Low-Dose Captopril for the Treatment
of Mild to Moderate Hypertension

VETERANS ADMINISTRATION COOPERATIVE STUDY Group

ON ANTIHYPERTENSIVE AGENTS

SUMMARY Short-term results of this double-blind control trial (previously reported) in patients
with initial diastolic blood pressures (DBP) in the range of 92-109 mm Hg indicated that doses of 12.5
or 25 mg captopril (C) three times daily (t.i.d.) and 37.5 mg twice daily (b.i.d.) had similar antihyper-
tensive effectiveness as 50 mg t.i.d. After 7 weeks of C, the addition of hydrochlorothiazide (H) to two-
thirds of the patients enhanced the antihypertensive response. This report presents the results of
unchanged and uninterrupted treatment for 9.5 months in 46 patients taking C alone, and for 7.8
months in 94 patients taking C plus H or H alone. With C alone, reductions in DBP averaged 8.3, 11.0,
15.1, and 17.5 mm Hg with the 12.5, 25, 37.5, and 50 mg doses respectively. The response to the 12.5
mg dose only was significantly less than the 50 mg dose. With H alone, the reduction in DBP averaged
10.6 mm Hg and with C plus H reductions averaged 15.6, 18.1, 16.8, and 18.7 mm Hg with the 12.5,
25, 37.5, and 50 mg doses of C, respectively. Reductions in DBP with C plus H regimens were
significantly different from H alone. There was no waning of effectiveness from short to long term
except for the 12.5 mg dose of C alone. During the long-term phase, two patients developed rash and
one lost the sense of taste. Neutropenia in one patient probably was not drug-related. There were no
terminations for elevated DBP > 104 mm Hg on two successive visits. Thus, C was well tolerated and

remained effective over the long term. (Hypertension 5 (supp TID): HE-139-I1I-144, 1983)

Key Worps ° hypertension + captopril
dosage ° toxicity

HE Veterans Administration Cooperative

Study Group has presented a preliminary re-

port on the short-term efficacy of captopril

(C) with and without a diuretic.' A total of 475 patients
with entry diastolic blood pressure (DBP) between 92
and 109 mm Hg were randomly assigned, double-
blind, to one of five regimens which included placebo
or four dose levels of C alone ranging from 12.5 to 50
mg three times daily (t.i.d.). The results of the short-
term trial may be summarized as follows: the average
reduction of DBP for all patients receiving C alone was
12.2 mm Hg, which was significantly greater than the
2.0 mm Hg reduction obtained in the placebo group.
The 12.5, 25, and 37.5 mg doses of C were as effective
in reducing DBP over a 7-week period as the 50 mg
dose. There was no significant difference between any
of the doses of C with respect to reduction of either

 

From the Cooperative Studies Program of the Veterans Adminis-
tration Medical Research Service, Washington, D.C.

Supported in part by a grant from E. R. Squibb & Sons. Inc.

Address for reprints: Edward D. Freis, M.D., Veterans Adminis-
tration Medical Center, 50 Irving Street, N.W., Washington, D.C.
20422.

treatment + blood pressure «

systolic blood pressure (SBP) or diastolic blood pres-
sure (DBP) in the sitting or standing positions.
After 7 weeks, hydrochlorothiazide (H) 25 mg twice
daily (b.i.d.) was added double-blind to all of the pla-
cebo group and to two-thirds of the patients receiving
C. The remaining third were randomized to C plus H
placebo, that is, they continued on C alone. Each pa-
tient remained on the originally assigned dose of C. In
the patients receiving C alone, the antihypertensive
response after 14 weeks was moderately but not sig-
nificantly less than at 7 weeks for the two lowest doses
of C. For the two highest regimens, the effect on DBP
was the same or slightly greater. The patients who
received C with H exhibited greater reductions of
blood pressure than with C alone, and there were no
significant differences in the antihypertensive re-
sponses between the various doses of C plus H. During
this short-term treatment period, only 4% of the pa-
tients were terminated from the study because of ad-
verse effects, none of which were life threatening.
Because of a possible waning of the antihyperten-
sive response to the 12.5 and 25 mg doses of C be-
tween the 7th and 14th week, an extension of the study
for an additional 6 months or more seemed indicated.
Also, the extension would permit additional observa-
tion for the possible development of toxic reactions.

