"22

Iieprivted from the Archives of IltterR
   A14gust 1962, Vol. 110, pp. m
Copyright 1962, by Anlerican Medical

      Double Blind
   Control Study of
Antihypertensive Agents

II. Further Report on the Comparative EffectivelzeJs
of Reserpine, Reserpine and Hydralazine, and Three
   Ganglion Blocking Agents, Chlorisondamine,
      .  Mecamylamine, and Pentolinium Tartrate

sociation

VETERANS ADMINISTRATION

COOPF.RATIVE STUDY ON

ANTIHYPERTENSIVE AGENTS*

WASHINGTON, D. C.

This report presents the results after one
year of follow-up of 759 hypertensive pa-
tients who were begun on one of a number
of randomized, double blind treatment regi-
mens using various antihypertensive agents.
The plan of the study and the methods of
procedure have been published previous1y.l

In brief, only patients whose diastolic blood pres-
sure levels averaged 90 mm. Hg or above from the
fourth through the sixth hospital days were in-
cluded in the study. These patients were divided
into categories of "mild, moderate, and severe" on
the basis of the scores obtained in 5 panels: basal

Submitted for publication Feb. 26, 1962.
Complete tabular data will be included in the
reprints.

* Participants : Mark L. Armstrong, M.D. ; John
L. Bakke, M.D. ; Harold Dodge, M.D. ; Loyal L.
Conrad, M.D. ; Edward D. Freis, M.D. (Chair-
man) ; Rudolph E. Fremont, M.D.; Walter M.
Kirkendall, M.D.; Clifford G. Pilz, M.D.; Eli A.
Ramirez, M.D.; David W. Richardson, M.D., and
John H. Williams, Jr., B.A.

These included the following Veterans Adminis-
tration Hospitals : Brooklyn ; Chicago West Side ;
Towa City; Oklahoma City; Richmond, Va. ; San
Juan, P.R. ; Seattle, and Washington, D.C.

diastolic pressure, optic fundi, and abnormalities of
the cardiac, renal, and central nervous systems.
Treatment for patients in the mild and half of the
moderately severe group consisted of 1 of 3 possi-
ble regimens as follows: (1) reserpine 0.5 mg.
twice daily for 2 weeks followed by 0.25 mg. twice
daily thereafter plus hydralazine 25 mg. 4 times
daily for 2 weeks followed by 50 mg. 4 times daily
thereafter, (2) reserpine as above plus placebo of
hydralazine as above, and (3) placebo of reserpine
plus placebo of hydralazine. Assignment of a given
regimen to an individual patient was carried using
a double blind, randomization technique.'  Each
regimen was continued unchanged for one year ex-
cept for death, default, or other special reasons
described below.

Treatment for the remaining half of the moder-
ately severe cases and for all of the severe group
consisted of reserpine in the dosages stated above
plus 1 of 3 ganglion blocking agents : mecamylamine,
chlorisondamine,  or pentolinium. The blocking
agents were specially prepared in approximately
cquipotent tablets so that titration of dosage could
be carried out in each case without revealing the
identity of the particular ganglion blocking drug
being administered.

In addition to determining clinic recordings of
blood pressure, each patient was given a blood pres-
sure apparatus for twice daily measurements in the

126


.)`TU/)Y 01; Ah'TIHYPEKTEn'SIVE AGENTS                             223

l~omc. Folloa-up reports were sun uuxri~etl ever?  groups may be due to the fact that the pa-
2 months, and a complete examination including
laboratory studies was carried out at the end of 1  tients tended to have more severe and symp-

year of follow-up.               tomatic disease and, hence, were more willing
                           to tolerate side-effects.
          Results            Deaths: Since all deaths among veterans

