Reprinted From The Journal of the American Medical Association
         December 17, 1967 Volume 202
    Copyright 7967, American Medical Association

Effects of Treatment on
Morbidity in Hypertension

    Results in Patients With Diastolic Blood Pressures
      Averaging 115 Through 129 mm Hg
Veterans Administration Cooperative Study Group on Antihypertensive Agents

A group of 143 male hypertensive patients with di-
astolic blood pressures (at the clinic) averaging between
115 and 129 mm Hg were randomly assigned to either
active (hydrochlorothiazide plus reserpine plus hydrala-
zine hydrochloride) or placebo treatment. Twenty-seven
severe, complicating events developed in the placebo-
treated patients as compared to two in the active group.
Four deaths occurred in the placebo-treated group and
none in the actively treated patients. Other complications
in the placebo group included grade 3 or 4 hypertensive
retinopathy, congestive heart failure, increasing azotemia,
cerebrovascular thrombosis, transient ischemic attacks,
cerebral hemorrhage, myocardial infarction, and severely
elevated blood pressure. Severe complications in the
active-treatment group were one cerebrovascular throm-
bosis and one case of multiple drug toxicity. Male pa-
tients with diastolic blood pressures averaging 115 mm
Hg or above represent a high-risk group in which antihy-
pertensive therapy exerts a significant beneficial effect.

T he value of antihypertensive drug treatment in
  malignant hypertension has been amply dem-
onstrated."" However, its effectiveness in preverit-
ing morbidity and mortality in less severe forms of
hypertension has been disputed.`." Adequately con-
trolled, prospective studies are needed to evaluate
this question in patients with essential hyperten-
sion.' An investigation of this type was initiated b.y
the Veterans Administration Cooperative Study
Group on Antihypertensive Agents in 1963. The
design of the study, including the precautions em-
ployed to maintain adherence to protocol and
avoidance of dropouts, has been described in a pre-
vious communication.`" The present report is con-
cerned with the results obtained in the patients

For complete list of participants, see page 1033.
Reprint requested to 50 Irving St NW, Washington, DC 20422
(Dr. Edward I>. Freis).

116

without signs of accelerated hypertension at admis-
sion whose diastolic blood pressures prior to treat-
ment averaged 115 through 129 mm Hg.

Plan of Investigation

All patients were hospitalized for the initial work-
up. Male patients whose diastolic blood pressures
from the fourth through the sixth day of hospital-
ization averaged 90 through 129 mm Hg without
treatment were considered for admission to the
prerandomization trial period.

Severity was evaluated in five categories. These
were the average diastolic blood pressure during
hospitalization and the degree of clinically detect-
able hypertensive damage in the following four tar-
get organs: the optic fundi, the brain, heart, and
kidneys. Severity of damage in each category was
graded on a scale from 0 (no detectable abnormal-
ity) to 4 (most severe changes). The criteria used
for grading severity have been described in detail
elsewhere." After doubling the scores for the aver-
age diastolic blood pressure and the severity of
damage to the optic fundi, the scores obtained in
each category were summed to obtain a total sever-
ity index. Patients with total scores of 2 through 7
were classified as mild, 8 through 15 as moderate,
and 16 or above as severe, the latter being excluded
from the trial.

Also excluded from the study were patients with
surgically curable hypertension, uremia, and con-
comitant fatal diseases such as carcinoma. Patients
with hemorrhages, exudates, or papilledema in the
optic fundi, history of cerebral or subarachnoid hem-
orrhage, dissecting aneurysm, or congestive heart
failure resistant to digitalis and mercurial diuretics
were excluded. Additional exclusions included pa-
tients who wished to return to the care of their
private physicians, those who for geographical or

JAMA, Dee 11, 1967 o Vol202, No 11


MORBIDITY IN  HYPERTENSION                            1029

other reasons would be unable to attend clinic regu-
larly, and patients of dubious reliability such as
alcoholics, vagrants, and poorly motivated patients.

Table l.-Background of Randomized Patients

Prerandomization Trial Period.-Following dis-
charge from the hospital, the patients entered a
prerandomization trial period of two to four
months' duration. They received two placebos,
known to the physician but not to the patient, and
were seen in the clinic at monthly intervals.

