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RESOLUTION OF THE JOINT COUNCIL SUBCOMMITTEE
ON CEREBROVASCULAR DISEASE CONCERNING THE
TREATMENT OF HYPERTENSION

At its September 21, 1970 meeting, the Joint Council Subcommittee on Cerebro-
vascular Disease, NHLI-NINDS, adopted the following resolution:

Several clinically oriented studies have suggested the effectiveness
of antihypertensive drugs in reducing the frequency of stroke, and
to a lesser degree, coronary heart disease.

The recent publications of the Veterans Administration Cooperative
Study present results of a well-controlled investigation, employing
random allocation of study subjects to experimental and placebo groups.
Over 500 men were studied for periods up to 5 years (average about

20 months).

In those persons with very high diastolic blood pressure, the results
favored the treatment group so dramatically that the investigators
considered that they must terminate the study for reasons of medical
ethics.

| In the group with modest elevation of diastolic blood pressure, the
study was allowed to run its course and also yielded results strongly
in favor of the treated group.

Blood pressure reductions achieved were substantial. The disease cate-
gories most markedly affected by the treatment were congestive heart
failure, accelerated hypertension, renal damage, and stroke. The re-
sults with coronary artery disease are somewhat equivocal but perhaps
show a genuine reduction in sudden deaths.

The results for stroke are summarized as follows:

Treated Control
All events 5 20
Most serious events 1 12

Thus, not only did the treated group have fewer stroke events, but those
that occurred were mich less likely to. be severe.

Since this represents a dramatic and extremely hopeful development in the
control of stroke, the Joint Council Subcommittee on Cerebrovascular Dis-
ease, NHLI-NINDS, strongly recommends that further steps should be taken
as_ expeditiously and aggressively as posstble; namely, that a committee
be_ convened to design studies to implement the application of antthyper-
tenstve therapy on _commmity bases.

 

The Joint Council Subcommittee recommended that the above resolution be for-
warded to the National Advisory Heart and Lumg Council, the National Advisory
Neurological Diseases and Stroke Council, and the National Advisory Council on
Regional Medical Programs.

 
    

AMA

THE JOURNAL of the American Medical Association

Copyright © 1970 by the American Medical Association

August, 17, 1970
Vol 213, No 7

 

 

 

 

 

EF ACt Oy 7 rymMmantr on
CuEreCUS OF L PCaALIMeNnt On
‘ : V2 Foy ° TT . LL. . ° _
fe WEN De 3 ! CTIYOPTARAIRAN
| VLOrolcity In Klypertension

IL. Results in Patients With Diastolic Blood Pressure
Averaging 90 Through 114 mm Hg

Veterans Administration Cooperative Study Group on Antihypertensive Agents

Three hundred and eighty male hypertensive patients with
diastolic blood pressures averaging 90 to 114mmH gwere
randomly assigned to either active antihypertensive agents
or placebos. The estimated risk of developing a morbid event
over a five-year period was reduced from 55% to 18% by
treatment. Terminating morbid events occurred in 35
patients of the control group as compared to 9 patients in the
treated sroup.-Nineteen deaths related to hypertension or
atherosclerosis occurred in the control group and 8in the
"actively treated group. In addition to morbid events, 20
control patients developed persistent diastolic levels of 128
mm Hg or higher. Treatment was more effective in prevent-
ing congestive heart failure and stroke thanin preventing the
complications of coronary artery disease. The degree of
benefit was related to the level of prerandomization
blood pressure. |

2
7

journa]' the Veterans Admin-

Pr a previous publication in this
istration’ Cooperative Study

 

For complete lst of participants, see
page 1152. .

Reprint requests to 50 Irving St NW,
Washington, DC 20422 (Dr. Freis).-

JAMA, Aug 17, 1970 © Vol 213, No 7

Group on Antihypertensive Agents |

reported on the beneficial effects of
antihypertensive drugs on morbidi-
ty in patients with moderately
severe hypertension. These were
patients with initial diastolic blood
pressures averaging 115 through 129

mm Hg who had been randomized
into a prospective double-blind trial
of active antihypertensive drugs vs
placebos. Twenty-seven patients de-
veloped assessable events in the

‘ control group as compared to two
patients in the group receiving ac-
tive antihypertensive agents. This
striking result favoring treatment
was in agreement with the results
of other prospective trials? in pa-
tients with hypertension of similar
severity. -

In hypertension of lesser severity,
however, there are Httle or no con-
trolled data available on the value
of antihypertensive drug therapy.
Resolution of this question is of
great importance not only because
of the large number of patients with.
mild hypertension but also because
the potential benefits of drug treat-
ment have been questioned espe-
cially in this group of hypertensive
patients.* The present report pre-
sents the results of a prospective,
controlled trial of drug treatment
on morbidity and mortality in a
group of 350 patients with mild or
moderate hypertension whose initial

Morbidity in Hypertension 1143

er meeny ene ©

 
 

\

diastolic blood pressure averaged
90 through 114 mm Hg.

Plan of Investigation

The clinical trial included 523

“male veterans who, while not re-

ceiving antihypertensive treatment,
exhibited diastolic blood pressures

‘averaging 90 through 129 mm Hg.

Randomization of patients began
in April 1964. However, in May
1967, the study was terminated in
the subgroup of 143 patients whose
diastolic blood pressures averaged
115 through 129 mm Hg prior to
randomization. Termination of the
study of this group as previously re-
ported' was necessitated by the
high incidence of morbid events in

the control as compared to the’

treated patients, demonstrating at
a relatively early date a highly sig-
nificant (P < 0.001) effect of treat-
ment. Such a significant difference
was not evident at the time, how-
ever, in the patients whose diastolic

: blood pressures averaged below 115

mm Hg prior to randomization.
These latter patients were con-
tinued in the randomized trial until
1989 and are the subject of the

' present communication,

The experimental design has been

’ described in previous  reports.'®

Initially all patients were hospital-
jzed for diagnosis and evaluation
of the severity of their hyperten-
sion. Patients whose diastolic blood

_ pressure averaged 90 through 129

mm Hg during the fourth through
sixth hospital day were accepted
for further follow-up. Patients whose

_ diastolic averages fell below 90 mm

Hg or rose above 129 mm Hg dur-

’ ing this period of hospitalization °

were excluded.