1. Loss of Patients from Given Treatment  are reported routinely to Veterans Adminis-
lieginten.-Of the 759 patients who were be-  tration Central Office, a complete follow-up
gun on one of the randomized regimens, 426  as to mortality was obtained. Death accounted
were treated without change of therapy for  for 14% of the losses (6% of the total
the full year.               started) during the first year of treatment.
Of the 333 lost to the study, 155, or 47%  As would be expected because of the in-
(20% of the total started), were patients  creased severity of disease the percentage
who did not return or could not or would not  dying was higher in the patients treated with
cooperate. The majority of these dropped out  blocking agents than in the groups on the

in the first 2 months of treatment. Such losses  other regimens. The causes of death were as

are inevitable when an effort is made to avoid  follows: renal failure 11, cerebrovascular ac-
selection, since a number of deteriorated,  cident 7, myocardial infarction 6, congestive
alcoholic, or uncooperative individuals will be  heart failure 2, sudden death 5, unknown 4,
included. The drop-outs were greater in large  and 1 each from ruptured duodenal ulcer,
cities, Brooklyn, Chicago, Washington, than  dissecting aneurysm, acute alcoholism, and
in a primarily rural area (Iowa City).    postoperative complications.

When the losses were classified according   Major Side-Effects: Of the losses, 9%
                          were due to side-effects which were sufficient-
to treatment regimen there were no great
differences between the various groups. The  ly troublesome to warrant discontinuation of

percentage lost ranged from 37% in the  therapy. The incidence was 15% of the

reserpine-hydralazine group to 54% in the  losses in patients taking reserpine plus hy-

chlorisondamine-treated patients. The rea-  dralazine, 6% in those receiving reserpine

sons for the losses, however, varied in inci-  alone, and 2% in the placebo-treated group.

dence in the different treatment categories.  It is probable that losses due to this cause

For example, 40 or 64% of the 62 losses  in the groups receiving active agents were in

in the hydralazine-reserpine group were due  reality higher than reported, since some of

to failure of the patient to return or to lack  those who failed to return may have done
                         so because of side-effects. Somewhat fewer
of cooperation as compared to only 17, or
37%, of the 46 losses in the placebo group.  of the patients receiving pentolinium tartrate
                         were lost because of side-effects than in those
The difference is probably explained by  receiving mecamylamine or chlorisondamine.
the higher incidence of side-effects on the  Further data on these cases are presented
former treatment regimen. The losses due to  below in the section on side-effects.
failure to return or to lack of cooperation   Treatment Failures: Of the losses, 12%
also was high (61%) in the cases treated  were due to failure of the regimens to pre-
with reserpine.               vent severe elevations of blood pressure or
Losses due to poor cooperation were lower  other menacing complications such as hyper-
in the patients treated with ganglion blocking  tensive encephalopathy. The criteria for dis-
agents, ranging from 32% of the total losses  continuing the double blind regimens were as
of patients taking mecamylamine to 41% in  follows: (1) home diastolic average 130 mm.
the case of pentolinium. Nevertheless, the  Hg or about for 3 weeks or longer confirmed
incidence of reported side-effects was high  by clinic readings; (2) home diastolic aver-
in the patients treated with ganglion blocking  age 140 or above for 1 week or longer; (3)
drugs. The reason for the smaller percentage  evidence of serious organic progression such
of voluntary drop-outs in the latter treatment  a~ an attack of acute hypertensive encepha-

127    V&runs Administration


224                              ARCHIVES OF INTERNAL MEDICINE

lopathy (accompanied by high diastolic pres-
sures), advancing congestive heart failure
despite digitalis and periodic diuretics, de-
velopment of hemorrhages, exudates, and/or
papilledema in the optic fundi.

The incidence of treatment failure was
highest in the placebo group (26%) and low-
est in the patients treated with reserpine plus
hydralazine (2%). The most common com-
plication necessitating a change in therapy
was resistant congestive heart failure. In ad-
dition there were 3 cases of cerebrovascular
accident and myocardial infarction in which
a change in treatment was considered neces-
sary.