HE 139
{II-140

RESPONSE TO HYPERTENSION THERAPY Supe III Hypertension Voi 5, No 5, SEPTEMBER-OcTOBER 1983

Methods

The present study is essentially a continuation of the
short-term trial. The design of the short-term trial will
be described in more detail in another communication?
and will only be briefly summarized here.

Following withdrawal of preexisting antihyperten-
sive drugs for 2 to 4 weeks, men aged 20-69 years
were given placebo (t.i.d.) for a maximum of 5 weeks.
Placebo counts were carried out and noncompliant pa-
tients were excluded. To qualify for randomization,
DBP had to be in the range of 92-109 mm Hg and the
patients had to be free of any exclusion factors. The
acceptable patients were then randomized, double-
blinded, to one of five regimens as follows: C 12.5 mg
t.id.,C 25 mgt.i.,C37.5 mgb.i.d.,C 50mgt.i.d.,
and placebo. Seven weeks following randomization, H
25 mg twice daily was added to two-thirds of the C-
treated patients while one-third were given H-placebo.
Active H was added to all of the placebo-treated pa-
tients. These regimens were continued for 7 additional
weeks. This completed the short-term phase of the
trial.

Because of a protracted recruitment period of 13
months, some patients were completing the short-term
trial before others were entering the study. Therefore,
although the trial was only of 14 weeks’ duration, the
clinics were operational for 16.5 months. Approxi-
mately midway in the study it was decided to evaluate
the patients completing the short-term phase on their
present regimens until the termination date of the trial.
Late entries, therefore, did not complete long periods
of follow-up. Because of limited numbers of patients
completing the longest follow-up treatment periods,
the 6-month interval was selected for evaluation of the
long-term results. Due to the additional 14 weeks for
patients on C alone and 7 weeks for patients on C plus
H during the short-term phase, the actual periods of
continuous treatment were 7.8 months (6 months plus
7 weeks) with combination therapy, and 9.5 months (6
months plus 14 weeks) with C alone. Only patients
whose treatment was uninterrupted from the time of
randomization were included. Routine laboratory and
physical examinations were carried out at 3-month in-
tervals during the long-term period.

Results

A total of 139 patients on C with H regimens entered
the long-term treatment phase. Of this number, 94
patients (68%) completed 7.8 months of continuous
treatment. In the C alone group, 62 entered, of which
46 (74%) patients completed a total of 9.5 months of
continuous treatment.

There were no significant differences between any
of the C plus H regimens or the C alone patients with
respect to race or mean age (table 1). In the C plus H
group, the racial distribution was nearly equal, with 45
whites and 48 blacks; in the captopril alone group,
whites moderately outnumbered blacks. The average
age of the patients among the various regimens were
similar, varying between 54 and 58 years.

Tape |. Race and Age Characteristics Among the Different
Long-Term Treatment Groups
Captopril (C) regimens with
hydrochlorothiazide (H)

 

 

C 12.5 C25 C375 bid. C50

Group H +H +H +H +H
White 8.0 4.0 9.0 10.0 14.0
Black 13.0 10.0 7.0 9.0 9.0
Other 0.0 1.0 0.0 0.0 0.0
Total 21.0 15.0 16.0 19.0 23.0
Age, mean (yrs) 55.2. 55.1 57.8 56.4 53.8

Captopril (C) regimens without
hydrochlorothiazide (H)

C 12.5 C25 C€37.5 bid. C50

 

 

White 3.0 5.0 10.0 9.0
Black 5.0 1.0 7.0 6.0
Total 8.0 6.0 17.0 15.0
Age, mean (yrs) 55.4 57.0 55.6 56.7

 

Because the long-term treatment patients represent-
ed a relatively small proportion of the total number of
patients completing the short-term (7-week) treatment
phase, their comparability was investigated with re-
spect to DBP both at baseline and after 7 weeks of
treatment. Pretreatment DBP at the time of randomiza-
tion was closely similar. In each treatment group with
or without H, the average DBP did not vary more than
2 mm Hg between the long-term patients and the total
short-term group. The average reductions of DBP,
however, were somewhat greater at 7 weeks for the
long-term subsample than for all patients, the differ-
ence averaging 3 mm Hg lower among the long-term
patients as compared to the total short-term treatment
groups.

