SYSTEMIC HYPERTENSION

Efficacy of Nadolol Alone and Combined with
Bendroflumethiazide and Hydralazine for
     Systemic Hypertension

VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP
        ON ANTIHYPERTENSIVE AGENTS

Nadolol (N) titrated from 80 to 240 mg or ben-
droflumethiazide (B) 5 to 10 mg, or the combination
(Bi-N), were randomly assigned double-blind to 365
men with pretreatment diastolic blood pressures
(BP) of 95 to 114 mm Hg. After 12 weeks of treat-
ment, a diastolic BP of <90 mm Hg was achieved
in 49 % who received N, 46 % who received B and
85% who received B-t-N. With N, the diastolic BP
decreased more in whites than in blacks; with B, this
racial trend was reversed. Side effects were infre-

quent; the most common were impotence, lethargy,
weakness and postural dizziness, which occurred
more often with B than with N. Addition of hydrala-
Line, 25 to 100 mg twice daily, controlled diastolic
BP at a level of <90 mm Hg in approximately 60 %
of those previously uncontrolled. N, and especially
B-l-N, provided an efficacious once-daily treatment
for systemic hypertension, and addition of hydral-
azine was effective in most nonresponders.

(Am J Cardiol 1983;52:1230-1237)

Beta-adrenergic blocking agents differ with respect to
cardioselectivity, intrinsic sympathomimetic activity
and membrane-stabilizing effects.l Nadolol (N) does
not exhibit any of these properties,2J but it has 2 char-
acteristics that are important for the treatment of sys-
temic hypertension. The first is long duration of action.
This permits once-daily dosage with a consequent gain
in compliance. The second is that in contrast to other
beta-adrenergic blocking agents, nadolol is not associ-
ated with a decrease in renal blood flo~,~,~ a desirable
feature especially in patients with hypertension.

The present study assesses the relative effectiveness
of 3 regimens: N alone, bendroflumethiazide (B) alone6,7
and B+N combined. In addition, the effectiveness of
adding hydralazine was assessed in patients whose blood
pressure (BP) was not controlled with one or the other
of these regimens.

             Methods
Four hundred eighty men, aged 20 to 69 years, were evalu-
ated for randomization out of 809 patients screened, of whom
365 were eventually randomized (Fig. 1). The untreated sitting

From the Cooperative Studies Program, Medical Research Service of
the Veterans Administration. Supported by a grant from E. R. Squibb
& Sons, Inc. Princeton, New Jersey. Manuscript received June 6, 1983;
revised manuscript received August 26, 1983, accepted August 30,
1983.
Address for reprints: Edward D. Freis,-MD, Senior Medical Investi-
gator, Veterans Administration Medical Center, 50 Irving Street, N.W.,
Washington, D.C. 20422.

diastolic BP (Korotkoff phase V) had to be 95 to 114 mm Hg
inclusive. Patients were excluded who had major cardiovas-
cular complications, serious systemic diseases or who had
preexisting conditions that would interdict the use of the test
drugs (see Appendix A).

Prerandomization placebo period: The nature of the
study was explained to the patient and written informed
consent was obtained. In the patients who met the age and
diastolic BP criteria for entry and had no exclusion factors,
antihypertensive therapy, if any, was discontinued for at least
2 weeks up to a maximum of 8 weeks, depending on the type
of drug taken. A history was taken that included volunteered
complaints, and a physical examination was performed. The
following laboratory studies were obtained: a chest x-ray (if
not taken within the previous 3 months), an electrocardio-
gram, complete blood cell count, urinalysis, serum potassium
fasting blood glucose, uric acid, cholesterol, triglycerides,
creatine, alkaline phosphatase, serum glutamic oxaloacetic
transaminase, fluorescent antinuclear antibodies and serum
bilirubin.