II. Antihypertensive Effffectiveness.-Un-
less stated to the contrary, the average blood
pressure levels reported in a post-treatment
period represent the average for 3-month
periods of twice daily recordings of blood
pressure taken by each patient or a member
of his family in the home. The pretreatment
control values are based on the averages of
recordings taken 4 times daily in the hospital
ward from the fourth through the sixth days
of hospitalization1

In general, the patients who did not com-
plete the full year exhibited a lesser antihy-
pertensive response than those who did. This
was probably due to the fact that treatment
failures and deaths were included in the
former group. Post-treatment data for those
patients lost during the first 2 months of
treatment are not included despite the fact
that nearly 50% of all losses occurred during
that interval. The reason for not including
them is that the results were considered to
be untrustworthy, since they,were constituted
predominantly from the uncooperative pa-
tients who failed to return for follow-up;
nor does it seem of great practical importance
to know which regimen was more effective
for patients who would not accept treatment.
Their prevalence in this study varied between
13% and 27% among the various regimens.

Average Changes in Blood Pressure on
Various Regimens : Since the post-treatment
averages were essentially unchanged from
quarter to quarter the third month results
were used; this included all patients (most

treatment failures and deaths) except those
who dropped out before completion of the
first quarter.

The results are similar in most respects
to those reported previously in a smaller
series of cases.l Reserpine was slightly su-
perior to placebos producing an average
reduction of 315.1 mm. Hg (systolic/diastol-
ic) as compared to an average elevation of
3.7/2.0 mm. Hg in the placebo-treated group.
Reserpine plus hydralazine resulted in an
average fall of 4.9/10.5 mm. Hg.

The results after the 3 ganglion blocking
agents did not differ greatly one from the
other. In the 88 patients who received me-
camylamine, the reduction of blood pressure
averaged 16.3/14.1 mm. Hg, in 91 patients
given chlorisondamine it was 15.2/12.3, and
in 65 given pentolinium tartrate the reduction
averaged 15.4/13.4 mm. Hg. In the moderate
group of hypertensive patients the average
reduction was approximately ll/lO mm. Hg
in each of the 3 regimens. In the severe group
the reductions were greater, averaging ap-
proximately 24/20 mm. Hg. Whereas reser-
pine plus hydralazine affected diastolic blood
pressure primarily, reserpine plus ganglion
blocking agents affected systolic slightly more
than diastolic pressure. If the reductions of
blood pressure seem rather small for all
regimens, it should be remembered that
"basal" hospital blood pressures were used
as the pretreatment control values. "Casual"
pretreatment blood pressures probably would
average considerably higher.

Percentage Distribution of Response on
Various Regimens: Distributions of the per
cent of patients with indicated amounts of
blood pressure change are shown in Figures
1 through 4. Figure 2 indicates the per-
centage distribution of changes in diastolic
pressure in the patients taking reserpine,
hydralazine, or their placebos. A reduction
of 5 mm. Hg or more was obtained in 70%
of the patients taking reserpine plus hydrala-
zine, 54% of those on reserpine alone, and
33% of the placebo group. The placebo group
displays a nearly normal distribution curve
for diastolic blood pressure with a mean close
to zero change in blood pressure. Corre-

Vol. 110, Aug., 1962     12x


            bV$UcN.OC                            D OASTQLOC

PERCENT oF CPlSES  RESERPINE + HYDRALAZINE                       RESERPINE + HYDRALAZINE
30

0
   44  36  26  20  12  404  12  26' 28  36  44      44 :6 ,`8 2'0 ,2 I 4 I 0 k  12 I 80 I 26 I  I
                                                                 36 44 I

             RESERPINE                                RESERPINE

I I I I , I I
44 36 26 20 I2 4 0 4 I;   I I I 1
                   20 28 36 44

PLACE50

  0
  414 :6 :6 :O I: 4! 0 : I: :o :* ?!6 14
Fig. I.-Percentage distributions of systolic pres-
sure  responses  with the reserpine-hydraIa~~ne
(above), the reserpine-placebo (middle), and the
placebo-placebo regimens. Per cent oi patients is
indicated on the ordinate and change in systolic
pressure on the abscissa with decrease of pressure
plotted to the right,

