l at the beginning of the study and effects was noticed: arthralgia, gastrointestinal dis-
592 ,tmol/l at the onset of side effect) developed comfort, hair loss, and supraventricular extra-
leucopenia with a white blood cell count of 2.3 x 109/l systoles. The last disappeared when captopril was
(absolute granulocyte count 520) eight weeks after withdrawn because of insufficient blood pressure
introducing captopril. At that time the dose of control.
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 Discussion
reduced dose of captopril (75 mg/day) again caused
leucopenia (2.9 x 109/l). Captopril treatment was The results of this study showed that captopril had a
again stopped and white blood cell counts promptly prompt and sustained effect in patients with various
returned to normal. Finally, this patient was again forms of severe hypertension, the vast majority of
re-exposed to a small dose of captopril (12.5 mg twice patients being resistant to previous treatment with a
daily) and over one year the white blood cell counts standard triple therapy. In each of the three groups
remained normal. The present dose of captopril is 50 examined (essential, renovascular, and renal
mg/day. parenchymatous hypertension) the effect of captopril
persisted up to 21/2 years. Others have described
Renal side effects A nephrotic syndrome developed similar results in these types of patients, although
in one woman with renal parenchymal disease most periods of observation have been shorter
(serum creatinine at the time of onset was 300 ,umol/l, (Brunner et al., 1979; Case et al., 1982; Ferguson et
captopril dosage 450 mg/day) 10 months after the al., 1980; McCaa et al., 1979; Zweifler et al., 1979).
start of captopril. Urinary protein excretion was then As already described (Havelka et al., 1982; Studer et
9.1 g/24 h. Captopril was immediately withdrawn and al., 1981), the reduction in blood pressure was more
 LONG-TERM EXPERIENCE WITH CAPTOPRIL IN SEVERE HYPERTENSION 75S

pronounced in patients with renovascular than in Woodhouse et al., 1979). with a few exceptions these
those with essential hypertension. side effects occurred within the first year of captopril
It is now generally accepted that the antihyper- therapy. Group specific analysis showed that side
tensive effect of captopril can be potentiated by effects were more common in patients with reno-
simultaneous application of a diuretic (Atkinson et vascular or renal parenchymatous hypertension than
al., 1980; Ferguson et al., 1980; White etal., 1980). It in those with essential hypertension, although the
is thus not astonishing that nearly 90% of our patients latter group received higher mean dosages of
required a diuretic as a second drug. Finally, in this captopril throughout the study. Kidney function,
study, as in others (Case et al., 1982; Ferguson et al., however, as expressed by serum creatinine values,
1980), a (3-blocker had to be given as a third drug in a was more greatly reduced in the patients with reno-
substantial proportion of patients to maintain a good vascular or renal parenchymatous hypertension.
blood pressure control. Several investigators Thus, kidney function seems to determine the
(Atkinson et al., 1980; Case et al., 1978) have occurrence of side effects. Furthermore, both
described appreciable and symptomatic hypotension patients with severe side effects (leucopenia,
in response to an initial dose of captopril. Such nephrotic syndrome) showed much increased serum
episodes were never seen in our 76 patients although creatinine values (592 and 300 ,umol/l respectively).
most of them had been pretreated with a diuretic. In conclusion, although captopril has a beneficial
In patients with severe hypertension a drastic antihypertensive effect in patients with severe
reduction in blood pressure is generally associated hypertension, one has to expect a relatively high
with an increase in serum creatinine values. The frequency of side effects in patients with severe
simultaneous rise in serum potassium may be caused hypertension since kidney function is often impaired.
both by the decrease in kidney function and by a The serious character of these effects requires careful
suppression of adrenal aldosterone release (Havelka clinical supervision with repeated laboratory examin-
et al., 1982; Studer et al., 1981). In this study an ations, including kidney function tests and blood cell
increase in serum potassium concentrations of more counts. The place of captopril in uncomplicated
than 1.0 mmol/l was observed in nine (11.8%) of the hypertension has still to be determined.
76 patients during captopril therapy, though absolute
values never exceeded 6.0 ,umol/l.
The frequency and type of side effects agree with We are indebted to Dr. U. Pfluger, SQUIBB AG, Zurich,
those reported in other studies (Brunner et al., 1979; for support of the study.
Ferguson et al., 1980; Forslund et al., 1981; Gavras et Address for reprints: W. Vetter, M.D., Department of
al., 1979, 1981; Grossman et al., 1980; Prins et al., Internal Medicine, University Hospital, CH-8091 Zurich,
1979; Rosendorff et al., 1980; Seedat 1979, 1980; Switzerland.

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