Clinical Science (1982) 63.443~445~

443s

Captopril: evaluation of low doses, twice-daily doses and the
addition of diuretic for the treatment of mild to moderate
          hypertension

VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP* ON
              ANTIHYPERTENSIVE AGENTS

From the Cooperative Studies Program of the Veterans Administration Medical Research Service

Summary

1. We randomized 475 men whose diastolic
blood pressure was 92-109 mmHg to either
placebo- or captopril-treated (37.5, 75 and 150
mg/day) groups for 7 weeks.

2. After 7 weeks, the placebo-treated patients
were given hydrochlorothiazide (25 mg twice
daily), as were two-thirds of each captopril-
treated group, and they were observed for 7
additional weeks.

3. Captopril reduced blood pressure by 12.2
+ O-8/9.4 f 0.4 mmHg at 7 weeks (n = 323)
and captopril plus placebo by 10.3 f 1.9110.2 +
0.9 at 14 weeks (n = 83); placebo by 2.0 +
l-7/3.4 + O-8 (n = 76); captopril plus hydro-
chlorothiazide by 24.4 f 1.1/16.2 f O-6 (n =
173). The effect of low-dose captopril was similar
to that of a high dose. The effect of twice-daily
captopril appeared to be equal to that of

* Study participants: (co-chairmen) B. J. Materson
and E. D. Freis; (participating investigators) W. W.
Neal, R. E. Borreson, J. T. Taguchi, B. Mukherji, H.
M. Perry, K. C. Mezey, W. Flamenbaum and R.
Hamburger;  (nurses or physician assistants) B.
Munze, P. Melly, R. Collins, M. Curry, P. Ulrich, R.
Berry, M. Fitzgerald, A. Faiella and B. Gregory;
(Biostatistical Center) S. Anderson. T. Tosch and J.
Foregger; (Central Laboratory) W.`Flamenbaum and
R. Hamburger; (Central Research Pharmacist) L.
Young; (Operations Committee) W. M. Kirkendall,
W. McF. Smith and C. M. Hawkins; (consultants) J.
Alexander, J. Stritar and J. Meyer; (Cooperative
Studies Program Central Administration) J. A.
Hagans, P. Huang, W. G. Henderson and M. Sather.

Correspondence: Dr Barry J. Materson, Miami
Veterans Administration Medical Center, 1201 N.W.
16th Street, Miami, FL 33 125, U.S.A.

/

thrice-dailv treatment but monitoring studies are
needed to confirm this.

4. Only 15 out of 384 (3.9%) of patients were
dropped from the study because of adverse
effects.

5. Low-dose captopril may be useful in
patients with mild to moderate hypertension.

Key words: captopril, hydrochlorothiazide.

Introduction

Captopril (SQ 14 225), an oral angiotensin
converting enzyme inhibitor, was proposed as an
ideal antihypertensive drug because it was tar-
geted to a major humoral system responsible for
sustaining elevated arterial pressure 111. Indeed,
captopril was effective in lowering arterial press-
ure even in patients who had low plasma renin
activity and it was not associated with the
adverse effects of the sympatholytic drugs 121.
Unfortunately, captopril had adverse effects,
including a rash, neutropenia and proteinuria. Its
initial use, however, had been restricted to
severely ill patients and patients with severe
hypertension resistant to multiple drug com-
binations. In general, very high doses (450 mg or
more) of captopril were used 131. We designed
this study on patients with mild, uncomplicated
hypertension to determine whether captopril was
effective as a hypotensive agent in doses much
lower than had been used previously and to
determine if lower effective doses were associated
with fewer adverse effects. We also sought to
determine the degree of hypotension induced by
the addition of hydrochlorothiazide to captopril
and to determine whether captopril could be
administered twice rather than three times daily.


444s

Low-dose captopril

Methods

We enrolled 722 ambulatory male veterans
whose diastolic (Korotkoff phase V) blood press-
ure was 92-109 mmHg and who met other quali-
fying criteria. All patients gave fully informed,
written consent before they were enrolled.
The protocol had been approved by a central
human studies committee and similar com-
mittees at each of the seven participating centres.
Patients were withdrawn from current medication
for at least 2 weeks and then given a placebo
capsule. Patients meeting the blood pressure
entry criteria and compliance requirements
(checked by count of pills remaining in a special
blister pack) were randomized to taking a capsule
which was identical in appearance with the
placebo capsule but contained one of the follow-
ing: placebo, captopril 12.5 mg, 25 mg, 37.5 mg
or 50 mg. All of these medications were to be
taken three times a day with the exception of
captopril 37.5 mg, which was taken twice daily.
The blind was preserved by placing a placebo as
the mid-day dose on the blister pack. After 7
weeks (phase A), all patients were given a tablet
that contained either hydrochlorothiazide (25.
mg) or placebo and were instructed to take it
twice daily. All patients previously given placebo
instead of active captopril were given active
hydrochlorothiazide so that no patients remained
in the study on placebo alone beyond this point.
All other patients receiving active captopril were
randomized such that one-third of each dose
group received placebo and two-thirds received
active hydrochlorothiazide. The patients were
followed for an additional 7 weeks (phase B), at