20

IO

0    I I I   I   I I1   I I I , I
   44  36  26  20  12  404  12  20  26  36  44

PLACEBO

     44  36  26  20  12  4 04  12  20 is  36  44
Fig. Z.-Percentage distributions of diastolic prcs-
sure responses. Other notations as in Figure 1.

mm. or more in diastolic blood pressure. The
distribution of both systolic and diastolic

sponding data for the ganglion blocking  pressure as shown in Figures 3 and 4 is quite

drugs shown in Figure 4 indicated that 69%  similar comparing one blocking agent with

to 77% of the patients exhibited a fall of 5  the others. The wide distribution of systolic
                    pressure shows the great variability of re-

PERCENl' OF CASES                                    DnAsuQnrlC
             MECAMYLAMINE

36  26  20    404  12  20 26  36  44      4'4 :6 2'6 2'0 ,: :0:  8: :O  /   I   I
                                                         28  36  44

           CHLORIS~NDAMINE
30 r-                                                  CHLORISONDAMINE

0                                      10
    i   I   I   I   I   I   I  1:   t   I   ,   I
   44  36  28                             0
          20  $2  4 0 4     20  28  36  44          44  36 :6         :O :8 3'6 44

PENTOLlNlUM TARTRATE

30 F                                             PENTOLINIUM TARTRAT
                      f                30 P                   T
20                     E?m

0
   d4 $6 :6 2'0 1: ::a k 1: :o 28 & 44
Fig. 3.--Percentage distributions            44 :6
                of systolic          :8 :O I:  I
                                                       4 0: I: :O :z, ;6
                              pres-                         44
sure responses of patients taking 1 of the 3 ganglion
blocking agents plus reserpine.            Fig. 4.-Percentage distributions of diastolic pres-
                         sure of same patients as in Figure 3.

I29    Veterans Administration


226

ARCHIVES OF INTERNAL MEDICINE

sponse to all of the ganglion blocking drugs
(Fig. 3).

Differences Between Hospitals : Tabula-
tion of the data by individual hospitals dis-
closed that results usually were comparable
within the various institutions. The hospitals
which treated more Negroes reported higher
average blood pressures under treatment for
patients on all agents including placebos.
There were no hospitals where one blocking
agent appeared more effective than the oth-
ers. In one hospital, reserpine alone was as
effective as reserpine plus hydralazine, but
there were only 12 patients on each of these
regimens.

Effects of Age and Race: With almost all
regimens the average reduction in systolic
blood pressure was greater in patients under
as compared to those over 50 years of age.
There were no other significant differences.
Similar comparisons were made between
Negro and Caucasian patients. No significant
differences were observed. Negroes appeared
to show no response to reserpine, but the
elevation with placebos was greater so that
the difference between the reserpine and
placebo groups was about the same in Ne-
groes as in Caucasians.

Influence of Pretreatment Level of Blood
Pressure: The degree of change in diastolic
blood pressure also was analyzed in regard
to the level of pretreatment blood pressure
and severity score for the various regimens.
The results indicated that regardless of the
antihypertensive agent used, the average re-
duction in diastolic pressure was greater in
the patients with high initial pressures. The
higher the pretreatment pressure, the greater
was the potential fall. It is probable that
greater reductions of blood pressure could
have been achieved by more aggressive dos-
age with the ganglion blocking drugs in pa-
tients with the lowest initial diastolic blood
pressure. The average daily dose in the mod-
erately severe group was about half that
administered to the patients with severe hy-
pertension. The reductions of blood pressure
were more than twice as great in the severe
group. It would appear that when the choice
of the dose is left to the discretion of the

clinic physician, he will treat most aggressive-
ly the patients with the highest blood pres-
sure levels.