Systolic and diastolic (Korotkoff, phase V) BP readings
were taken 3 times in the sitting position at each clinic visit
and once in the standing position. Readings were taken in the
right arm using a standard mercury sphygmomanometer. The
median of 3 determinations of BP with the patient sitting was
used for analysis. The patient qualified for randomization if
the median diastolic BP on 2 successive weekly visits was 95
to 114 mm Hg and if 80 to 110% of the prescribed number of
tablets had been taken as estimated by pill counts. A maxi-
mum of 4 weekly visits was allowed to fulfill these require-
ments. The patient was excluded from the study at any clinic
visit if the diastolic BP was >119 mm Hg. Patients were also

1230


December 1, 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 52

1231

                           Patients    Entering Pre-                            Completed
                          Screened    randomization   Randomized         B      Terminated    Study     % at CBP

                                              81 - 13 - 68' - 46%
FIGURE 1. Flow chart of phase A
showing numbers of patients screened,                                   ,

entering prerandomization and ran-                                      N
domized double-blind to the 3 regimens
of bendroflumethiazide, nadolol and the
combined drugs. Also shown are the   809 - 480 - 365      132 - 28 -  104 - 49%

number terminated, completing the trial
and the percentage controlled at dia-
stolic blood pressure <90 mm Hg.
Phase B (hydralazine) is not shown.        B . Bendroflumethiazide
                              N . Nadolol                   152 - 16 - 136
                            GBP . Goal Blood Pressure

`Includes one patient terminated at last clinic visit Phase A

terminated if the diastolic BP was <95 mm Hg or >114 mm
Hg on each of the 2 successive visits.

The patient was given 2 bottles that contained placebos and
was instructed to take 1 tablet daily from each. He also was
requested to return the bottle of remaining tablets to the clinic
each visit. A check list of known side effects associated with
the administered drugs was reviewed at each visit before as
well as after randomization.

One hundred fifteen patients were dropped during the
prerandomization phase: 62 because the diastolic BP was
below the acceptable range (<95 mm Hg) and 7 because the
diastolic BP was above the acceptable range (>114 mm Hg);
30 patients were noncompliant, of whom 20 failed to return
to the clinic; and 16 patients were dropped for miscellaneous
reasons.

Postrandomization period (phase A): Of the 365 patients
who were randomized into the study, 308 completed phase A.
Recruitment goals were met or exceeded in most of the clinics;
the hospital with the lowest number of randomizations
achieved 94% of its quota.

The study was a randomized, double-blind trial in which
patients were assigned to 1 or 3 regimens: B plus placebo of
N (81 patients), N plus placebo of B (132 patients) or B+N
(152 patients). The reason for the unequal randomization is
as follows: the patients eligible for entering phase B (addition
of hydralazine) were those whose diastolic BP failed to de-
crease to <90 mm Hg on N alone, B alone or the combination
of B+N. We estimated that the combination would be the
most effective in reducing BP and, therefore, would provide
fewer patients eligible to receive hydralazine. Consequently,
more patients were randomized to the 2-drug regimen so as
to provide approximately equal numbers of eligibles for entry
into phase B.

It was estimated that for phase A only, in order to provide
90% power and a type I error of alpha = 0.05/2 for the 2 com-
parisons, a sample size of 60 patients per group would be
needed. This was based on the assumption that 50% of pa-
tients receiving B or N and 80% receiving the combination
would attain the goal diastolic BP of <90 mm Hg. However,
larger sample sizes were chosen because of the need to provide
sufficient patients for entry into phase B. With an additional
allowance for dropouts the number of patients required for
randomization was estimated to be 350, or 50 patients per
hospital.

The patients were assigned to the 3 treatment groups using
simple randomization in a ratio of 3:5:6. The randomization
was blocked after every 14 patients within each hospital and
also across hospitals, i.e., each 2 consecutive patients across
7 hospitals equalled the block of 14. More patients were ran-

domized to N than to B to gain more experience with the
former drug.