Changes in Blood Pressure
Captopril Alone

The changes in blood pressure after 9.5 months of
continuous treatment are shown in table 2. The average
diastolic reductions were related to dosage and ranged
between — 8.3 mm Hg for the 12.5 mg dose to — 16.5
mm Hg for the 50 mg dose. These changes were essen-
tially the same as the short-term (7-week) reductions
except for the 12.5 mg regimen where there was a rise
of 4.7 mm Hg in average DBP between the short-term
and long-term readings. Systolic reductions also were
dose-related. Compared to the 7-week values, the
average systolic blood pressure rose by 4.8 and 5.0
mm Hg with the 12.5 and 25 mg regimens, respective-
ly. Such lessening of the antihypertensive effect with
time was not seen, however, with the 37.5 b.i.d. and
50 mg t.1.d. doses of C.

Because of the relatively small sample sizes, par-
ticularly in the two lowest dose groups, it was possible
that the variations noted among doses with respect to
blood pressure reduction may not have been represen-
tative of the true long-term differences. Therefore, ad-
ditional comparisons were made utilizing the readings
taken at three long-term clinic visits at 6.5, 9.5, and
VA LONG-TERM TRIAL ON CAPTOPRIL/VA Cooperative Study Group

TABLE 2. Blood Pressure Changes During Long-Term Treatment
in Patients taking Captopril Alone

 

Dose of captopril (mg)

 

 

37.5
12.5 25 b.i.d. 50
No. of patients 8 6 17 15
Mean DBP (mm Hg)
Randomization 96.3 98.7 96.1 96.0
After 9.5 mos
treatment 88.0 87.7 81.1 79.5
Change ~8.3 —-11.0 —-15.1 —-17.5
After 7 wks treatment 83.3 88.0 80.3 80.7
Change, 7 wks to
9.5 mos +4,7 —0.3 +0.8 —1.2
Percent < 90 mm Hg 50 50 100 93
Mean SBP (mm Hg)
Randomization 136.5 149.3 145.6 146.8
After 9.5 mos
treatment 135.8 137.7 124.7 125.3
Change -0.8 -11.7  ~20.9  ~—21.5
After 7 wks treatment 131.0 132.7 123.4 128.9
Change 7 wks to
9.5 mos +48 450 41.3 —3.6

 

12.5 months following randomization. There were no
significant differences at the 0.05 level between any of
the regimens at any of the three visits. There was a
questionably significant difference between the C 12.5
and C 50 mg regimens at the 0.10 level at all three
visits. However, there were no significant differences
between the C 25 mg and the C 50 mg doses at any of
these visits. Furthermore, the DBP with the C 25 mg
dose averaged lower at the 6.5- and 12.5-month visits
than at the 9.5-month visit. Thus, the only consistent
change from short-term to long-term follow-up was a
moderate waning of the antihypertensive effect of the
12.5 mg dose, which was not present with the other
doses.

T-141

The percentage of patients achieving a reduction of
DBP to below 90 mm Hg with the 12.5 mg dose was
60% at 6.5 months, 50% at 9.5 months, and 67% at
12.5 months. With the 25 mg regimen, it was 75%,
50%, and 100% at each of these time intervals. With
the two highest doses, the response rate varied between
76% and 100% at each of the three visits.

Captopril plus Hydrochlorothiazide

The reductions in DBP recorded after 7.8 months of
continuous treatment with C plus H regimens were
greater than with H alone (table 3) or with comparable
doses of C alone (table 2). The reductions in DBP were
significantly greater with the C 25 + H (p = .03) and
the C 50 + H (p = 0.01) regimens than with H alone.
The SBP was also lower with the combined drugs than
with the single entities, the differences from the com-
parable dose of C alone being significant with C 12.5
mg (p = 0.05) and C 50 mg (p = 0.04) doses. The
above changes in DBP and SBP at 7.8 months ap-
peared to be representative as they were essentially the
same as those recorded at 4.8 and 10.8 months.