Home Versus Clinic Levels of Blood Pres-
sure: The averages of blood pressure levels
recorded after a 15minute rest period in
the clinic 1 were consistently higher than the
averages of recordings made at home. This
held true for all regimens including placebos.
The relative antihypertensive effectiveness
of one regimen as compared to another was
about the same whether home or clinic blood
pressure averages were used for determining
the results. Since the home recordings rep-
resent a far greater number of readings
(twice daily) and since the average home
recordings in the placebo group were much
closer to the average of the pretreatment hos-
pital recordings, they probably reflect more
accurately the general levels of blood pres-
sure during the treatment period than do the
clinic readings.

Stability of Average Blood Pressures : The
average of home recordings in a given pa-
tient usually varied little from one quarter to
another. There often was, however, consid-
erable variation from one home recording to
the next or from one clinic reading to the
next. Thus, the blood pressures of the hyper-
tensive patients seemed to fluctuate more or
less widely about a mean, the average gen-
erally being fairly stable although subject
to change depending on the treatment regi-
men imposed. Although generally fairly
stable, the averages for individuals usually
were not as constant as the averages for
groups of individuals. The variation of group
average blood pressure from one quarterly
period as compared to the other quarters
never exceeded 4 mm. Hg systolic or 3 mm.
Hg diastolic in any of the treatment groups.

Effects on Organic Changes: A prelimi-
nary analysis of the effects of treatment on
organic changes was attempted in the patients
who completed 1 year of treatment. These
patients were subdivided into 4 groups ac-
cording to height of initial blood pressure
and then further divided as to whether they
did or did not obtain a significant reduction
of blood pressure. The average severity

Vol. 110, Aug., 1962    130


S-TUDY Ot' A!\:TIHPPI~KTENSIV~ AGENTS                              227

scores in the fundic, cardiac, central nervous
system, and renal panels as well as their totals
were then compared before and after 1 year
of treatment.

This method of lumping severity scores
into averages is inadequate, since it makes
the incorrect assumption that 2 grades tif 2
equals 1 of Grade 4. For a preliminary sur-
vey of directional changes, however, it of-
fered a convenient method of comparison
with the understanding that the table should
be interpreted only in the most general terms.
In all groups there was a decrease in severity
scores. For example, in the group treated
with placebos the cardiac and central nervous
system panel averages showed significant im-
provement at the end of 1 year, and even the
renal panel was slightly improved.

Some of this apparent evidence of im-
provement might be accounted for by the
fact that data only on the patients treated
throughout the year on the same regimen
were tabulated. Thus, the unfavorable cases
of patients who died or became treatment
failures were not included. Since the inci-
dence of treatment failures was higher in
the groups who did not show a significant
reduction of blood pressure, the bias intro-
duced would tend to favor these subdivisions,
particularly the placebo group. With the pos-
sible exception of the patients with initial
diastolic pressure levels above 120 mm. Hg
the percentage improvement in total panel
scores did not indicate significant differences
after 1 year between those whose pressures
were reduced and those exhibiting no reduc-
tion. A longer period of follow-up will be
required, however, before any judgment can
be made as to the effects of antihypertensive
drugs on the progression of organic disease.

III. Side-Effects.-Major Side-Effects: A
further breakdown of the major reactions in
which the side-effects were judged to be suffi-
ciently troublesome to warrant change of
treatment is as follows: Of the 9 cases in
the hydralazine-reserpine group there were 2
instances of depression, 1 of sleep disturb-
ance with severe nightmares, 1 of edema of
the hands and feet; 1 complained of im-
potence, 1 of severe headaches, 1 of nausea

131    Veterans Administration

`eutaq~h &aunq paJ!q!yxa I `ssauyzz!p pun
but without other evidences of lupus, and 1
had a gastrointestinal hemorrhage of unde-
termined cause. Not all of these reactions can
be ascribed definitely to drug effects. More
appeared to be those associated with reser-
pine than with hydralazine. In the 4 cases
taking reserpine alone, treatment was dis-
continued in 2 because of depression and in
the other 2 because of impotence. The latter
cases are of interest, since reserpine general-
ly is not believed to have effects on sexual
function. Treatment was discontinued in one
case taking placebos because of a generalized
dermatitis.