The placebos, which appeared identical to the active drugs,
were used to maintain the double-blind nature. The initial
dose were 80 mg of N and 5 mg of B, each given once daily
before breakfast in the morning. Patients were seen in 1 week
and were managed as follows: If the diastolic BP was >75 mm
Hg, B or its placebo was increased to 10 mg, which dose was
continued througout the study; if the diastolic BP fell to 175
mm Hg, the patient was removed from the trial. N was titrated

TABLE I  Baseline Characteristics of 365 Randomized
      Patients

Bendroflu-
methiazide
(W

Nadolol (N)

B+N

No. of pts

;gW
White

Weight (kg)

Blood pressure
  (mm Hg)
  (Standing)
Systolic
Diastolic
Blood Pressure
  (mm W
  (Sitting)
Systolic
Diastolic

Heart rate
(beatsimin)
Uric acid (mg/dl)
Serum potassium
(mEq/liter)
Creatinine (mg/dl)
Fasting blood sugar
O-Wdl)
Cholesterol (mg/dl)
Triglycerides
fma/dl)

81

5oi55 `.'
35;

196.7 f 4.1

146.7 f 1.7
103.7 f 0.8




146.9 f 1.6
101.8 f 0.6

77.1 f 1.1


6.0 f 0.2

4.2 f 0.0


1.2 f 0.0

99 f 2.0


233 f 7.0

171 f 14.0

   132

49.4 f 1.0
  62%
  38%

197.8 f 3.7

145.5 f 1.4
103.3 f 0.6

144.7 f 1.2
101.3 f 0.4

76.2 f 0.9

6.4 f 0.1

4.2 f 0.0

1.1 f 0.0

100 f 2.0


220 f 4.0

152

51.1 f 0.8
57%
43%

192.0 f 2.7

148.9 f 1.4
104.9 f 0.6

148.4 f 1.3
101.8 f 0.4

76.4 f 0.9

6.2 f 0.2

4.3 f 0.0

1.2 f 0.0

97 f 1.0

223 f 4.0

176 f 11.0'   147 f 8.0'

o Significance of difference <0.05.
Values are mean f standard error of the mean.


1232   NADOLOL IN HYPERTENSION



TABLE II  Mean Changes in Sitting Blood Pressure (BP) and Heart Rate in Blacks and Whites After 12 Weeks of Treatment

    Variable                   Bendro            Nadolol          Combination     Significance

Number (blacks/whites)
Attained goal blood pressure
Blacks
Whites
p Value
Baseline systolic BP (mm Hg)
Blacks (178)
Whites (136)
Ch;kyk;ystol+c BP (mm Hg)
Whites
Baseline diastolic BP (mm Hg)
Blacks (178)
Whites.(l30)
Chs;ykirastolic BP (mm Hg)
Whites

Baseline pulse rate (beatsjmin)
Change pulse rate (beatslmin)

68i:2:36)
46;
  46%
146.?& 1.7
148.6 f 2.2
143.8 f 2.6
-17.4 f 1.7
-19.9 f 2.4
-13.3 f 2.0
101.0 f 0.6
101.2 f 0.8
100.5 f 0.8
-11.6 f 1.2
-12.4 f 1.5
-10.2 f 1.7
76.3 f 1.1
0.8 f 1.4

1044(96$/43)
31;
  77%
<o.oo 1
144.1 f 1.4
145.1 f 1.8
142.7 f 2.1
-10.5 f 1.6
-5.8 f 2.1
-17.2 f 2.3
101.4 f 0.4
101.2 f 0.5
101.6 f 0.7
-12.1 f 0.8
-9.6 f 0.9
-15.6 f 1.2
75.7 f 1.0
-16.1 f 1.0

1362;761)
84;
  85%
147.;; 1.3
149.6 f 1.9
145.5 f 1.9
-25.3 f 1.4
-27.3 f 2.1
-22.9 f 1.7
101.6 f 0.4
101.9 f 0.6
101.2 f 0.6
-17.9 f 0.7
-18.1 f 1.0
-17.7 f 0.8
75.4 f 0.8
-15.8 f 0.8