The changes in blood pressure from short-term (7
weeks) treatment to long-term (7.8 months) treatment
are also shown in table 3. The average DBP reductions
at each of these two points in time are nearly identical
except for the C 12.5 + H regimen, which exhibited
an insignificant increase of 2.9 mm Hg. SBP reduc-
tions also showed no essential change from short-term
to long-term readings, including the C 12.5 mg dose.

The percentage of patients attaining the goal DBP of
< 90 mm Hg varied between 79% and 94% with the
various C plus H regimens and was not dose-related. '
There also were no significant differences in response
between blacks and whites.

Terminations

Terminations during the first 6 months of the long-
term treatment phase were classified as medical and
administrative (table 4). There was no correlation be-
tween either medical or administrative terminations

 

 

TABLE 3. Blood Pressure Changes During Long-Term Treatment in Patients taking Captopril (C} with Hydrochloro-
thiazide (H)
H C1l25+H C25+H C37.5bid. +H CS50+H
No. of Patients 21 1S 16 19 23
Mean DBP (mm Hg)
Randomization 96.6 97.2 99.8 98.8 99.5
After 7.8 mos treatment 86.0 81.6 81.6 82.0 80.8
Change — 10.6 — 15.6 — 18.1 — 16.8 —18.7
After 7 wks treatment 81.9 78.7 82.4 82.4 80.3
Change 7 wks to 7.8 mos +41 +2.9 -0.8 —0.4 +0.5
Percent < 90 mm Hg 716 93 94 79 ot
Mean SBP (mm Hg)
Randomization 143.6 150.3 150.0 149.8 150.1
After 7.8 mos treatment 128.6 120.5 121.4 124.7 121.7
Change — 15.0 —29.7 — 28.6 ~ 25.1 — 28.3
After 7 wks treatment 124.9 122.4 120.1 117.7 124.5
Change 7 wks to 7.8 mos +3.7 -1.9 +1.3 +7.0 —2.8

 
III- 142

RESPONSE TO HYPERTENSION THERAPY Supp IJ HyperTENSION VoL 5, No 5, SEPTEMBER-OCTOBER 1983

and the dosage of captopril. There were seven medical
terminations, two in patients taking C alone and five in
the patients receiving H regimens. There were two
instances of pruritic maculopapular rash. One occurred
9 months after C 50 + H was begun. The rash cleared
after the drug was stopped and recurred promptly when
reinstituted. The second patient had received C alone
37.5 mg b.i.d. for 9 months prior to the appearance of
the rash. Another patient receiving captopril 25 + H
developed loss of taste. A black patient receiving 37.5
mg C alone was terminated because of neutropenia.
The white blood count was 2.6 x 1000/mm? with 38
segmented leucocytes. However, since this patient
was an alcoholic and exhibited a low white blood count
of 3.6 X 1000/mm prior to randomizations, the rela-
tionship to captopril is problematical. The remaining
medical terminations were due to unrelated causes
such as impotence, weakness, headache, and atrial
fibrillation. There were no terminations resulting from
elevation of blood pressure, the criterion for which was
an elevation of DBP to 105 mm Hg or higher on two
successive clinic visits.

TABLE 4. Terminations During Long-Term Treatment

There were 16 terminations for administrative rea-
sons, eight among the C alone patients, and eight in the
C plus H group. The most frequent causes were failure
to return to clinic, tardiness in returning to the clinic so
that treatment was interrupted, or the patient’s request
to terminate.

Laboratory Examinations

The major laboratory change observed during the
short-term trial was a statistically significant but clini-
cally unimportant rise in serum potassium with C alone
and a slightly lessened reduction with C plus H as
compared to H alone. The changes in serum potassium
were similar during the long-term treatment period
(table 5). C alone resulted in a slight rise in serum
potassium levels averaging 0.11 mEq/liter. H alone
was associated with a significant reduction averaging
0.54 mEq/liter, which was significantly greater (p <
0.001) than the average fall of 0.39 mEgq/liter with C
plus H.