Characteristic

          NCL
No. Placebo
Treated  pv:!J

Riboflavin (5 mg) was incorporated into one of
the placebos. Riboflavin produces a yellow fluores-
cence of the urine when the latter is viewed under
ultraviolet light. At each visit, a urine specimen was
examined for fluorescence. Patients were required
to return all bottles of medication, at which time
the tablets were counted to assess the patient's
reliability. To qualify for admission to the study,
the patients were required to have no "violations"
on two successive clinic visits. A violation consisted
either of failure to appear at the regularly scheduled
clinic appointment, or failure of the urine to ex-
hibit fluorescence, or a tablet count (of either of the
two types of placebos) which ws outside the ac-
ceptable range. The upper limit of the acceptable
range was defined as the return of no more than a
10% excess of the calculated number of tablets re-
maining if all doses had been taken as prescribed,
while the lower limit was a return of five tablets less
than the same calculated number. Nearly one half
of the patients accepted into the trial period were
excluded prior to randomization because of failure
to pass the above tests of reliability.

Total randomized
White
N&!g;rCl
Family history of hypertension
NO"2
Present
Unkncwn
Cardiac symptoms
Non.2
Present
Heart size by roentgenogram
Ungerleider normal
Ungerleider enlarged
Electrocardiogram
Left ventricular hypertrophy absent
Left ventricular hypertrophy present
Prior cardiovascular thrombosis
Occipital headaches
Diabetes absent
Diabetes present

70       73
35       31
35       42

19       23
48       49
3        1

48       52
22       21

39       44
31       29

48       49
22       24
5        6
12        10
65       65
5        a

Table 2.-Measurement Data

       Characteristic
Age (yr)
Height (in)
Weight (lb)
Duratlo" known
hypertension (yr)
Average hospital diastolic
pressure (mm Hg)
Average clinic systolic (mm Hg)
Average clinic diastolic (mm Hg)
Severity grades (0.4)*'
Fundi (hvaertensive)
Fundi (&erotic)
Cardiac
Central nervous system
Re"al
Blood glucose, fasting (mg/lOO cc)
Blood glucose, 2.hr postprandial
Cholesterol (mg/lOO cc)

Placebo
----\ /
Mean SD
51.4 10.8
69    2.6

182.9 34.5

5.4   4.4

105.8   a.4

  Active
__;\
Mean  SD
50    a.7
68.7   2.9
185.2  36.7

5.3   4.7

186.8 17.2
121    4.7

106.5   a.4
185.6 15.4
121.2 5

1.3   . . .
1.4   . . .
1    . . .

Also excluded were patients who during the trial
period exhibited diastolic blood pressures (while in
the sitting position) averaging below 90 or abovt
129 mm Hg. Thus, the final decision to accept the
patient into the study was based on both reliability
and the Ieve of diastolic blood pressure determined
in the clinic during the trial period.

1.2   . . .
1.3   .  .
1.2   . . .
0.4   .
0.5   .
96.8  20.6

0.3   . . .
0.3   . . .
97.7 la.9

ii8   41.5     116.1  54.3
251.3  59.5    242   51.5

*Detailed criteria for grades 0 through 4 are given in reference 11.

Table S.-Trends of Diastolic Blood Pressure

Placebo

Postrandomization Period.-At the time of ran-
domization, a sealed envelope was opened which
assigned the patient to one of two possible regi-
mens-active antihypertensive medications or their
placebos. A table of random numbers was utilized
by the statistician in determining the assignments.
Patients classified by severity scores as having mild
hypertension were randomized in a separate strati-
fication from those with moderate hypertension.
The double-blind technique was employed by uti-
lizing a series of complex code numbers to disguise
the identity of the randomized treatments and by
making active drugs and placebos identical in ap-
pearance. It is realized, however, that blood pres-
sure levels and side effects made the maintenance
of such a double-blind study difficult and imperfect.

--

   Time of      No. Patients
Observation     Observed"
Prerandomization      70
At 4 months         57
  a              50
12             44
16             33
20             27
24              23

Average '
Diastolic,
mm Hg
121
118.5
120.3
i 18.8
118.5
115.2
119.7

     Active
----,
         Average
No. Patients Diastolic,
Observed   mm Hg
   73      121.2
   68       93.1
   64       92.2
   58       91.6
   47       92.1
   40       89.4
   32       91.5

&The decline I" the number of patients observed is due primarily
to the fact that patients were admitted over a 2%year period. Hence.
many were not in the study long enough to be observed at the longer
time periods.