B-C+, N-Ct
B-C*, N-C+
B-N+, B-C+

B-N+, B-C+, N-C
B-N+, B-C*, N-C+
N-C', B-C'

B-C+, N-C'
B-C+, N-C*
B-N+, B-C+

B-Nt, B-Cf

B-N = significance of the difference between bendroflumethiazide (B) and nadolol (N); B-C = significance of the difference betweeh B and
combination (C); N-C = significance of the difference between N and C; NS = not significant.

as necessary biweekly until goal diastolic BP, defined as <90
mm Hg, was achieved. The once-daily doses of N or its placebo
were increased from 80 to 160 to 240 mg. After attaining goal
diastolic BP, each regimen was then continued at the same
dosage until the 12th week after randomization. If the diastolic
BP was >119 mm Hg at any clinic visit or >104 mm Hg at 2
successive clinic visits during this phase of the study, the pa-
tient was terminated from the study. These patients were
removed from the trial and were treated openly. They did not
enter phase B. The duration of phase A was 12 weeks and in-
cluded initially 4 visits at l-week intervals followed by 4 bi-
weekly visits.

Postrandomization period (phase B): The effects of
adding hydralazine to the treatment regimens of patients who
failed to achieve the goal diastolic BP of <90 mm Hg during
phase A was assessed at completion of phase B. Hydralazine
was added in an initial dose of 25 mg twice daily, but was in-
creased to 50 mg and then 100 mg twice daily until either the
diastolic BP fell to <90 mm Hg or intolerable side effects su-
pervened. The duration of phase B was 9 weeks. Patients were
seen at 1 week for the first week only and then were scheduled
for biweekly visits.

TABLE Ill  Terminations During Phase A Treatment Period

Termination Cause       Bendro o   Nadolol Combination

DBP elevated+
Dropouts        z   z
Lapse in treatment
Drug intolerance      :   s
Cardiovascular complication      1
All other           ;
Total        1:
No. randomized             81   132;
Percent terminations          17       21

0
:
4
1
1:
152
11

o Bendroflumethiazide, 5 to 10 mglday.
+DBP>l19mmHgatanyvisit,DBPll4-119mmHgon2suc-
cessive weekly visits during titration or > 104 mm Hg on 2 successive
visits after maximum titration.
DBP = diastolic blood pressure.

Characteristics of randomized patients: The mean BP
at the time of randomization was 146.7/101.6 mm Hg and did
not differ significantly among the treatment groups (Table
I). The mean age was 50.4 years. The racial distribution was
61% black and 39% white. There were no significant differ-
ences in these characteristics among treatment groups or in
heart rate and the various blood chemistry values except tri-
glycerides, which averaged lower (p <0.05) in the group that
received both drugs (Table I).

Statistical analysis of results was carried out using the 2
sample t test to compare mean values between independent
samples. The comparison of percentages between independent
samples was accomplished using the Z test based upon the
normal distribution. Comparison of changes within patients
was done using the paired t test.

Results

Changes in blood pressure during phase A: The
percentage of patients who achieved goal BP (defined
as a diastolic BP <90 mm Hg) at the last or 12th week
of treatment was determined (Table II, Fig. 1). In the
patients treated with N alone who either completed the
l%-week treatment period or else were terminated be-
cause of elevated diastolic BP, 49% were controlled, 44%

TABLE IV  Leading Side Effects in Phase A*

                 % Complaining

Complaint Any Visit    Bendro

Nadolol

Both Drugs

Weakness
Lethargy      i    ;    l
Impotence                                2
Postural dizziness    i    :         2
Insomnia               0          3          1

o Complaint made on at least 2 visits during Phase A but not during
placebo baseline period.
Bendro = bendroflumethiazide.