Serum uric acid concentration rose significantly by
an average of 1.40 mg/dl with H alone, which was

Regimens with hydrochlorothiazide (H)

 

 

 

 

 

 

 

Termination H C125 +H C25+H C375bid. +H CS0+H ~ Total
Medical 1 0 3 0 1 5
Administrative 0 2 3 2 ! 8
Total 1 2 6 2 2 13
Regimens with captopril (C) alone
“C125 C 25 C 37.5 bid. C 50 Total

Medical 0 0 2 0 2
Administrative 2 3 2 1 8
Total 2 3 4 l 10
TABLE 5. Changes in Laboratory Tests During Long-Term Treatment with Captopril (C) and Hydrochlorothiazide (H)
Laboratory test C alone C+H H alone
Serum potassium (mEq/liter)

Baseline 4.18+0.06 4.21 +0.05 4.23 +0.09

Change 0.11 £0.06* —0.39+0.06*t —0.54+0.097
Serum creatinine (mg/dl)

Baseline 1.14+0.03 1.18+0.03 1.17+0.03

Change —0.06+0.03 — 0.02 + 0.03 0.09 +0. 11
Uric acid (mg/dl)

Baseline 6.27+0.18 6.69+0.13 6.53 £0.25

Change 0.38 +0.18*¢ 1.1740.14*¢ 1.40+0.32T
Cholesterol (mg/dl)

Baseline 228.9 + 6.6 223.044.6 210.748.5

Change 2.2+4.4 —3.843.5 —0.748.6
Urine protein (mg/24 hrs)

Baseline 134.94 14.4 127.5+12.3 123.5+24.0

Change ~2.2+20.0 —15.5+13.1 25.0+38.8

 

*Significant change from baseline, p < 0.05.
TSignificant change from baseline, p < 0.001.

+Significant difference in the extent of change between groups, p < 0.001.
VA LONG-TERM TRIAL ON CAPTOPRIL/VA Cooperative Study Group

significantly greater than the average increase of 1.17
mg/dl observed with C plus H. Unlike the short-term
findings, serum cholesterol did not rise with H alone or
with the combination of C plus H. There were no
significant changes in serum creatinine or 24-hour
urine protein excretion. Other routine biochemical and
hematological tests revealed no significant changes.

Discussion

The major objective of the present study was to
determine whether C either alone or combined with H
would maintain its antihypertensive effectiveness una-
bated or whether there would be some waning of its
activity with the passage of time. The results indicated
that the antihypertensive effect is maintained over the
long-term with the exception of the smallest (12.5 mg
t.i.d.) dose of C alone. This was not the case, howev-
er, with C plus H where all doses including the 12.5
mg maintained unabated antihypertensive activity as
compared to short-term results. That this was not due
to the action of H alone is indicated by the fact that all
of the combined regimens lowered DBP to a signifi-
cantly greater degree than did H alone. Despite the
moderate rise of blood pressure from short-term to
long-term with the 12.5 mg dose of C alone, it should
be noted that 50% of the patients maintained control of
DBP after 9.5 months of continuous treatment.

The long-term results are more subject to bias than
was the case in the short-term study where the great
majority of the randomized patients were followed to
completion of the short-term trial. The patients in the
long-term study, on the other hand, represent a residu-
al of short-term patients who chose to enter the long-
term trial. Therefore, they may represent the patients
who responded the best in terms of DBP reduction. In
this regard, during the short-term treatment period,
there was a 3 mm Hg greater reduction in DBP among
the long-term patients than in the short-term treatment
group as a whole. Therefore, they may represent to
some extent at least a selected group of responders.
Within these limitations, however, it is apparent that
drug resistance did not develop over the long-term.

A further limitation of the long-term trial was that
when subdivision was made into nine different regi-
mens, four with C alone and five with H-containing
regimens, some of the sample sizes became quite
small, particularly with the smallest doses of C alone.
This deficiency was partly compensated for by evalu-
ating the results not only 6 months into the long-term
phase but also at 3 and 9 months of long-term follow-
up. Since the blood pressure changes at these two other
time periods confirmed the results observed at the 6-
month interval, it seems likely that the results probably
are valid in spite of the small size of some of the
samples.