which time they were either returned to placebo
for 2 weeks or entered into a long-term trial of
captopril. Appropriate tests of leucocytes, blood
chemistry and urine protein excretion were made.

Results

Of the 722 men enrolled, 475 (65.8%) qualified
for randomization; 399 completed phase A and
3 15 finished phase B. The data which follow have
been derived from these patients. The racial
distribution was 248 (52.2%) white, 222 (46.7%)
black and 5 (1.1%) other. Their average age was
55.0 years and 58.4% of them had previously
received treatment for hypertension.

The blood pressure results are presented in
Table 1. During phase A, all doses of captopril
were equally effective in reducing blood pressure.
The twice-daily performed as well as the thrice-
daily dose and the percentage at goal (diastolic
blood pressure less than 91 mmHg) was the
same. During phase B, the 83 patients who were
randomized to have placebo instead of active
hydrochlorothiazide added to captopril main-
tained approximately the same level of blood
pressure as in phase A, except for an increase of
systolic pressure in patients taking 12.5 mg thrice
daily and a slight additional blood pressure
reduction in patients taking 37.5 mg twice daily
and 50 mg thrice daily. The 173 remaining
captopril-treated patients who received hydro-
chlorothiazide experienced a marked further
reduction in both systolic and diastolic blood
pressure. There was no difference in the response

     TABLE 1. Bloodpressure reduction achieved by captopril and captoprilplus hydrochlorothiazide
Mean blood pressures are reported in mmHg f SE. Base, baseline; SBP, systolic blood pressure; DBP, diastolic blood
pressure; Goal, goal blood pressure (<91 mmHg diastolic); HCTZ, hydrochlorothiazide; n = number in group. Captopd
      doses are recorded by mg given thrice daily (except 37.5 mg, which was given twice daily).

PlX&G         Phase A                           Phase B

          Captopril         Captopril plus placebo      Captopril plus hydrochlorothiazide


      12.5  25 mg   37.5  50 mg   12.5  25 mg  37.5 50mg HCTZ   12.5  25 mg  37.5 50mg
      w         w         mg        Tz             w         mg

n          76     79    78    85    81    23    20    22    18    59    44    41    39    48
Base SBP     146.0   147.6  147.6  149.3  147.4  149.4  148.9  149.9  145.0  145.6  146.1   148.1   148.8  146.8
         21.6   k1.7   k1.3   f1.5   k1.8   i3.1   f2.8   f3.6   k3.1   kl.8   1-2.4   k1.7   kl.9   22.3
-A SBP       2.0    9.9   11.6   13.7   13.3    3.1   11.6   13.1   14.7   11.6   23.3   26.5   25.8   22.5
         21.7   il.7   k1.6   fl.7   f1.5   k2.4   23.7   k3.9   k4.9   kl.7   k2.6   k2.2   t2.6   fl.8
Base DBP     97.8   97.0   98.1   97.5   97.9   97.7   98.6   97.4   96.8   97.6   96.2   98.2   97.5   98.4
         f0.5   -to.4   F0.5   f0.5   f0.5   f0.9   kO.8   io.9   +1.2   kO.6   -CO.6   kO.7   kO.7   to.7
-A DBP      3.4    8-6    9.2    9.5   10.3    8.3    8.2   12.6   11.9    8.2   16.6   15.5   14.5   17.6
         f0.8   kO.9   +0.9   kO.9   f0.8   ?I.7   kl.7   f2.1   k2.0   k1.0   il.1   21.2   11.2   il.1
96 at goal     36.8   65.8   58.9   63.5   70.3   56.5   47.3   76.1   83.3   55.9   95.5   85.3   82.1   89.5


Veterans Administration Cooperative Study Group            445s

of the two groups which received 75 mg of
captopril per day.

During phase A, white patients tended to
respond to captopril better than black patients.
Black patients responded better when hydro-
chlorothiazide was added to placebo during
phase B and the racial differences were abolished
in the captopril-treated groups by the addition of
the diuretic.