Following hospitalization the pa-
tients entered a prerandomization
observation period of two to four
months’ duration during which time
they received placebos of antihy-
pertensive agents. The patients

- whose diastolic blood pressures dur-

ing the last two clinic visits of the

observation period averaged 90
through 129 mm Hg were entered
into the trial, providing there were
no other reasons for exclusion.
Blood pressure was measured by a
physician with the patient in a
sitting position.

Other reasons for excluding pa-

tients from the trial, in addition to
diastolic blood pressure, are detailed
in other reporis.’* Such reasons
included a history of a severe hy-
pertensive complication such as a
cerebral or subarachnoid hemor-
rhage, hypertensive neuroretinop-
athy, dissecting aneurysm, or renal

_ failure, but did not include athero-
sclerotic complications such as cor-

onary artery disease or cerebrovas-

cular thrombosis. Also excluded:

were (1) patients with surgically
curable hypertension, (2) with un-
related fatal diseases such as malig-
nant tumors, (3) those unwilling or
unable to return to clinic, and (4)
poorly motivated or otherwise un-
cooperative or unreliable patients.

The outpatient prerandomization
observation period provided a fur-
ther opportunity to check on the
reliability of the patients. Ribo-
flavin, which produces bright yellow
fluorescence of the urine, was incor-
porated in the placebos. At each
clinic visit a urine specimen was
examined under ultraviolet light.
In addition, pill counts were made
at each clinic visit. No patient was
accepted into the randomized trial
unless the urine exhibited fluores-
cence and the pill counts were with-
in a stipulated range, at each of two
successive visits during the preran-

_domization observation period.

_ Accepted patients were then ran-
domly assigned double-blind to
either active drugs or placebos.
Active drugs consisted of two types
of tablets, one being a combination
tablet containing 50 mg hydrochlo-
rothiazide and 0.1 mg_ reserpine
which was given twice daily. The
other was 25 mg of hydralazine
hydrochloride given three times

1144 JAMA, Aug 17, 1970 © Vol 213, No 7

«

daily. The latter medication was
raised to 50 mg three times daily if
the diastolic blood pressure re-
mained at 90 mm He or higher.
Obviously, practically all of the
patients in the placebo group had
their “doses” raised to this. level.
Provision was made for reduction
of doses if hypotensive reactions or
other disturbing side cifects oc-’
curred, Patients in the conirol group
received placebos identical in taste
and appearance to the active drugs.
Indicated symptomatic treatment,
including drugs other than antihy-
pertensive agents, was permitted in
all patients.

Postrandomization clinic visits
were at monthly intervals for the
first two months and at bimonthly
intervals thereafter. Annual exami-
nations included taking a history
and a physical examination, roent-
genogram of the chest, electro-
cardiogram, pertinent chemical an-
alyses of the blood, and renal func-
tion tests. Additional interim visits
could be scheduled when indicated.

Characteristics of Patients

Three hundred and eighty pa-
tients with diastolic blood pressures
averaging 90 through 114 mm Hg
were randomized into the trial. Of
this number, 186 received active
drugs while 194 were given place-
bos. Tables 1 and 2 indicate that.
the two groups were comparable
according to the indicated variables.
The median ages were 49.2 and
48.1 years and the average ages
were 52.0 and 50.5 years in the con-
trol and treatment groups, respec-
tively. Negro patients comprised
42% of the control group and 41%
of the treated group. Blood pressure
as measured in the clinic during
the posthospitalization observation
period prior to randomization zver-
aged 165.1/104.7 mm Hg in the
control group and 162.1/103.8 mm
Hg in the treated patients. There
were no significant differences be-
tween the control and treated pa-

Morbidity in Hypertension

 

 
 

 

tients with regard to findings from
renal function tests, fasting blood
sugar value, serum cholesterol value,
uric acid level, and left ventricular
enlargement as assessed by x-ray
films and electrocardiography. By
all factors measured the two groups
were comparable.

Duration of Observation

Patients were entered into the
trial from April 1964 to September
1968, and the study was terminaied

in October 1969. Thus, the earliest _

entrants were observed for 5.5 years
and the latest entrants for a mini-
mum of 1 year. The average poten-
tial duration .of observation, disre-
garding losses and terminations,
was 3.9 years for the contro] group
and 3.7 years for the treated pa-

tients. However, because of the

losses and terminations due to ele-
vated diastolic blood pressure de-
scribed below, the actual duration
of postrandomization . observation
was 3.3 years for the control group
and 3.2 years for the treated pa-
tients. ,

Changes in Blood Pressure

Systolic and diastolic blood pres-
sure fell promptly and significantly
in the treated patients and re-
mained at reduced levels through-
out the trial. The changes in blood
pressure at the fourth month of
observation in the treated and con-
trol patients are depicted in Fig 1.
The mean change in systolic blood
pressure was an increase of 4.2 mm
Hg in the control group and a fall
of 27.2 mm Hg in the treated pa-
tients from the levels recorded dur-
ing the prerandomization observa-
tion period. The mean change in
diastolic blood pressure was a rise
of 12 mm Hg in the control pa-
tients and a fall of 17.4 mm Hg in
the treated group curing this same
interval. The distribution of the
changes in blood pressure as shown

in Fig 1 indicates a marked shift to

JAMA, Aug 17, 1970 @ Vol 213, No 7

®

 

_ Table 1,—Background of Randomized Patients: Numeration Data

 

 

 

 

 

 

 

 

: Control Group Treatment Group

Characteristic “No. % ~ No. % Total

Total randomized . 194 186 320
Negro Si 42 76 4) 157
Other _. 14 58 109 59 223
Heart size by roentgenogram : ° - : J °
~~ Ungerleider enlarged a 42 220 53 29 a: e
Electrocardiogram _ ae * ° - __

Left ventricular hypertrophy i 32 16 30 16, €2

 

*in addition to whites, this group includes four patients of Asiatic extraction, two in“the con-

. tro! group and two in the treated group.

