Reprinted from the Journal of the American Medical Association

August 17, 1970 Volume 213

Copyright 1970, American Medical! Association

Effects of Treatment on
Morbidity in Hypertension

IT. 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 114 mm Hg were
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 group. Nineteen deaths related to hypertension or
atherosclerosis occurred in the control group and 8 in the
actively treated group. In addition to morbid events, 20
control patients developed persistent diastolic levels of 125
mm Hg or higher. Treatment was more effective in prevent-
ing congestive heart failure and stroke than in preventing the
complications of coronary artery disease. The degree of
benefit was related to the level of prerandomization

blood pressure.

journal' the Veterans Admin-
Study

I a previous publication in this

istration Cooperative

 

For complete list 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 little 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 380 patients with mild or
moderate hypertension whose initial

Morbidtty in Mypertension 1143
diastolic blood pressure averaged
90 through 114 mm Hg.

Pian 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
int 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
1969 and are the subject of the
present communication.

The experimental design has been
described in previous reports.'*
Initially all patients were hospital-
ized 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

1144

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 reports.’’> 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 wa
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

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 Hg 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 effects oc-
curred. Patients in the control 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 aver-
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 terminated
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 control 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 1.2 mm Hg in the control pa-
tients and a fall of 17.4 mm Hg in
the treated group during 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 194 186 380.

Negro “B1 42 76 41 157

Other* ‘ 114 58 109 59 223
Heart size by roentgenogram

Ungerleider enlarged 42 22 53 29 95
Electrocardiogram

Left ventricular hypertrophy 32 16 30 16 62

 

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

trol group and two in the treated group.

 

Table 2.—Measurement Data Prior to Randomization

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Control Group Treatment Group
Characteristic Mean Mean
Age (yr) 52.0 50.5
Age (median, yr) 49.2 48.1
Height, cm (ft, in) 175.3 (5, 9) 172.7 (5, 8)
Weight, kg (Ib) 82.0 (180.9) 79.8 (176.1)
Duration known hypertension (yr) 4.4 4.6
Average hospital diastolic pressure (mm Hg) 101.3 100.2
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
Total severity score* 6.7 6.8
Renal score (0-4) 0.2 0.2
Cardiac score (0-4) 0.8 0.9
CNS? score (0-4) 0.3 0.3
Serum creatinine (mg/100 cc) 1.26 1,24
BUN (mg/100 cc) 15.6 16.2
Serum potassium (mEq/liter) 44 44
PSP¢ excretion (% in 2 hr) 58.8 60.0
Fasting blood glucose (mg/100 cc) 96.5 100.4
Cholesterol (mg/100 cc) 250.1 245.0
Uric acid (mg/100 cc) 6.3 6.0

 

 

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

tCNS signifies central nervous system.
PSP signifies phenolsu!fonphthalein.

the left into the “decrease” zone for
the treated patients as compared to
the control group. Also apparent is
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
and another of penicillin anaphy-

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 infiltrates in
the lungs. 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
 

 

  

 

x
La. — I
“ PLACEBOS “ PLACEBO
xf z 30
DECREASE i INCREASE DECREASE
Le |
2 by 2
10 r b 7
w Y Y e
~ z
St Y YY _| =
=< o a 0
a
% oOo
_ =
2 Lal
ws eo
oo
a ~ a
= 4 ACTIVE ORUGS a 4 ACTIVE DRUGS
a
oT 30
20 20
10 10
0 0

   

 

  

 

 

+16 4320 +48

 

 

 

-32 -16 0 +16 +32 +48

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.—Fifty-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
1 month to 49 months. Six patients
moved away from the area of the
clinic. Two were lost from follow-up
because of closure of one participat-
ing clinic. Four returned to the care
of their private physicians. Fifteen

1146

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-
lems 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

JAMA, Aug 17, 1970 ¢ Vol 213, No 7

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 con-
trol group and 22 in the treated
patients. Of this number 20 control
patients developed an increase in

Morbidity in Hypertension
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 preventing morbid
events,

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
11.8% 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 18.09% amongst
the controls and only 9 of 186 or
4.8% in the treated group (Table
3). 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-
EASE.—Twenty-seven patients died
of hypertensive or atherosclerotic
complications, 19 occurring in the

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

 

Table 3.—Summary of Assessable Events

 

 

 

 

 

 

 

 

Control Group Treated Group
e A—— To A. %
No. % No. % Effectiveness*
Terminating morbid eventst 35 18.0 9 4.8 73
Nonterminating B events 21 13
Total morbid events 56 28.9 22 11.8 a)
Terminated on account of
elevated blood pressure 20 0
Total assessable events 76 39.2 22 11.8 70
No. patients randomized 194 100.0 186 100.0
*See text.

tincludes 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 )
Dissecting aneurysm 1 0
Deaths due to class B events
Myocardial infarction 3 2
Sudden death 8 4
Cerebrovascular thrombosis 3 1
Ruptured atherosclerotic aneurysm 0 1
Total related deaths* 19 8

 

 

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

group (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

Treated
Group

Control
Group

 