Treatment was changed because of side-
effects in 5 patients receiving mecamylamine.
The reactions consisted of 1 each of the fol-
lowing disturbances: orthostatic hypotension,
dizziness and constipation, paralytic ileus,
impotence and gastrointestinal complaints,
and upper abdominal pain with vomiting. In
10 patients receiving chlorisondamine, ortho-
static hypotension accounted for 3 losses,
difficult voiding for 1, abdominal pain for 1,
diarrhea for 1, and multiple complaints for
4. Treatment was discontinued in the pento-
linium group because of orthostatic hypo-
tension in 1 and multiple complaints in 1.

Minor Side-Effects: An attempt was made
to determine the incidence of minor side-
effects by a questionnaire-interview method.'
Each patient was interviewed by the clinic
secretary or physician at regular intervals.
The interview was made from a check list
containing standard questions relating to
side-effects generally believed to be asso-
ciated with the agents under study.

Unfortunately, the interviews carried out
prior to treatment revealed a high incidence
of the side-effects usually attributed to reser-
pine and hydralazine. For most of the side-
effects the changes from the pretreatment
incidence were insignificant at both 1 month
and 1 year after treatment and also during
the intervening quarterly periods. Headaches
decreased in the drug-treated and placebo
groups. The incidence of nasal stuffiness in-
creased in the patients receiving reserpine
either alone or with hydralazine as compared


228

ARCHIVES OF INTERNAL MEDICINE

to the placebo group. Increased appetite was
noted in the reserpine-treated groups but was
equally prominent in the placebo-treated pa-
tients. For the remaining side-effects of joint
pains (hydralazine), lethargy and fatigue,
depressed feeling, and nightmares (reser-
pine), there were no significant changes
after as compared to before treatment in
either the drug-treated or placebo groups.
The number of patients failing to return
because of side-effects was, of course, un-
known.

Side-effects related to the gastrointestinal
tract were common after the ganglion block-
ing drugs, the frequency of complaints be-
ing definitely higher during treatment than
before. As compared to the pretreatment
period the incidence of constipation increased
after treatment by 21% to 36%, depending
on the blocking agent. Other gastrointestinal
side-effects including bloating, distention, and
anorexia were increased by 16% to 40% and
dryness of the mouth by 14% to 27%. The
incidence of orthostatic faintness was not in-
creased in the period between 1 and 12
months after beginning treatment but may
have been higher in the earlier period of
dosage regulation, Complaints of impairment
of visual accommodation increased after
treatment especially in the patients taking
chlorisondamine where 19% were required
to wear dark glasses when exposed to bright
sunlight. Difficult voiding appeared to be an
uncommon side-effect.

Comment

The results of the present study confirm in
general the previous preliminary report1 It
was not possible from the preliminary results
in a smaller series of patients to determine
whether reserpine exerted a significant anti-
hypertensive effect as compared to placebo.
The more extensive data reported here indi-
cate that oral reserpine does have an anti-
hypertensive effect, although it is not very
great.

The constancy of results obtained from
the first 3-month period to the next for each
of the regimens used indicated that 3 months

was a sufficient period for the evaluation of
antihypertensive effectiveness of these par-
ticular agents. Such a short period, however,
may not reveal chronic toxicity.

The double blind method as employed here
did not appear to be a sensitive method for
detecting minor side-effects. Part of the dif-
ficulty may be due to the fact that side-effects
were reported at 1 month and then quarterly
when most of the acute disturbances such as
headache and palpitation from hydralazine,
and constipation and dry mouth, etc., from
the ganglion blocking drugs had abated. In
addition, some of the early drop-outs may
have occurred because of side-effects which,
of course, would not be reported. In the pre-
treatment period, the high incidence of com-
plaints similar to the expected side-effects
indicates the need for caution in interpreting
the true prevalence of minor side-reactions
in studies when such pretreatment evalua-
tions have not been made.