It has been suggested that the antihypertensive effect
of a combination of C with a diuretic should have a
synergistic effect.? Loss of sodium and water with di-
uretics stimulates the production of angiotensin and
aldosterone, which in turn should limit the sodium

eC)

loss. When this defense reaction is inhibited by C, the
diuretic-induced loss of sodium and water might be
greater than normal, leading to a considerable fall in
blood pressure. In the present trial, however, as well as
in other smaller studies,* * the reduction in blood pres-
sure did not exceed the sum of the antihypertensive
effects of C and H given separately.

There were relatively few terminations due to ad-
verse reactions. They occurred in only 3.5% of the
patients during the 6-month period of long-term fol-
low-up. Furthermore, only three reactions, none of
which was severe, appeared to be drug-related. It is
doubtful that the single case of neutropenia was related
to C. The patient was a heavy consumer of alcohol,
which could in itself produce neutropenia, and had
already exhibited a reduced white blood count at the
time of randomization. The absence of the more seri-
ous reactions associated with C such as pancytopenia®
and glomerulopathy® may be due to the exclusion of
patients with severe hypertension, renal disease, or
immune system disorders, and also to the fact that the
doses of C were relatively low.®

Captopril given alone has been associated with sig-
nificant elevations in serum potassium concentra-
tions.’ These elevations occurred, however, mostly in
patients with renal impairment or with high doses of C.
In the present trial, there was only a small rise from
baseline in serum potassium with C alone. There was,
however, a significantly smaller reduction in serum
potassium levels with the combination of C with H
than with H alone. The combination did not block the
reduction completely, but rather reduced its extent. A
similar blunting of the H-induced hypokalemia re-
sponse has been reported by Weinberger,’ who also
noted a diminution in the degree of elevation in serum
uric acid and cholesterol associated with administra-
tion of thiazides. A similar slight but significant effect
on serum uric acid was noted in the present long-term
trial which was not found in the short-term phase. In
the short-term phase of the present study, a moderating
effect of C on the H-induced increase in serum choles-
terol was confirmed. However, in the long-term phase,
the H group did not exhibit a rise in serum cholesterol,
which may account for the failure to observe a signifi-
cant difference between the diuretic alone and the com-
bination. An increase in serum cholesterol with admin-
istration of thiazides is not a constant finding® ' and, if
present, may disappear with long-term treatment."

Captopril represents a new approach to the treatment
of hypertension in that its principal action is to inhibit
the renin-angiotensin system. This novel drug has now
been added to the three existing categories of antihy-
pertensive agents, namely, diuretics, sympatholytics,
and vasodilators. While C resembles the vasodilators
in its effects on the cardiovascular system, there are
some important differences. There is no significant
reflex tachycardia with C and no tendency toward re-
tention of salt and water.

Captopril may be used as a Step 1, Step 2, or Step 3
drug. Because of the great effectiveness of a diuretic
plus C in doses as low as 12.5 mg, it would appear to
TI-144

RESPONSE TO HYPERTENSION THERAPY Supp II] HypPerTENSION VoL 5, No 5, SEPTEMBER-OcTOBER 1983

be most useful as a Step 2 agent. The effectiveness of
small doses of C with H would seem to be a most
important consideration in view of the observation that
toxicity is associated more with high doses of the
drug.* '? Possibly other converting-enzyme blockers
currently under study will provide additional therapeu-
tic benefits. However, with accumulating experience
as to dosage and selection of patients, it is apparent that
C itself represents a major therapeutic advance.

Acknowledgments
Participants

Co-Chairmen: Edward D. Freis, M.D. (Washington, D.C.); Barry
J. Materson, M.D. (Miami, Florida).

Participating Investigators: William W. Neal, M.D. (Dallas,
Texas); Richard E. Borreson, M.D. (Houston, Texas); James T.
Taguchi, M.D. (Dayton, Ohio); Bangshi Mukherji, M.D. (Topeka,
Kansas); H. Mitchell Perry, M.D. (St. Louis, Missouri); K. C.
Mezey, M.D. (East Orange, New Jersey); Walter Flamenbaum,
M.D. and Robert Hamburger, M.D. (Boston, Massachusetts).