December 1, 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 52    1233

were not controlled and 7% had to be terminated for
elevated BP during the treatment period. With B, 46%
were controlled, 43% were not controlled and 11% had
to be terminated for BP above the acceptable range.
The combination of the 2 drugs was significantly more
effective (p -CO.0011 than either of the single drug regi-
mens, with 85% controlled, only 15% uncontrolled and
no terminations because of high BP.

In the patients receiving N alone, 31% achieved goal
BP with 80,10% with 160 and 13% with 240 mg/day. In
the group receiving the combination, which included 10
mg of B, 46% attained goal BP with the 80-mg dose of
N, 29% with 160-mg dose and 10% with the 240-mg dose.
Forty-three percent of the patients who responded to
B alone did not achieve goal blood pressure immediately
after taking the lo-mg dose, but required several more
weeks before this dose decreased the diastolic BP to <90
mm Hg.

The average changes in BP, which includes only the
patients who completed phase A of the trial, were as
follows: of the 104 patients assigned to N, the BP aver-
aged 144.1DO1.4 during the prerandomization period
and 133.6189.3 mm Hg by the end of the 12-week
treatment period, a reduction of lO.Ul2.1 mm Hg
(Table II). The average BP of the 68 patients who re-
ceived B decreased from 146.8/101.0 mm Hg before
randomization to 129.4189.4 mm Hg at the end of the
treatment period, a reduction of 17.4/11.6 mm Hg. The
-reduction in systolic but not diastolic BP was signifi-
cantly greater with B than with N (p <O.Ol). With the
combination of B+N, the BP averaged 147.7/101.6 mm
Hg before treatment and 122.4/83.7 mm Hg at the end
of treatment, an average reduction of 25.3/17.9 mm Hg.
The reductions in both systolic and diastolic BP were
significantly greater with the combination than with
either of the drugs given alone (p <0.001/p <O.OOl).

A racial difference was observed in the response to N
(Table II). In white persons the average decrease in di-
astolic BP was 15.6 mm Hg, significantly (p <O.OOl)
greater than the 9.6 mm Hg average reduction attained
in black persons. In the patients treated with N alone,
77% of whites achieved a diastolic BP <90 mm Hg,
compared with only 31% of blacks (p <O.OOl). By con-
trast, the diastolic BP response of the blacks to the
thiazide diuretic was somewhat, but not significantly,
greater than the response of the whites (12.4-mm Hg
reduction in blacks and 10.2-mm Hg in whites). The
greater reduction of systolic BP to B in blacks (19.9 mm
Hg) compared with whites (>13.3 mm Hg) was almost
significant (p = 0.055). There was essentially no racial
difference in the response of diastolic BP to the com-
bination of the 2 drugs, with average reductions of 17.7
mm Hg in whites and 18.1 mm Hg in blacks.

The degree of reduction of diastolic BP was correlated
with the height of the baseline diastolic BP in that the
higher the baseline diastolic BP, the greater the de-
crease. For example, in patients with a pretreatment
diastolic BP of 95 to 99 mm Hg, the reduction of dia-
stolic BP averaged 8.8 mm Hg with N, 8.2 mm Hg with
B and 16.8 mm Hg with the combination. In contrast,
the reductions of diastolic BP in patients with baseline
levels of 110 to 114 mm Hg averaged 19.3 mm Hg with
N, 23.5 mm Hg with B and 24.1 mm Hg with the com-
bination. To assess the effects of age in the response to
the various regimens, the patients were subdivided into
2 age groups, those age 50 years or less and those older
than 50 years. The mean reductions in diastolic BP were
almost identical in the 2 groups.