It is of interest that in patients with mod-
erate hypertension, reserpine plus hydralazine
resulted in a slightly greater reduction in
diastolic pressure than that produced by re-
serpine plus ganglion blocking agents, al-
though the latter produced a slightly greater
fall in systolic pressure. As mentioned pre-
viously, the reduction of blood pressure in
the patients treated with ganglion blocking
agents might have been greater if more ag-
gressive dosage had been employed. On the
other hand, the participating physicians were
experienced in the use of these agents and
administered doses which resulted in a sig-
nificant incidence of the side-effects associ-
ated with ganglionic blockade. The reserpine
and hydralazine regimen employed an un-
complicated, fixed dose schedule; side-effects
ascribable to drug action were lower than in
the patients treated with ganglion blocking
agents, and hydralazine toxicity was not a
prominent feature with the doses of the drug
employed in this study. These considerations
favor the use of reserpine plus hydralazine
over ganglion blocking drugs in the manage-
ment of patients with moderately severe hy-
pertension, at least as an initial trial before
resorting to the blocking agents.

Vol. 110. Aug., 1962     132


\-TIJDY OF ANTIHYPERTENSIVE AGENTS                             229

Summary

Various antihypertensive agents were ad-
ministered using a randomized double blind
technique to male patients with elevations of
basal diastolic pressure above 90 mm. Hg
with the following results.

Of 759 patients entering the study, 426
completed one year of treatment. Of the
losses, 47% were due to failure to return or
to lack of cooperation, the majority occurring
within the first 2 months of treatment. Deaths
accounted for 14% of the losses, severe eleva-
tion of blood pressure or acute hypertensive
complications for 12%, and side-reactions
for 9%.

The average blood pressures in the various
treatment groups remained essentially un-
changed from the third month to the end of
the,year.

In 86 patients with "mild" and "moderate"
hypertension receiving placebos, there was a
slight elevation of blood pressure averaging
3.7/2.0 mm. Hg. In 136 similar patients given
reserpine in a maintenance dose of 0.5 mg.
daily, there was a slight reduction averaging
3.0/5.4 mm. Hg. In 139 patients given the
same amount of reserpine plus hydralazine in
a maintenance dose of 200 mg. per day, the
average reduction of blood pressure was
4.9/10.5 mm. Hg.

Reserpine 0.5 mg. daily plus 1 of 3 gan-
glion blocking agents-mecamylamine, chlori-
sondamine or pentolinium-was tested in

treatment groups each comprising 65 to 91
"severe" and "moderately severe" hyperten-
sive patients. The antihypertensive effects of
the 3 ganglion blocking agents were essen-
tially similar, averaging approximately 15.5/
13 mm. Hg.

With all of the antihypertensive regimens,
the higher the pretreatment level of blood
pressure, the greater was the degree of fall.
Age or race did not seem to influence anti-
hypertensive effectiveness significantly.

In general, inter-regimen differences were
similar in each of the participating hospitals.

Llie wish to thank Dr. Edward Dunner, Research
and Education Section, Central Office, Veterans
Administration, for efficient management and co-
ordination of administrative matters connected with
this investigation. We also wish to thank the mem-
bers of the Departments of Clinical Investigation
of Ciba Pharmaceutical Products, Merck Sharp &
Dohme, and Wyeth Laboratories for manufacture
of special tablets, bottling, and code labeling of
the various pharmaceutical products used in this
study. Finally, the helpful advice and criticism of
our consultants, Dr. Earle Estes and Dr. Eugene
Stead, are gratefully acknowledged.

Edward D. Freis, M.D., Chairman, Antihyper-
tensive Drug Study, Veterans Administration Hos-
pital, 2650 Wisconsin Ave., N.W., Washington 7,
D.C.

REFERENCE

1. Veterans Administration Cooperative Study on
Antihypertensive Agents : A Double Blind Control
Study of Antihypertensive Agents, Arch. Intern.
Med. 106 :81-96, 1960.

133

Veterans Administration    Printed and Published in the United States of America