Nurses or Physician Assistants: Betsy Munze, P.A. and Pat Mel-
ly, P.A. (Dallas, Texas); Ruth Collins, R.N. (Houston, Texas),
Margaret Curry, R.N. (Dayton, Ohio); Pat Ulrich, P.A. (Topeka,
Kansas); Robert Berry, R.N. and Margery Schiffman, R.N. (St.
Louis, Missouri); Mary Fitzgerald, R.N. (East Orange, New Jer-
sey); Anne Faiella, R.N. (Boston, Massachusetts); Barbara Greg-
ory, R.N. (Washington, D.C.).

Biostatistical Center: Sharon Anderson, Ph.D.; Thomas Tosch,
Ph.D.; Jane Foregger (Hines, Illinois).

Central Laboratory: Walter Flamenbaum, M.D. and Robert
Hamburger, M.D. (Boston, Massachusetts).

Central Research Pharmacist: Larry Young, R.Ph. (Albuquer-
que, New Mexico).

Executive Committee: Barry J. Materson, M.D.,; Edward D.
Freis, M.D.; Sharon Anderson, Ph.D.; Thomas Tosch, Ph.D.; H.
Mitchell Perry, M.D.; Richard E. Borreson, M.D.; Walter Flamen-
baum, M.D.; Robert Hamburger, M.D.; Larry Young, R.Ph. (Ad
Hoc).

Operations Committee: Walter M. Kirkendall, M.D., Chairman
(Houston, Texas); W. McFate Smith, M.D. (San Francisco, Cali-
fornia); C. Mort Hawkins, Sc.D. (Houston, Texas).

Consultants: John Alexander, M.D.; Jeffrey Stritar, M.D.; Joseph
Meyer, Ph.D. (Squibb Institute for Medical Research).

Hines Cooperative Studies Program Coordinating Center Hu-
man Rights Committee: Jennie McKoy, B.S.N., M.S.,; Patrick J.

Moran; Mary Davidson, Ph.D.; Kenneth C. Elmer; Rev. Douglas
D. Hall.

Cooperative Studies Program Central Administration: James
A. Hagans, M.D., Ph.D. (Miami, Florida); Ping Huang, Ph.D.
(Washington, D.C.); William G. Henderson, Ph.D. (Hines, Illi-
nois); Mike Sather, R.Ph., M.S. (Albuquerque, New Mexico).

This paper was written by Dr. Freis and prepared by Linda
Archie.

References

1. Veterans Administration Cooperative Study Group on Antihy-
pertensive Agents: Captopril: evaluation of low doses, twice
daily doses and the addition of diuretic for the treatment of
mild to moderate hypertension. Clin Sci 63: 4433, 1982

2. Lijnen P, Fagard R, Staessen J, Vershueren LJ, Amery A:
Dose response in captopril therapy of hypertension. Clin Phar-
macol Ther 381: 310, 1980

3. MacGregor GA, Markandu ND, Banks RA, Bayliss J, Raul-
ston JE, Jones JC: Captopril in essential hypertension; con-
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Discussion
DiscussaNnTs: G. MACGREGOR

MacGrecor: We have been presented three very
large-scale American studies on captopril, which
are obviously important in determining long-term
treatment safety. I don’t want to be aggressive,
but do we need this size of study in order to show
the correct dose of the drug and the correct
amount of diuretic? This goes back to what Dr.
Brunner was showing earlier in a few normoten-
sives. Surely the pharmacology of the drug can be
shown in many fewer subjects using careful, ran-
domized crossover studies.

E. FREIS
J. LEDINGHAM

Frets: I don’t agree. It depends on the degree of
precision — if this is to be high, you need a more
representative sample than merely 20 or 30, or
even 50, especially if you’re subdividing them
into smaller groups.

LepINGHAM: You also need a sizable placebo group
to demonstrate the placebo effects.

Freis: [| agree.