The active drugs were incorporated in the two
tablets as follows: tablet A contained 50 mg hydro-
chlorothiazide plus 0.1 mg reserpine, and tablet B
contained hydralazine hydrochloride. Tablet B was
available in two strengths, 25 and 50 mg. Placebos
were made up to correspond with each tablet of the
active drugs.

Treatment was begun with either tablet A, one
twice daily, plus the 25-mg t.ablet B, one tablet
three times daily, or else with the placebos of both
of these tablets. At the next visit, tablet B was
increased to the 50-mg strength. Thus, the regular
maintenance daily dose to patients randomized to
the active regimen was 100 mg of hydrochlorothia-
zide, 0.2 mg of reserpine, and 150 mg of hydrala-
zine hydrochloride. However, if there were hypo-
tensive reactions or other severe side effects, doses
could be reduced to a tolerable level.

In order to further minimize losses due to drug

JAMA, Dee 11, 1967 o Vol 202, No 11

117


1030                            MORBIDITY IN HYPERTENSION

                                    IO

       CHANGI IN sY*ToLI` BLOOD PRESSURI ^ mm M                CH*NCf IH OIISToc1C BLCOD PRlSsURt ml n9

Changes in systolic (left) and diastolic blood pressure (right) after four months of treat-
ment in 57 oatients eiven Dlacebos (above) and 68 Datients treated with hydrochloro-

thiazide plus' reserpine plus'hydralazine (below).

.

group have since been
given active treatment.
The total number of
high-risk patients ran-
domized was 143. Of this
total, 70 received pla-
cebos,  and 73 received
active  antihypertensive
drugs during the random-
ization trial. Their aver-
age age was 51 years with
a range of 30 to 73 years.
The average weight was
83.5 kg (184 lb). Seven-
ty-seven patients were
Negroes and 66 whites.
There were no significant
differences with regard to
age, weight, duration of
known hypertension, or
family history of hyper-
tension, between the pla-
cebo- and active-treat-
ment groups (Tables 1

toxicity, two special A tablets were available on
request. One contained hydrochlorothiazide with-
out reserpine for patients becoming depressed or
having active peptic ulcer or other reserpine-associ-
ated severe side effects. The other contained reser-
pine without hydrochlorothiazide for toxicity asso-
ciated with the latter, such as hyperglycemia or
acute gout. These special A tablets were available
in both active and placebo forms.

The patients visited the clinic at monthly inter-
vals for the first two months following randomiza-
tion and at bimonthly intervals henceforth.
Additional interim visits were scheduled if needed.
Tablet counts were made at all clinic visits and
fluorescence tests of the urine were made at alter-
nate visits. Annual examinations included complete
physical examination, roentgenogram of the chest,
electrocardiogram, blood chemistry, and renal func-
tion tests. General medical care measures and
symptomatic treatment, with the exception of
known active antihypertensive drugs, were em-
ployed in all patients.

Characteristics of Patients

Only the patients whose diastolic blood pressures
averaged 115 to 129 mm Hg during the last two
prerandomization clinic visits are included in the
present report. For this high-risk group the study
was ended in May 1967. The patients with lower
prerandomization diastolic readings are continuing
in the study and will be reported on later. The
study was terminated in the 115 mm Hg and above
group at, an earlier date than expected when it
became apparent that the risk rate increased sharp-
ly at these levels of diastolic blood pressure and
that the clinical course of such patients appeared
to be favorably influenced by antihypertensive drug
treatment. Therefore, all patients in this high-risk

and 2). There were more Negro and diabetic pa-
tients in the actively treated than in the placebo
group, but the differences were not significant. The
various indices of severity such as hospital and
clinic blood pressure; funduscopic, cardiac, central
nervous system, and renal abnormalities were es-
sentially similar in the two groups.
The 143 patients were admitted into the study
from April 1964 to December 1966. Observations
on all these patients ended in May 1967. Thus,
there is considerable variation in the duration of
observation (Table 3). Nevertheless, 38ye of the
patients were observed for two years or more. The
duration of the postrandomization phase of the
study averaged 15.7 months for the placebo-treated
patients and 20.7 for the active-drug group. Twen-
ty-six of the placebo patients were in the postran-
domization period of the study for less than one
year as compared to 15 of the active group. Twen-
ty-three placebo-treated patients exceeded a two-
year period of postrandomization follow-up as
opposed to 32 of the actively treated patients. The
briefer period of follow-up of the patients in the
placebo group was caused by the larger number
of terminating events which developed in this
group.