During phase A, 2.6% of patients taking
placebo and 3.1% taking captopril developed a
rash. During phase B, 1.7% of the patients
receiving the placebo plus hydrochlorothiazide,
3.6% of those receiving captopril plus placebo
and 1.2% of those receiving captopril plus
hydrochlorothiazide had a rash. The overall
incidence of the development of a rash in the
captopril-treated patients was 15 out of 384
(3.9%), of which five patients were receiving the
150 mg/day dose. Therefore the incidence in the
low dose group was 2.4%.

Eighteen patients were withdrawn from the
trial owing to drug intolerance. These were evenly
distributed across all of the groups. Two patients
taking captopril 37.5 twice daily and 50 mg
thrice daily were withdrawn on account of
urticaria; three taking diuretic plus captopril
12.5, 25 and 50 mg thrice daily had a maculo-
papular rash; two taking the diuretic plus 25 mg
thrice-daily and 37.5 mg twice-daily captopril
had loss of taste, which returned on dis-
continuation of the drugs; two taking the diuretic
plus captopril 12.5 and 25 mg thrice daily had
nausea and vomiting. Proteinuria occurred in
three patients. Urinary protein excretion rose in
one patient taking captopril 12.5 mg thrice daily
from a baseline value of 126 mg to 665 mg after 5
weeks of captopril treatment and returned to
baseline after captopril had been discontinued. In
another patient urinary protein excretion rose
from a baseline level of over 453 mg/day to 1600
mg/day after 12 weeks of captopril 50 mg thrice
daily. One patient who was randomized to
placebo treatment excreted 800 mg/day and
1200 mg/day of protein 4 days later. He returned
to normal within 1 month without intervention.
Three patients were withdrawn owing to intoler-
able hypotension; two were taking 50 mg of
captopril thrice daily and one the diuretic and 25
mg of captopril thrice daily. One patient taking
37.5 mg of captopril twice daily complained of
intolerable headaches. Two patients taking
placebo were withdrawing owing to drug in-
tolerance. One complained of weakness, dizziness
and dry mouth after the first dose and refused to

return. One complained of headache, impotence,
dysuria and urinary frequency after 5 weeks of
therapy.

Discussion

Captopril 50 mg thrice daily was included in this
experimental design because it was then con-
sidered to be the lowest effective dose. This study
demonstrates clearly that captopril alone in lower
doses (37.5 and 75 mg daily) reduces blood
pressure in mildly hypertensive patients as well as
captopril 150 mg daily. The expected enhancing
effect of added diuretic was also clear. We believe
that our data suggest that captopril can be
administered twice rather than thrice daily, but
definitive proof requires blood pressure monitor-
ing experiments. Previous unpublished data have
suggested that captopril would not be effective
alone in black patients, but our study shows a
good effect. Racial response was equalized by the
addition of a diuretic. Withdrawals for adverse
effects were very low and in the range we have
experienced in previous studies of diuretics and
/I-adrenoceptor-blocking agents. That is not to
imply that effects such as rashes did not occur,
but that discontinuation of the drug was usually
unnecessary. It was also very difficult to be
certain whether a rash was due to captopril or to
the diuretic or to the combination.
We believe that this short-term study demon-
strates that the use of captopril in low doses may
be extendable to the general population of hyper-
tensive patients and might no longer need to be
restricted to severe or resistant hypertensive
patients.

Acknowledgments

This study was supported by a grant from the
Squibb Institute for Medical Research.


References

Ill RUBIN, B., ANTONACCIO, M.J. & HOROWITZ, Z.P. (1978)
Captopril (SQ 14.225) (D~3~mercapto-2~methylpropanoyl~l-
proline), a novel orally active inhibitor of angiotensin-con-
verting enzyme and anti-hypertensive agent. Progress in
Cardiocascular Diseases, 21, 183-194.

121 GAVRAS. H.. BRUNNER, H.R., TURINI, G.A.. KERSHAW, G.R.,
TIFFT, C.P., CUTTELOD, S., CAVILAS, I., VUKOVICH, R.A. &
MCKINSTRY, D.N. (1978) Anti-hypertensive effect of the oral
angiotensin converting-enzyme inhibitor SQ 14,225 in man.
New England Journal oJMedicine, 229,991-995.

131 W&EBER, B., GAVRAS, I., BRUNNER, H.R. & GAVRAS, H.
(198 I) Safety and efficacy of chronic therapy with captopril in
hypertensive patients: an update. Journal of Clinical
Pharmaco/ogy, 21,508-j 16.