Subtotal

Treatment failures
Cerebrovascular thrombosis, severe
Progressive azotemia

Fundi, one striate hemorrhage
and ? early papilledema

Fundi, one striate hemorrhage
and ? encephalopathy

Hypotension
Subtotal
Total

control group and 8 in the treated
patients (Table 4). Five deaths
associated 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

eh Ol eee eo

.
Ree Oo © OG e;ooo0d0

|
Axor

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 infarction 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
 

Table 6.—Nonterminating Class B Events

 

 

 

 

 

 

 

Control Treated

Type Group Group
CVA, thrombosis or TIA* 8 4
Congestive heart failuret 6 0
Myocardial infarction 2 5
Atrial fibrillation 2 3
Heart-block 1 1

Serum creatinine, persistent,

>2.0 mg/100 cc 1 0
Proteinuria, persistent, >1+ 1 0
21 13

 

 

Total

 

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

tack with objective neurological signs.

7Controfled by administration of digitalis and short-term diuretics.

 

Table 7.—Classification of Morbid Events by Diagnostic Categories

 

Total Events
A.

Terminating Events

 

 

 

 

 

 

 

 

Diagnosis Control Treated Control Treated
Cerebrovascular accident 20 5 12 1
Coronary artery disease 13 11 11 6
Congestive heart failure 11 0 5 0
“Accelerated” hypertension 4 0 4 0
Renal damage 3 0 1 0
Other 5 6 2 2

Total 56 22 35 9
death in the treated group was ure.” * ur we ~ associated with
caused by a rupture of an ather-  cerebrovascu’:  ccidents diagnosed

osclerotic aneurysm of the aorta.

Oruer 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
restriction, 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-
lopathy with accompanying neuro-
logical signs.

OTHER 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-

1148

clinically as tor mbosis rather than
hemorrhage but which resulted in
such severe inc::pacity that the pa-
tients were urable to attend the
clinic. Two additional control pa-
tients were removed from the study
because «* the appearance of a
single st: ate 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 neteworthy 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 @ Vol 213, No 7

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
13 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 of the
degree 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
 

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

 

 

 

 

 

 

 

 

Control Group Treated Group
. Patients With . Patients With
Prerandomization “Morbid Event” “Morbid Event”
Blood Pressure, Patients Patients ie
mm Hg Randomized No. % Randomized No. % Effectiveness
Systolic <165 98 15 15.3 108 10 9.3 40
Systolic 165-+- 96 41 42.7 738 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 75
Total 194 56 186 22
Table 9.—Incidence of Morbid Events With Respect to Age 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 15 15.2 102 7 69 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 (37/55).

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
Discnostic Catecories.—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 renal 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 patients 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 events 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 35% 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 effectiveness of treat-
ment being 64% in patients with
initial 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
TERMINATING MORBID EVENTS

—e-
—
e-——e

2 5
Years of Observation

ALL MORBID EVENTS

AC ee Meer tt)

Control group

e——*-—* Treated group

Control group

© Treated group

 

2. Estimated cumulative incidence of morbidity over
a five-year period as calculated by life-table method.
Terminating morbid events (top) and all morbid events (bottom).

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-
tiveness of treatment cannot be ac-
cepted with the same degree of
confidence as in the older patients.

RELATIONSHIP TO RaAce.—The in-

1150

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, 25.9% 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 effects

JAMA, Aug 17, 1970 © Vol 213, No 7

will be made in a subsequent com-
munication. The two patients lost
to protocol 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 regimen
will be considered.

Administration of either reserpine
or hydrochlorothiazide or 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 reser-
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
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 control
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 Hg.

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.

Because of the gradual progres-
sion of atherosclerosis, the negative
result with regard to prevention of
myocardial infarction and sudden
death 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 into the study.
Further trials are needed in a more
selected population to 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 benefit of treat-
ment was quickly manifested in the
latter series. Thirty-eight percent of
the control patients in that series
developed assessable events 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 Hg accelerated
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 effective in a
group of patients 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 the 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 Efson, MD; Edward D. Freis,
MD, Chairman; Rudolph E. Fremont, MD;
Michael A. Harris, MD; David Littman,
MD; Eli A. Ramirez, MD: and J. R.
Thomas, MD.

Other Members: Luis A. Arias, 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; Pittsburgh;
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 Office Coordinator: Harold W.
Schnaper, MD.

Consultants: Jacques Genest, MD; Ray
W. Gifford, Jr.. MD; Walter M. Kirken-
dall, MD; Louis Lasagna, MD; 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, NJ.

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-
hyperterisive Agents. JAMA 202:1028-
1084, 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
196-211.

3. Wolff FW, Lindeman RD: Effects of
treatment in hypertension: Results of a
controlled study. J Chronic Dis 19:227-240,
1966.

4. Relman AS: Comment on who needs
drugs for hypertension in Ingelfinger FJ;
Relman AS; Finland M (eds): Controversy
in Internal Medicine. Philadelphia, W B
Saunders Co, 1966, pp 101-102.

5. Freis ED: Organization of a long-
term multiclinic therapeutic 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
Med 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 cc.

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 Hg on each of three suc-
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.

3. Atrial fibrillation or flutter 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

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