Modification in Treatm.ent Regimens.-Of the 73

   Table 4.-Incidence of Mortality and Morbidity

                     Placebo-Treated Actively Treated
                         Patients       Patients
Deaths                        4           0
Class A events                   10           0

Subtotal                     14           0
Other treatment failures             7           1

  Total terminating events         21           1
Class 6 events
(nonterminattng)                 6           1

  Total                      27           2

118                                                   JAMA. Dee 11, 1967 o Vol 202. Ng 11

.


MORBIDITY IN HYPERTENSION                           1031

patients randomized to active antihypertensive
drugs, 45 received the standard maintenance doses
of hydrochlorothiazide, 50 mg plus reserpine 0.1 mg
twice daily, and hydralazine hydrochloride, 50 mg
three times daily, throughout their participation in
the study. Dosages were reduced in the remaining
patients because of low blood pressure levels with
the standard regimen or because of side effects
such as severe headache or weakness. There were
no cases of systemic lupus erythematosus. Two
patients were transferred to the special A tablets,
one because of depression and the other because
of a hyperglycemic reaction.

Sixty-six of the 70 placebo-treated patients re-
ceived standard maintenance dosages. Reduced
doses of tablet B were given to two patients be-
cause of presumed hydralazine-induced side effects.
Special tablet A placebos were substituted in two
other patients because of depression.

Dropouts.-The total number of dropouts was
12 or 8.4%. Nine occurred during the first two
months following randomization. Seven had been
randomized to placebos and fivt: to active drugs.
Thus, the dropout rate was small and was approxi-
mately equally divided between the active- and
placebo-treated patients.

Changes in Blood Pressure.-Systolic and dia-
stolic blood pressures fell promptly and significant-
ly in the actively treated patients and remained at
these reduced levels throughout the trial. The pro-

spective trends for diastolic blood pressure recorded
with the patients in the sitting position are shown
in Table 5. After 24 months of active treatment.
the reduction from prerandomization levels of clinic
blood pressure averages 43 mm Hg systolic and
29.7 mm Hg diastolic. By contrast,, the placebo-
treated patients showed no significant changes in
average blood pressure levels following random-
ization (Table 3). The distribution oi: individual
changes are shown in the Figure. There is a marked
shift to the left into the "decrease" zone for th<l
treated patients as compared with the placebo
group. This marked shift is evident for both sys-
tolic and diastolic changes. Also apparent is the
wide variation in individual responses.

Assessable Morbid Events

As shown in Table 4 assessable morbid events
occurred in 27 placebo-treated versus two activel)
treated patients. Using the chi-square test, and
assuming that the treatment has no effect, this
result is statistically significant at the P<.OOl
level. If the possible effect of the 12 patient drop-
outs is considered and the most adverse assump-
tion made, namely, that the seven placebo-treated
patients would have had no countable event if the!.
had stayed in the study and the five patients tak-
ing active drugs each would have had a countable
event (a most unlikely occurrence!), then the
score would have been 27 to 7. But even this con-

Table 5.-Terminating Events

No.
Placebo

Rat.

Prerandomizod     Time in     Class
Blood Pressure,   Randomized     of
  mm HR     Trial, Months   Events"

Nature of Terminating Event

  1     57      W      185/126        16       A. D     Dissecting aortic aneurysm
~--
  2     59      W    2147120         6       A. D     Dissecting aortic aneurysm

  3     55      N       177/117         2       8. D     Sudden death
            ~-
  4     65      W      230/127         2       B, D     Ruptured abdominal aorlic aneurysm

  5 65      N       211/121         4 A      Cerebral hemorrhage. bloody xanthrochromic spinal fluid

  6 49      W      192/123        24 A      Fundi striate hemorrhage and papilledema

  7 69      W      225/123         12 A       Fundi striate hemorrhage and papilledema
-
  8 53      W      180/122         2 A      Fundi hemorrhage
                                                     striate and sort exudates
-                --.-
  9 68      W      214/117        12 A       Fund1 striate hemorrhage and sott exudates
10-- 37      N       211/122      -------.-__ 8 A -.-- Fundi bilateral ---. -~
                                                         striate hemorrhage