 

Table 2.—Measurement Data Prior to Randomization

 

Control Group Treatment Group

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

- Characteristic fhean Mean
Age (yr) 52.0
Age (median, yr) 49.2
Height, cm (ft, in) 175.3 (5, §)
Weignt, kg (1b) 82.0 (180.5)
Duration known hypertension (yr) 4.4 +.
Average hospital diastolic pressure (mm Hg) 301.3 160.2
Average hospital systolic pressure (mm Hg) ~ 157.5 ~ > 154.0
Average clinic diastolic pressure (mm Hg) 104.7 —~ 103.8
Average Clinic systolic pressure (mm Hg) 165.1 ‘ 162.1
Totai severity score* 6.7 6.8
Renal score (0-4) 0.2 - 0.2
Cardiac score (0-4) _ 0.8 . 0.9
CNS?7 score (0-4) 0.3 0.3
Serum creatinine (mz/109 cc) nm 1.26 1.24
BUN (mg/100 cc) oo 15.6 16.2
Serum potassium (mEq/liter) 4.4 4
PSP excretion (% in2hr) 58.8 69.0
Fasting blood glucose (mz/100 cc) _ - 96.5 100.4
Cholesterol (ma/1C9 cc) 250.1 265.0
Uric acid (mg/103 cc) 6.3 6.0

 

*Detailed criteria for grades 0 through 4 given in reference 6.

TCNS signifies central nervous system,
#PSP signifies phenolsulfonphthalein.

the left into the “decrease” zone for |
the treated patients as compared to
the control group. Also apparent js
the wide variation in individual
responses particularly with regard
to systolic blood pressure,

Losses Other Than Assessable
Events

Deaths Due to Unrelated Condi-
tions._Four patients died of dis-
orders unrelated to hypertension.
Two of the patients were in the
control group. One died of general-
ized carcinomatosis demonstrated
at autopsy and the other of uremia
secondary to carcinoma of the uri-
nary bladder. One patient in the
treated group died of a subdural
hematoma following a skull fracture

laxis. Postmortem examination was
carried out in both of these patients.

Losses Due to Drug Toxicity.—
Two patients in the treatment group
developed reactions thought to be
due to drug toxicity. The first pa-
tient developed orbital edema with
fever and malaise. Roentgenogram
of the chest revealed infilirates in
the Jungs. There was no dermatitis
or arthritis. Lupus cells were not
found in the blood although the
antinuclear antibody test was pos-
itive. Protocol drugs were discon-
tinued because of the possibility of
lupus syndrome associated with
hydralazine. The second patient de-
veloped purpura one month after
beginning active drug treatment.
Findings from examination in the

hospital, including biopsy, were con-

Morbidity in Hypertension 1145

a
 

 

 

 

 

     
 

 

 

 

 

 

 

   

 

 

 

 

x
Op - PLACEBOS - 40 PLACEBO _I
1 0,
| DECREASE |. DECREASE ~rrANCREASE

» 20 “
a 10 | a1 ij
= w |
=o = 0
= a
us 3S
_ =
z uw
: o
ot ~ ~ o 7
g 4 ACTIVE DRUGS we a0 ACTIVE DRUGS

L . a x

30 30

20 20

10 10

fommey | J demons! |
: 0
ho Ci a 48-3216 HGH

1. Changes in systolic (left) and diastolic blood pressure (right) after four months of treatment in patients
given placebos (top) and in patients treated with active drugs (bottom). Mean of changes (X).

_ sistent with anaphylactoid purpura.

The purpuric lesions cleared two
weeks after protocol treatment was
discontinued and‘reappeared within
three days after administration of
active drugs began again. Protocol
treatment was, therefore, discon-
tinued.

Drop-Outs.—Yifty-six or 15% of:

the 380 randomized patients were
classified as drop-outs during the
course of the trial. Of this number
27 had been randomized to receive

placebos and 29 to receive active -

drugs. The average period of follow-
up prior to dropping out was 17.6

‘months with a range from less than

i month to 49 months. Six patients
moved away from the area of the

linic. Two were lost from follow-up
oecause of closure of one participat-
ing clinic. Four returned to the care
of their private physicians. Fifteen

1146 JAMA, Aug 17, 1970 ® Vol 213, No 7

complained of side effects prior to
dropping out. Nine of these patients
had been receiving drugs, and six
were taking placebos. Five patients
had psychiatric or alcoholic prob-
Jems of such severity as to make
continued protocol treatment im-
practical. In the remaining patients
the reason for drop-out could not be
determined. It should be noted that
three of the patients taking pla-
cebos sustained nonterminating
morbid events prior to their drop-
ping out.