Pulse rate did not change significantly with B alone;
the average pulse rate increased, but only by 0.8 beats/
min. The average pulse rate decreased significantly from
baseline, by 16.1 beats/min with N alone and by 15.8

TABLE V  Changes in Serum Chemistry Values After 12 Weeks of Treatment

   Serum Chemistry                    Bendro                    Nadolol            Both Drugs
Potassium (mEq/liter )
  No. of patients                                                                    134
   Baseline           4.26Y 0 05       4.269f90.04            4.28 f 0.03
  Change                        -0.57 f 0:06t                0.08 f 0.04           -0.44 f 0.05t
Uric acid (mg/dl)
  No. of patients          6.76:         6.4y0.1                 126
   Baseline                                0.2                                     6.5 f 0.1
  Change                          1.7 f 0.27                 0.4 f 0.1 o            1.9 f 0.1t
Fasting glucose
  Number of patients        100.66:                       97                   133
   Baseline                               2.0                103.0 f 1.9             97.2 f 1.3
  Change                       +6.1 f 2.lt               +2.4 f 1.8            +7.4 f 1.17
Cholesterol
  No. of patients                         60                                            121
   Baseline                        234.9 f 8.0       223.68f85.0             227.2 f 4.9
  Change                          11.5 f 4.3t                -1.5 f 3.9              3.5 f 3.6
Triglycerides
  No. of patients         169.66f6        172.39f411.6                132
   Baseline                               14.2                                   149.3 f 8.3
  Change                          34.6 f 14.8'                38.7 f 13.2'           67.8 f 11.97

   Values are mean f standard error of the mean.
  Significant changes from baseline:
  o p <O.Ol.
  t p <O.OOl.
   Bendro = bendroflumethiazide.


1234   NADOLOL IN HYPERTENSION

beatslmin with the combination (p <O.OOl). Body
weight decreased on the B and B+N regimens. At the
second visit after randomization, when most patients
had received their maximal dose, the mean reductions
were 3.0 and 2.8 pounds body weight, respectively, for
B alone and for the B+N. Body weight did not change
in the patients taking N alone.

Terminations: Thirteen (16%) of the randomized
patients receiving B, 28 (21%) of those receiving N and
16 (11%) of those receiving both drugs were terminated
from the study (Table III). Nine patients receiving each
of the single drug regimens were terminated because of
an elevated diastolic BP. None of the patients receiving
both drugs were terminated for this reason. Two pa-
tients receiving N, 4 receiving both drugs and none re-
ceiving B were terminated because of suspected drug
intolerance.

Side effects: The only complaints for each patient
that were considered as possibly drug-related were those
that were not manifest during the prerandomization
placebo period. To be counted as a side effect, the
complaint also had to be registered on more than 1 clinic
visit during the drug treatment period. With these cri-
teria, subjective side effects were relatively few (Table
IV). The most frequently noted complaint was sexual
impotence. This occurred with all regimens, but most
frequently with B alone (9% of patients). Also, the
complaints of weakness, lethargy and postural dizziness,
while relatively infrequent were associated mostly with
the thiazide-containing regimens. An exception was
insomnia, which occurred in 3% of the patients receiving
N, none receiving B and 1% of patients receiving
B+N.

Serum chemistries: Changes in serum chemistries
reflected primarily those usually associated with the
thiazide diuretics (Table V). Serum potassium de-
creased significantly and serum uric acid increased
significantly (both p <O.Ol) with B and B+N, but they
remained essentially unchanged with N alone. Fasting
serum glucose increased by an average of 6.0 and 7.4
mg/dl on B and B+N, respectively, and remained es-
sentially unchanged after treatment with N alone.
There was no significant change in serum creatinine
with any of these regimens.

Baseline triglyceride levels averaged 149.3 mg/dl in
patients receiving the combination of drugs, compared
with 169.6 and 172.3 mg/dl for the B and N groups, re-
spectively. Serum triglycerides increased significantly,
by 34.6 mg/dl(20%) with B, 38.7 mg/dl(23%) with N and
67.8 mg/dl(45%) with the combination of drugs. Serum
cholesterol increased 11.5 mg/dl (4.9%) after B alone.
Serum cholesterol averaged 1.5 mg/dl lower in pabients
receiving N alone. With B+N, it increased 3.5 mg/dl
(1%).