  11     45      N       zoo/121         2       A      Fundi bilateral striate hemorrhage and congestive heart fallurc
-                                                            ____-.___.-.
  12 50      W      180/118         17 A       Fundi bilateral striate hemorrhage and congestive heart fadure
                                 ~--___________~
  13 67      N       215/120         2 A      Elevated 1-I to 71 mg/lOO cc
                                                       BUN
14- 55     W      186/125     ___-. 5 A      Rehospitalization. basal diastolic 136 mm
                                                             pressure average w
                                                              ~--__~       ___-
  15 46      W      17Of 125        10 TF      Fundi sin- #oft exudate
                           ___.-
  16 53      W      196/128        24 TF     Rehospitakzaw. basal diastolic pressure average 128 mm w
                             -         --
  17 69      W      188/116        24 TF     Fundi hemorrhage and exudate but also diabetic
                           -.          I -,       -
  18 44      N       193/127        16 TF     Rehospitakation. basal diastolic pressure average 100 mm m
~____                  ___.-
  19 68      W      197/121         26       TF      Fundi hemorrhage and soft exudates plus BUN level 70 mg/100 Q
                                                   but also diabetic
                  -        -llll_l__.l
  20 34      N       165/117        13 TF      Creatinins level increase 1.1 to 3 and BUN level 18 to 28 mg/lOb cc
                                              in young patient               ______---___-
  21 60      N       205/115         4 TF
                                          B.      Cerebrovswular accident, paralysis, and Invalidism
          -                                 -
Active
  22 47      W      167/118         7       TF      Hyperglycemia. depressIon
`A := class A event. D-m-- death. TF :. treatment failure. and B  class B event

JAMA, Dee Il. 1967 o Vol 202 No 11                                                        119


1032                          MORBIDITY IN HYPERTENSION

Table 6.-Class B (Nonterminating) Events

                   Time in Trial. mo
              Preran- <-- ; __-
P$$n,     d;", "H; Before   After      Nature
     AW  Race         Events Events    of Events
1     48    W   182/117    4     24   Myocardial
                                Infarction
2    45    N   l-55/115 18     10   Myocardial
                                infarction
3    46 w   175/121 11     9   Congestlvs
                                heart failure
4     68 W   180/120 20     9   Congestive
                                heart failure
5    59 N   217/119    2     4   Cerebrovascular
                                thrombosis
6    4s    W   181/120    5t    15   Transient
                                ischemic attacks
7    66 w   188/124    1     26   Cerebrovascular
                                thrombosis

Patients 1 through 6 received placebos; patient 7 received actwe
therapy

iSubsequent lschemlc atticks at 13 and 15 months after random.
1zat1on.

servative hypothetical "result" is statistically sig-
nificant at the .OOl level.

When deaths and class A hypertensive compli-
cations are combined, such events occurred in 14
placebo-treated patients as compared to none in
the group receiving antihypertensive drugs. The
total number of patients with terminating events,
which includes deaths, class A events, and other
treatment failures, was 21 in the placebo group
versus one in the actively treated group.

Terminating Euents in Placebo-Treated Patients.
-The 21 placebo-treated patients having compli-
cations which required discontinuation of the pro-
tocol assigned treatment are listed in Table 5. The
average age of these patients was 55.2 years, which
was four years older than the average age of the
total randomized population. Thirteen of the ter-
minating events occurred in whites and eight in
Negroes. The average clinic blood pressure of the
21 patients prior to randomization was 196.9/
121.5 mm Hg, a slightly higher systolic average
than that found in the entire group at risk.

The shortest period from randomization to ter-
minating event was 2 months, the longest 26
months and the average 11 months. Terminating
events were well distributed among the 15 partici-
pating hospitals, 14 contributing one or more
events.

1. There were four deaths, all of which were
related to cardiovascular diseases. Dissecting aortic
aneurysm occurred in two, ruptured abdominal
aneurysm in one, and sudden death at home in
one (Table 5). No autopsy was obtained in the
latter instance. The diagnosis of dissecting aortic
aneurysm was verified either at surgical exploration
or at autopsy. The diagnosis of ruptured abdominal
aortic aneurysm with fatal hemorrhage was veri-
fied at autopsy.