' Assessable Morbid Events

The records of the. patients re-
ported as having assessable morbid
events were reviewed by two con-
sulting physicians who had not
participated in the trial. All assessa-
ble events’ were reviewed. except
those related to the development of

t
i

electrocardiographic signs of left
ventricular hypertrophy or of roent-
genographic evidence of cardiac en-
largement, which will be reported in
a subsequent communication. All
available data pertaining to each
organic complication, except the
type of protocol treatment and the
level of blood pressure, were pre-
sented to the reviewers and their
decisions regarding the occurrence
and classification of an event ac-

cording to the definitions given in

the protocol (see list of assessable
events at the end of the communi-
cation) were accepted as final.
Table 3 summarizes the assessa-
ble events by major categories. Such
events occurred in 98 of the 380
randomized patients, 76 in the cox.-
trol group and 22 in the treated
patients. Of this number 20 control
patients developed an increase in

Morbidity in Hypertension

eee te

 

 

 
diastolic blood: pressure to levels
exceeding 124 mm Hg on three

_ separate clinic visits and persisting

for 3 weeks or longer. Since these
patients were removed from the
trial only because of persistent

’ blood pressure elevations and not

for an organic complication, they
will not be included in the subse-

- quent assessment of effectiveness of

treatment in préventing morbid
events, 7

The remaining 78 patients had
organic complications subdivided as
follows: 56 of 194 or 28.9% of the
control group and 22 of 186 or
"411.8% of the treated patients. The
-most striking evidence of benefit of
treatment was manifested in the
count of class A events (hyperten-

sive complications defined in the-

protocol which required removal of
‘the patient from the study.’ There
were none among the treated pa-
tients but 14 among the controls.
These included five class A deaths
“(Table 4) plus nine other class A
events (Table 5). When other car-
diovascular (class B) deaths and
‘treatment failures were added, the
-comparisons were still impressive,
_35 of 194 patients or 18.0% amongst
the controls and only 9 of 186 or

' 4.8% in the treated group (Table

8). The effectiveness of treatment
(difference in percent incidence of
complications between control and
‘treated groups divided by the per-
cent incidence in the control group)
in preventing terminating organic
complications was 73% (Table 3).
The decision to discontinue the trial
-was based on this favorable evidence
supplemented by the life-table an-
‘alyses described below which sug-
‘gested that the benefit of treatment
was continuing through time and
was not solely concentrated in the
first year or two of treatment,
Terminating Events. — DEATHS
RELATED TO CARDIOVASCULAR Dis-
FASE.—T wenty-seven patients died
of hypertensive or atherosclerotic

. complications, 19 occurring in the

JAMA, Aug 17, 1970 © Vol 213, No 7

oN

 

 

Table 3.—Summary of Assessable Events

 

_ Control Group

Treated Group

or

re % .
% No. % Effectiveness?

 

 

 

 

 

= _. No.
Terminating morbid eventst 35 18.0 9 4.8 73
Nonterminating 8 events . 21 13
Total morbid events 56 28.9 22 11.8 59
Terminated on eccount of

elevated blood pressure . 20 oO
Total assessable events _ 76 39.2 22. 11.8 . 70,
No. patients randomized 194 100.6 186 100.0

 

'*See text.

jincludes cardiovascular deaths, class A events, and treatment failures except those due to_

diastolic levels >124 mm Hg.

 

Table 4.—Causes of Death

 

 

 

 

 

 

 

 

 

Control Treated
Cause Group Group
Deaths due to class A events _ _
Cerebrovascular hemorrhage _ 3 Q
Subarachnoid hemorrhage 1 0
Dissecting aneurysm _ 2 0
Deaths due to ciass B events
Myocardial infarction 3 2
Sucden death 8 4
Cerebrovascular thrombosis J | 3 i
Ruptured atherosclerotic aneurysm _ _. o i
Total related deaths* 19 - 8

 

 

*Does not include four unrelated deaths, two in the control group and two in the treated

Sroup (see text),

 

Table 5.—Terminating Morbid Events Other Than Death

Type of Event

Class A events ,
Uncontrolled cardiac failure
Dissecting aortic aneurysm
Subarachnoid hemorrhage
Fundi, striate hemorrhages
Acute hypertensive encephalopathy

Subtotal ee _ __
Treatment failures
Cerebrovascular thrombosis, severe
Progressive azotemia
Fundi, one striate hemorrhage
and ? early papiliedema
Fundi, one striate hemorrhage
and ? encephalopathy
Hypotension
Subtotal
Total

control group and & in the treated
patients (Table 4). Five deaths
agsociated with class A or hyper-
tensive events (see list of assessable
events at the end of the communi-
cation) were cerebral hemorrhage
in four and dissecting aortic an-
eurysm in one, all occurring in the
control group of patients. Deaths
resulting from class B events were

Treated
Group

Control
Group

Of mt et ee on
o1/oo0°o

Qwnon & my
RKeIH Oo Oo OC

associated predominantly with cor-
onary artery disease. Eleven pa-
tients in the placebo group and 6 in
the treated group had either a docu-
mented myocardial infarciion or a
“sudden death.” Cerebrovascular
thrombosis as opposed to hemor-
rhage was the cause of death in
three contro] patients and in one
treated patient. The remaining

Morbidity in Hypertension 1147

 

 
 

a

 

 

— 1148

 

Table 6,—Nonterminating Class B Events

 

 

 

 

 

 

 

 

 

 

Control “Treated *

Type Group Group
CVA, thrombosis or TIA® 8 4
Cdngestive heart | fatluret : 6 6
Myocardial infarction 2 5
Atrial fibrillation ~ 2 3
Heart- block - : . . _ —1 Al

Sérum creatinine, persistent, - =
>2.0 mg/100 cc 1 0
Proteinuria, persistent, Dit a — 1 0
Total - — 21 13

 

——

*Cerebrovascular accident, either a thrombosis (clinical diagnosis) or transient ischemic at-

tack with objective neurological signs.

{Controlled by administration of digitalis and short-term diuretics.

 

Table 7.—Classification of Morbid Events by Diagnostic Categories

 

Total Events
y

Terminating Events
—.