2. Class A events were those hypertensive com-
plications as defined in the protocol which re-
quired treatment with known active agents and
permanent removal from protocol assigned ther-
apy. They included the following: funduscopic evi-
dence of grade 3 or 4 hypertensive retinopathy
(multiple striate hemorrhages or soft exudates in

120

more than one quadrant, or bilateral papilledema),
doubling of blood urea nitrogen (BUN) to levels
above 60 mg/lOO cc; dissecting aortic aneurysm;
cerebrovascular hemorrhage as opposed to throm-
bosis; subarachnoid hemorrhage; congestive heart
failure persisting despite digitalis and mercurial
diuretics; and elevation of diastolic blood pressures
to 140 mm Hg or higher on three repeated visits
and average rehospitalization diastolic pressure to
130 mm Hg or higher.

The case histories of patients having terminating
events were reviewed by a panel of four members
consisting of two participants and two consultants.
The panel determined in each case whether the
criteria for a class A event as defined in the pro-
tocol were fulfilled. Terminating events which did
not fully meet these criteria were classified as treat-
ment failures as described below.

There were ten class A events in which the pa-
tients lived. Two of these were considered irre-
versible, and eight proved to be reversible following
active antihypertensive treatment. One of the irre-
versible events was a cerebrovascular hemorrhage
as evidenced by hemiplegia, stiff neck, and bloody
and xanthrochromic spinal fluid. The other occurred
in an azotemic patient whose renal function de-
teriorated rapidly.

Seven of the eight reversible class A events in-
cluded grade 3 or 4 changes in the optic fundi. In
two, striate hemorrhages and papilledema were
present. In two others, multiple bilateral striate
hemorrhages and cotton wool exudates were visual-
ized; in two additional patients bilateral striate
hemorrhages and resistant congestive heart failure
were present simultaneously; and in the seventh
patient, striate hemorrhages were present bilateral-
ly but without exudates (Table 5). The remaining
reversible class A event was associated with severe-
ly elevated blood pressure, the diastolic pressure
during rehospitalization averaging 136 mm Hg.

3. Treatment failures were those events which
did not meet the specific criteria for any one class A
event as defined in the protocol. Nevertheless, be-
cause the complications were considered to be life
threatening, protocol drugs were removed and
treatment instituted with known antihypertensive
agents. Seven of the terminated placebo-treated
patients were classified as treatment failures. In
two, multiple striate hemorrhages and soft exudates
were seen in the optic fundi, but these patients
also had diabetes mellitus. That the retinopathy
probably was primarily associated with hyperten-
sion is suggested by the fact that, in both instances,
the changes in the fundi cleared within two months
after initiation of treatment with known antihyper-
tensive agents. In a third nondiabetic patient only
one cotton wool exudate and no striate hemor-
rhages were observed.

Two patients were classified as treatment failures
because the diastolic blood pressures in the clinic
were frequently recorded above 140 mm Hg but
averaged below 130 mm Hg during rehospitaliza-

JAMA, Dee 11. 1967 o Vol202, No 11


MORBIDITY IN HYPERTENSION                           1033

tion. Additionally, a 34year-old patient was re-   of severe hypertensive complications occurring in
moved from protocol therapy because previously   placebo-treated patients over a two-year period of
normal levels of BUN and serum creatinine in-   observation was reported by Wolff and Lincleman."
creased to 28 and 3 mg/lOO cc respectively at the  They attributed this in part to the fact that their
time of annual examination. The final treatment   clinic populaticn was primarily a lower-income
failure was a cerebrovascular accident diagnosed   Negro group. IIowever, in the present report more
as thrombosis rather than hemorrhage, but which  whites than Negroes had hypertensive complica-
resulted in complete invalidism and inability to   tions despite equal numbers of each race random-
return to the clinic.                  ized to placebos.

Terminating Event in Actively Treated Pa-
tients.-The single terminating events in the 73
patients who received active drugs occurred in a
patient with multiple drug toxicity. Five months
before terminat,ion the patient was found to have
a blood glucose level of 450 mg/lOO cc and a serum
potassium value of 2.5 mEq/liter. Both abnor-
malities disappeared when the special A tablet
containing only reserpine was substituted. How-
ever, five months later he had a mental depres-
sion.