 

 

 

 

 

 

 

Diagnosis o Control Treated “Control Treated
Cérebrovascular accident _ 20 5 12 I
Coronary artery disease - 13 “hl 11 6
Congestive hear failure : “Ud =O 5 . 0
“Accelerated” hypertension 4 0 4 oO

. Renal damage _ | 3 0 1 0
Other : - ° ~ 5 - 6 2 2
Tota! 56 22 . 35 9

 

death in the treated group was
caused by a rupture of an ather-
osclerotic aneurysm of the aorta.

Orsrr Crass A Events.—Nine
patients in the control group as
opposed to none in the treated
group developed nonfatal class A
events (Table 5). Five of the pa-
tients had congestive heart failure
which could not be controlled by
administration of digitalis, sodium
yestriction, and the intermittent ad-
ministration of diuretics. In the four
remaining patients there was one
instance of each of the following
complications: dissecting aortic an-
eurysm, subarachnoid hemorrhage,
multiple striate retinal hemorrhages,
and acute hypertensive encepha-
Jopathy with accompanying neuro-

- logical signs.

Oruer TERMINATING EVENTS.—
Additional organic complications,
which did not fulfill the criteria for
class A events but which were
nevertheless of sufficient severity to
require terminating protocol treat-
ment occurred in eight patients of
which seven were in the control
group. These are listed in Table 5
under the subtitle “treatment fail-

ure.” Four were associated with
cerebrovascular accidents diagnosed
clinically as thrombosis rather than
hemorrhage but which resulted in
such severe incapacity that the pa-
tients were-unable to attend the
clinic. Two additional control pa-
tients were removed from the study
because of the appearance of a
single striate retinal hemorrhage
associated in one with symptoms
suggesting acute hypertensive en-
cephalopathy, and, in the other,
with questionable .early papillede-
ma. The remaining control patient
exhibited increasing azotemia. One
patient in the treated group was
removed from the study because of
hypotension following a myocardial
infarction which resulted in his in-

_ ability to tolerate the antihyperten-

sive regimen. It is noteworthy that
of the 17 nonfatal terminating
events (class A and others) 16 oc-
curred in the control group and
only one in the treated patient
(Table 5).

Nonterminating (Class B) Events.
~—Class B events include organic
complications which require no or
only temporary suspension of proto-

JAMA, Aug 17, 1970 © Vo! 213, No 7.

*

Sete gat te 5
. ‘

col treatment (see list of assessable
events listed at the end of the com-
munication). Objectively demon-

strable atherosclerotic complications *

predominate as class B events, but
the category also includes conges-
tive heart. failure responsive to rou-

tine therapy other than administra-_

tion of antihypertensive drugs and

certain less severe manifestations, of

renal disease.

Nonfatal class B events occurred
in 21 of the control patients and in
18 of the treated patients (Table
6). Six patients developed conges-
tive heart failure controllable by
digitalis and short-term administra-
tion of diuretics. It is noteworthy
that all six of these patients were
in the control group. Also, the in-
cidence of nonterminating cere-
brovascular accidents was twice as
great in the control as in the treated
patients. However, nonfatal myo-
cardial infarction occurred in five
of the treated patients as opposed
to two of the control group. The in-
cidence of atrial fibrillation and
conduction defects was essentially
the same in the two groups.

Life-Table Analysis.—The bene-
fit of treatment is more precisely
analyzed using life-table methods
(Fig 2). This method has the fol-
lowing advantages: (1) it adjusts
for the fact that patients enter the
study at different times and thus
are observed for varying lengths of
time; (2) the method adjusts for
any differences in losses to observa-
tion between the control and treated
groups; and (3) most important, it
determines whether the benefit of
treatment occurs early or late or is
continuing through time. The dis-
tance separating the control and
treatment lines is a measure ot the
degreé of benefit.

It is clear from Fig 2 that the
benefit of treatment manifested it-
self early and continued throughout
the entire five years of follow-up.
The life-table analysis of either ter-
minating or all morbid events indi-

Morbidity in Hypertension

:

worse

 

 
 

«

a

‘AD wa dee ger tL.

2 Rate tet te . . ad

 

Table 8.—Incidence of Morbid Events With Respect to Level of Prerandomization Blood Pressure

 

Control Group
a A

Prerandomization

Patients With ‘
“Morbid Event”

Treated Group

Patients With
“Morbid Event"

 

 

 

 

 

 

Blood Pressure, Patients Patients rer 7 %
mm Hg Randomized No, % Randomized No. % Effectiveness
Systolic 165 98 15 15.3 108 10 9.3 40
Systolic 1654- 96 41 42.7 78 12 . 15.4 64
Total . 194 56 186 22
Diastolic 90-104 84 21 : 25.0 . 86 14- 16.3 35
Diastolic 105-114 110 35 31.8 _100 8 8.0 . (78
Tota! 194 56 186 22
Table 9.—Incidence of Morbid Events With Respect to Ase and Race
Control Group Treated Group
. Patients With ‘ Patients With -
“Morbid Event’ “Morbid Event"
Patients Patients %
‘ Randomized No. % Randomized No. % Effectiveness
Age (on admission) .
<50 yr 99 i5 15.2 - 102 7 6.9 55
50 & over 95 41 43.2 84 15 17.9 59
Total 194 56 , 186 22
Race .
Negro 81 21 25.9 76 8 10.5 54
Other _ 113 35 31.0 110 14 12.7 59
Total. 194 56 : 186 22

 

cates that the benefit increased with
time. For example, with respect to
“all morbid events” it may be seen

- that at three years the estimated

cumulative incidence of morbidity
in the control group is twice as
great as in the treated patients.
This suggests that treatment was
about 50% effective at three years.
At five years the spread between

- the two curves was substantially

greater indicating an increasing
degree of benefit with the passage
of time. Specifically, at five years
the cumulative incidence rate of

- events for the control group rises to

55%. By contrast, for the treated
group the indicated incidence of
events at five years is only 18%. It
can be estimated, therefore, that
over a five-year period treatment
prevented 37% morbidity (55%
minus 18%), and this represents a
67% effectiveness (87/55).

The standard errors at five years
were 6.3% for the control patients
and 4.0% for the treated group. The
significance of the difference be-
tween the two rates of 55% and

JAMA, Aug 17, 1970 © Vol 213, No 7

18% yielded a t-value of 5.0 which
is highly significant. A crude esti-
mate gave confidence limits of 49%
to 81% for the observed 67% effec-
tiveness. . :
Relationship’ of Treatment to
Other Factors.—RELATIONSHIP TO
Diacnosric CaTEGoRIES.—It is re-
vealing to examine the incidence of
morbid events as related to treat-
ment when the events are classified
according to diagnostic categories
(Table 7). Thus, in the control vs
the treated groups, the prevalence
of congestive heart failure was 11:0,
of rena! deterioration 3:0, and of
“accelerated” hypertension (hyper-
tensive neuroretinopathy or enceph-
alopathy) 4:0. The number of
cerebrovascular complications also
seemed to be considerably influ-
enced by treatment since the ratio
of cerebrovascular events in. the
control vs treated patienis was 20:5,
and, of the more severe or terminat-
ing cerebrovascular events, it was
12:1. On the other hand, assessable
events caused by coronary artery
disease (myocardial infarction or

sudden death) were nearly the
same in the two groups, 13 in the
control and 11 in the treated, al-
though fatal coronary evenis were
somewhat greater in the control
group.

RELATIONSHIP TO PRERANDOMIZA-
TION BLoop Pressure.—The bene-
ficial effect of treatment was most
evident in the patients with higher
Initial levels of blood pressure. With
respect to diastolic blood pressure
the effectiveness of treatment was
75% in the patients with preran-
domization diastolic blood pressure
averaging 105 through 114 mm Hg
as opposed to only 3525 in the
group averaging 90 through 104 mm
Hg (Table 8}. A similar although
somewhat less striking trend was
noted with respect to systolic blood
pressure, the efiectiveness of treat-
ment being 64% in patients with
iniflal systolic levels averaging 165
mm Hg and above as opposed to
40% in the group with lower initial
systolic blood pressure.

RELATIONSHIP TO AGE.—The ma-
jority of the patients developing

Morbidity in Hypertension 1149

 

 
 

 

 

 

cons
iS

[aye
,

—
te

2. x

e 3

VORS WE CR ATIN

Gr
ar tT

TERMINATING MORBID EVENTS

e——9-- *

Control group

 
    

rete ong

we Oe

   

Treated group i

1 £

 

  

ALL MORBID EVENTS

1
'

CTH

7s

 

Control group

SE PRT EHR E te me wets

 

 

 

Vea G7 CREAN

- or hydrochlorothiazide or

 

 

2. Estimated cumulative incidence of

morbidity over

a five-year period as calculated by life-table method,

Terminating morbid events (top) and

morbid events were in the older age.
group. Of the 56 control patients
developing morbid events 41 were
50 years of age or older at the time
of admission to the study, while
-only 15 were below age 50. A sim-
ilar distribution was found with
respect to the treated patients. The
percent effectiveness of treatment
was approximately the same in the
younger and older groups (Table
9). However, because of the lower
number of: events in the patients
below age 50 the estimated effec-
.iveness of treatment cannot be ac-
cepted with the same degree of
confidence as in the older patients.

RELATIONSHIP TO Race.—The in-

1150

all morbid events (bottom).

cidence of morbid events was no
greater in Negro patients. In fact,
in the control group the incidence
of events was slightly lower in
Negroes, 23.9% as opposed to
31.0% of the other patients. A
similar relationship was noted in
the treated patients (Table 9). The
percent effectiveness of treatment
was essentially the same in the two
racial groups. .

Side Effects

In the treated group of patients
dosage adjustments frequently were
required because of hypotensive and
other symptoms. A complete analy-
sis of these and other side efiects

JAMA, Aug 17,°1970 @ Vol 213, No 7

.

will be made in a subsequent com-
munication. The two patienis lost
to protoco) because of drug toxicity

have been described above. In addi- —

tion, in the present report only
those side effects requiring removal
of either reserpine or hydrochloro-
thiazide from the treatment reginien
will be considered. ,
Administration of either reserpine
their
placebos was withdrawn because of
side effect in 29 patients. Reserpine

; "and hydrochlorothiazide were ad-

ministered combined in a single
tablet. In order to avoid losses to
protocol because of side effects pre-
sumably caused by one or the other
of the two agents, provision was
made to permit substitution of a
tablet which contained either rese:-
pine or hydrochlorothiazide alone
and omitted the offending medica-
tion. These special tablets were
made available on request of a
participating physician. Similar-
appearing placebo tablets were
made available for the control pa-
tients and the physician did not
know whether the substitution rep-

‘ resented active drugs or placebos.

In the majority of the 29 patients
substitution of the special tablet
was necessitated by presumed res-
erpine-induced side effects. Mental
depression occurred in 12 patients.
However, only seven of these pa-
tients had been receiving active
drugs while the remaining five had
been randomly selected to receive
placebos. Ten patients developed
peptic ulcer of which six had been
taking ‘active drugs and four place-
bos. In two patients substitution
was made because of impotence;
one of these two had been randomly
selected to receive the placebo regi-
men. The remaining six patients all
were receiving active treatment.
Their side effects included sleep-
iness, severe nasal stuffiness, gout,
seizures presumably caused by hy-
potension, and abnormal results
from the glucose tolerance test.