Nonterminating (Class B) Morbid Events.-
Class B events (Table 6), as opposed to class A
events, were those which did not require permanent
discontinuation of protocol treatments. Patients
with developing B events could be treated with
known antihypertensive agents for as long as six
months, after which, protocol treatment had to be
reinstituted. Class B events included organic com-
plications associated with atherosclerosis, such as
cerebrovascular thrombosis  (as constrasted to
hemorrhage which was considered a class A event)
or myocardial infarction. Congestive heart failure
which responded to routine therapy with digitalis
or mercurials and did not require antihypertensive
agents also was classified as a B event.

The majority of prior reports on the effects of
antihypertensive drug treatment in essential hyper-
tension have not contained randomized control
groups. Hodge et al"' utilized as their control the
patients who refused to undertake treatment. They
found a 50% reduction in mortality in the treated
group over a period of 1 to 8 years of observation
in patients with grade 2 hypertensive retinopathy.
Leishman's untreated patients were those who de-
clined or who were considered unsuitable for sym-
pathectomy.' ' He found morbidity and mortality
reduced by two thirds in the treated group. Hood
and his associates'i using a nonrandomized un-
treated control group concluded that mortality was
considerably reduced by treatment in essential
hypertension.

Seven patients, in addition to those described
above under terminating events, had class B com-
plications during the course of the trial (Table 6).
These events occurred in six placebo-treated pa-
tients and in one actively treated. In the placebo-
treated group myocardial infarction accompanied
by diagnostic electrocardiographic and serum trans-
aminase changes occurred in two patients. Con-
gestive heart failure occurred in two others, the
symptoms and signs of which cleared following
treatment with digitalis. Cerebrovascular throm-
bosis was diagnosed in the fifth case, and the sixth
had repeated transient episodes of left-sided hemi-
paresis. The single class B event in the active-
treatment group occurred in a 68-year-old man
who had hypotensive levels of blood pressure ac-
companied by a left-sided hemiparesis.

A prospective, randomized control study was
carried out by Wolff and Lindeman in 87 patients."
Twelve percent defaulted. Over a two-year period
the incidence or morbid events in the treated pa-
tients was one third of that observed in the place-
bo group. Hamilton'" alternately assigned 61 pa.
tients with clinic diastolic blood pressures averaging
110 mm Hg or higher to active treatment and
placebo. Thirty were treated with antihypertensive
agents and 31 were not. Over an eight-year period
of follow-up, 16 of the untreated patients had com-
plications, primarily strokes? as compared to five
of the treated group. Of the latter, four exhibited
poor blood pressure control. If they are excluded.
only one of the treated patients had a severe com-
plication.

The evidence provided by these earlier studies
plus the present report leaves little doubt as to
the value of antihypertensive drug therapy in es-
sential hypertension associated with clinic diastolic
blood pressures of 115 mm Hg or more. It appears
that the majority of such patients can be managed
satisfactorily with combinations of thiazides, reser-
pine, and hydralazine," none of which require more
than minor dosage adjustments.

Comment

Although essential hypertension is generally re-
garded as a slowly progressive disorder, such did
not appear to be the case in these male patients
with clinic diastolic blood pressures of 115 mm Hg
or higher. An extremely high incidence of severe
complications, especially early funduscopic mani-
festations of accelerated hypertension occurred in
the placebo-treated group. A similar high incidence

Participants

JAMA, Dee 11, 1967 o Vol 202. No 11

121


1034                            MORBIDITY IN HYPERTENSION

Overbeck, MD; Eliseo C. Perez-Stable, MD; Eli A. Ramirez, MD;     Biostatisticians: Russell B. Tewksbury, ScD, and Lawrence W.
and 6. H. Thomas, MD.                                Shaw.
Participating Veterans Administration Hospitals: Bronx;     Consultants and Associates: Walter M. Kirkendall, MD; David
Brooklyn; Dearborn, Mich; Iowa City; Jackson, Miss; Memphis;   W Richardson, MD; and Louis Lasagna, MD.
Nashville; Oklahoma City; Pittsburgh; Richmond, Va; Salt Lake    The special medications used in this investigation were pre-
City; San Juan. PR; Washington. DC; West Haven. Conn: and   pared by William E. Wagner, MD, of Ciba Pharmaceutical Co.,
West Roxbury. Mass.                                Summit. NJ.

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JAMA. Dee 11, 1967 . Vol 202, No 11