Morbidity in Hypertension

mn moe

 

 
 

 

~ Comment

The effectiveness of treatment
“was clearly demonstrated in the
patients with prerandomization sys-
tolic blood pressures above 164 or
diastolic pressure above 104 mm
Hg. The difference in the incidence
of morbid events between contro]
and treated patients was less clear
cut in the patients with blood pres-
" sures below these levels. This may
‘be due to the fact that organic com-
plications appear slowly in mild
‘hypertension as indicated by the
considerably lower incidence of
such events in patients with blood
pressures below 165/105 mm Fig.
As would be expected, a greater
‘incidence of organic complications
occurred in the older than in the
younger patients. Of considerable
importance is the observation that
‘treatment was found to be effective
in reducing the number of such
complications in these older pa-
tients. Although the indicated effec-
-tiveness of treatment was essentially
_ the same in patients above and
below age 50 years, the results were
not as convincing in the younger
group because of the low incidence
‘of morbid events in both the control
and treated patients. It should be
mentioned, however, that in the
“group ‘of 20 control patients, not
counted, as having morbid events
but who were removed from the
study because of persistent eleva-
tion of diastolic blood pressure
greater than 124 mm Hg, 14 so re-
moved were below 50 years of age.
_ Treatment was most effective in
‘preventing hypertensive complica-
-tions and least effective in prevent-
“ing atherosclerotic complications,
‘particularly those associated with
coronary artery disease. Complica-
tions such as congestive heart fail-
ure, renal damage, cerebrovascular
hemorrhage, and accelerated hyper-
tension occurred only in the control
group. On the other hand, the in-
cidence of complications associated

JAMA, Aug 17, 1970 @ Vol 213, No 7

with coronary artery disease was
essentially the same in the control
and treated patients. Lote

Because of the gradual progres-
sion of atherosclerosis, the negative
result with regard to prevention of
myocardial infarction and sudden
deaih cannot be taken as evidence
that treatment is ineffective. Con-
tinuation of the present study was
not justified because of the favor-
able evidence with regard to pre-
vention of hypertensive complica-
tions. If follow-up had been longer,

and if administration of antihyper-.

tensive drugs had been started at an
earlier age, a significant difference
might have been demonstrated. The
average age of the patients was 51
years and hypertension could have
been present for many years prior
to randomization. Atherosclerosis of
the coronary arteries, therefore,
may have been well established at
the time of entrance inio the study.
Further trials are needed in a more
selected population io determine
whether antihypertensive treatment
helps prevent coronary artery dis-
ease. . ,

It is of interest to compare the
results of the present.series of pa-
tients whose initial diastolic blood
pressures averaged 90 through 114
mm Hg with the results previously
reported in the patients whose dia-
stolic blood pressures at the begin-
ning of study averaged 115 through
129 mm Hg.) The bencfit of treat-
ment was quickly manifested in the

latter series. Thirty-eight percent of

the contro] patients in that series
developed assessable evenis over an
average period of only 15.7 months
of postrandomization follow-up,

* whereas such events occurred in

only 3% of the treated patients. A
considerably longer period of fol-
low-up was required to demonstrate
a significant benefit of treatment in
the presently reported series of pa-
tients with lower levels of diastolic
blood pressure. ,

The distribution as to type of

events also was different in the two
groups of patients divided accord-
ing to level of initial diastolic blood
pressure. In the’ control patients
with initial diastolic levels of 115
through 129 mm He acceleraicd
hypertension with hypertensive
neuroretinopathy was the most fre-
quent complication. In the present
series cerebrovascular disease, con-.
gestive heart failure, and coronary
artery disease were the most fre-
quent morbid events occurring in
the control group. Of the four con-
trol patients who died in the pre-
viously reported series of patients
with high diastolic pressures, three
deaths were caused by dissecting
or ruptured aortic aneurysm where-
as the most common causes of death
in the series of patients with lower

diastolic pressures were strokes,
myocardial infarcts, and sudden
death.

It should be emphasized that the
present study dealt with a selected
population. Many uncooperative
and unreliable patients were iden-
tified and eliminated from the trial
on the basis of pill counts, urine
fluorescence test results, and irreg-
ularity of clinic attendance during

‘a prerandomization observation pe-

riod. Treatment obviously would
not have been as efiective in a
group of patienis less carefully se-
lected with regard to their desire
to cooperate. The population was
further limited in that it excluded
female patients and patients with
labile hypertension whose diastolic
blood pressures averaged lower than
90 mm Hg during the fourth through
the sixth day of hospitalization.
Finally, the incidence of morbid
events in the group below age 50
was relatively low. Further studies
are needed to evaluate the effective-
ness of treatment in labile hyper-

-tension and in ihe prevention of

atherosclerotic complications, par-
ticularly coronary artery disease.
Such studies would seem to require
larger numbers of younger patients

Morbidity in Hypertension 1151
 

 

who can be followed up for long
periods of time.

Within the limits defined by this
study, however, the present results
leave little doubt that antihyper-
tensive drug treatment is beneficial.
The present results together with
those previously reported in pa-
‘tients with initial diastolic blood
pressures of 115 through 129 mm
Hg’ indicate clearly that the higher
the level of blood pressure the
“greater the degree of benefit of such
therapy. Certain complications such
as congestive heart failure, hyper-
tensive neuroretinopathy,’ strokes,
and renal deterioration were re-
duced or essentially eliminated in
the treated patients. In addition,
treatment prevented elevation of
diastolic blood pressure to levels
where the risk of developing hyper-
tensive complications is greatly in-
creased. The effectiveness of the
treatment in preventing such pro-

‘gression is indicated by the fact

that while persistent elevation of
diastolic blood pressure exceeding
124 mm Hg occurred in approxi-
mately 10°% of the control patients,
they were completely absent in the
treated group.

Participants

Permanent Members of the Study Group:

Massimo Calabresi, MD; C. Hilmon Castle,
MD; Leo Elson, MD; Edward D. Freis,
MD, Chairman; Rudolph E. Fremont, MD;
Michael A. Harris, MD; David Littman,
MD; EH A. Ramirez, MD; and J. R.
‘Thomas, MD.

Other Members: Luis A. Atias, MD;
Mark L. Armstrong, MD; Alston W.
Blount, MD; Thomas A. Bruce, MD; Ovid
B. Bush, Jr., MD, deceased; Eugene C.
Clark, MD; Annette Fitz, MD, R. M. Free-
man, MD; Edward D. Frohlich,. MD;
Arthur Gear, MD; John D. Kyriacopoulos,

MD; Alan F. Lyon, MD; Gloria D. Mas- -

saro, MD; Donald McCaughan, MD; Jean
Morgan, MD; Henry W. Overbeck, MD;
Eliseo C. Perez-Stable, MD; Mitchell
Perry, MD; Roger Sutton, MD; and James
Taguchi, MD.

Participating Veterans Administration
Hospitals: Allen Park, Michigan: Birming-
ham, Ala; Brooklyn, NY: Dayton, Ohio;
Iowa City; Jackson, Miss; Memphis; Nash-
ville, Tenn; Oklahoma City; Pittsburgiy;
Richmond, Va; Salt Lake City; St. Louis;
San Juan, PR; Washington, DC; West

1152

Haven, Conn: and West Roxbury, Mass.

Biostatisticians: Russell B. Tewksbury,
ScD, and Lawrence W. Shaw.

Central Oftice Coordinator: Harold W.
Schnaper, MD. i ,

Consultants: Jacques Genest, MD; Ray
W. Gilford, dr, MID; Walter M. Kirken-
dall, MD; Louis Lasagna, 31D; David W.
Richardson, MD; and Robert W. Wilkins,
MD.

The special medications used in this in-

vestigation were prepared by William E. -

Wagner, MD, of Ciba Pharmaceutical Co.,
Summit, Nd.

References

1. Effects of treatment on morbidity in
hypertension: Results in patients with
diastolic blood pressures -averaging 115
through 129 mm Hg. Veterans Administra-
tion Cooperative Study Group on Anti-
hypertensive Agents. JAJA  202:1028-
103-£, 1967.

2. Hamilton M: Selection of patients for
antihypertensive therapy, in Gross F (ed):
Antihypertensive Therapy: Principles and
Practice, an International Symposium.

' New York, Springer-Verlag Inc, 1966, pp |

195-211. :

3. Wolf FW, Lindeman RD: Effects of
treatment in hypertension: Results of a
controlled study. J Chronic Dis 19:227-240,
1955.

4, Relman AS: Comment on who needs
drugs for hypertension in Ingelfinger FJ;
Relman AS; Finland M (eds): Controversy
tn Internal Medicine. Philadelphia, W B
Saunders Co, 1986, pp 101-102.

5. Freis ED: Organization of a long-
term multiclinic therapeuiic trial on hyper-
tension, in Gross F (ed): Antihypertensive
Therapy: Principles and Practice, an Inter-
national Symposium, New York, Springer-
Verlag Inc, 1966, pp 345-354.

6. A double-blind control study of anti-
hypertensive agents: I. Comparative effec-
tiveness of reserpine and hydralazine, and
three ganglionic blocking agents, Veterans
Administration Cooperative Study Group
on Antihypertensive Agents. Arch Intern
fed 106:81-96, 1960.

Assessable Events

Abbreviated definitions of terminat-
ing events (class A and treatment fail-
ures) and nonterminating (class B)
events.

Class A Events

1. Striate hemorrhages in more than
one retinal quadrant or cotton wool
exudates or papilledema.

2. Cerebral or subarachnoid hemor-
rhage.

3. Dissecting aortic aneurysm.

4. Inability to control congestive
heart failure without using antihyper-
tensive agents. ;

5. Elevation of blood urea nitrogen
level (BUN) by more than 50% of pre-
vious level and exceeding 59 mg/100 ce.

JAMA, Aug 17, 1970 © Vol 213, No 7

6. Acute hypertensive encephalopa-
thy requiring hospitalization.

Treatment Failures

1. Diastolic blood pressure exceed-
ing 124 mm He on each of three sue-
cessive visits and persisting for three
weeks or longer.

2. Assessable organic complications
not fulfilling criteria for class A events
but of sufficient severity to require dis-
continuation of protocol regimen.

Class B Events

Cardiac

1. Myocardial infarction document-
ed by characteristic electrocardiogram
or serum enzyme changes.

2. Congestive heart failure control-
lable by routine therapy other than
antihypertensive agents including digi-
talis, restricted activity, low salt diet,
and intermittent diuretics.

8. Atrial fibrillation or fluiter or ven-
tricular tachycardia without evidence
of quinidine or digitalis intoxication.

4, Heart-block such as bundle-
branch block, second or third degree
heart-block or first degree heart-block
with P-R interval of 0.28 seconds or
more.

5. Left ventricular enlargement by
ECG or roentgenogram.

6. Pulmonary embolism or infarc-
tion.

Central Nervous System

1. Cerebrovascular thrombosis or
embolism.

2. Transient ischemic attacks with
objective neurological changes during
the attack.

Aorta
1. Arteriosclerotic aneurysm.

Renal

1. Doubling of BUN (but to below
60 mg/100 cc) or creatinine levels to
values above normal limits not due to
primary renal disease.

2. Proteinuria (2-+ or more in three
or more specimens) in absence of con-
gestive heart failure, primary renal dis-
ease, or lower urinary tract disease.

3. Persistent hematuria (> 5 cells
per high power field centrifuged sedi-
ment) not due to primary renal ‘or
lower urinary tract diseases.

Morbidity in Hypertension