Changes during phase B, addition of hydralazine:
The number of nonresponders (failure to achieve a di-
astolic BP <90 mm Hg) during phase A who entered
phase B, when hydralazine was added, included 30 re-
ceiving B, 40 receiving N and 19 receiving the combined
drugs (Table VI). The addition of hydralazine resulted
in similar decreases in diastolic BP, averaging 7.5 mm
Hg with either B or N alone and 7.7 mm Hg with the

combination. The percentage of these previously un-
controlled patients who attained a diastolic BP of <90
mm Hg after the addition of hydralazine was 57% in the
patients receiving B alone, 68% in the N-treated pa-
tients and 58% of those receiving the combination of
these drugs. Thus, hydralazine was effective in more
than half of the previously incompletely controlled
patients. In contrast to the diuretic and beta blocker,
there were no racial differences in the response to hy-
dralazine. Heart rate increased by an average of 5.6,2.4
and 4.1 beats/min after hydralazine was added to B, N
and the combination, respectively (Table VI).

Terminations from the study because of side effects
were few. One patient receiving hydralazine with B re-
quested discontinuation because of impotence. Four
patients receiving N with hydralazine and 1 patient
receiving all 3 drugs were terminated because of head-
ache. There were no other terminations associated with
drug intolerance.

Discussion

In designing the trial, care was taken to minimize
known sources of bias. The double-blind nature was
maintained as much as possible, with each drug and its
placebo identical in appearance. Possible carryover
effects from the prior regimen that may occur with
crossover designs were avoided by using parallel treat-
ment groups. The randomization procedure was suc-
cessful in preventing significant differences between
treatment groups with respect to any of the important
prerandomization characteristics. The sample size
quotas were met on time and with no great differences
in recruitment among the various hospitals. All of the
randomized patients were tested for compliance, and
on the basis of tablet counts, all ingested 280% of the
placebos prescribed during the prerandomization pe-
riod. The results reported, therefore, may be better than
the general experience because identified noncompliant
patients were excluded.

The 2 drugs given as single entities had approxi-
mately the same effectiveness. However, the combina-
tion of the 2 drugs was considerably more efficacious
than either drug used alone. The percentage of patients
whose diastolic BP was controlled <90 mm Hg (goal
diastolic BP) was significantly greater with the com-
bined drugs than with either agent used alone. In the
group receiving the combination, 85% achieved goal
diastolic BP, compared with 49% with N alone and 46%
with B. This result is similar to that in a previous trial
by our group.8 In that study, propranolol alone was
compared with propranolol plus hydrochlorothiazide
in patients with mild hypertension. Propranolol con-
trolled the diastolic BP in 52% of these patients, whereas
with the combination, 81% attained goal diastolic BP.
The impressive results using the combined drugs should
not negate the fact that N alone controlled BP in half
of the patients, indicating that it is a highly effective
treatment for hypertension, although not as effective
as the N-diuretic combination.

B produced a somewhat greater fall in systolic BP
than N. This greater effect of the diuretic compared
with the beta blocker on systolic BP was also found in


December 1, 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 52    1235

TABLE VI  Mean Changes in Sitting Blood Pressure (BP) and Heart Rate After 9 Weeks of Added Hydralazine

                                   Hydralazine, 25-100 mg b.i.d., plus

    Variable

No. of patients
Systolic BP (mm Hg)
prehydralazine
Change systolic BP (mm Hg)
Diastolic BP (mm Hg)
prehydralazine
Change diastolic BP (mm Hg)
Pulse rate beats/min
prehydralazine
Change pulse rate (beatsimin)

Bendro           Nadolol

  30               40

134.1 f 1.5         143.0 f 2.1
-4.3 f 1.9         -7.7 f 1.9

95.5 f 1.0         94.9 f 0.7
-7.5 f 1.0         - 7.5 f 1.1

74.2 f 1.9         59.8 f 1.4
5.6 f 2.0          2.4 f 1.4

Combination

   19

133.6 f 2.4
-6.9 f 2.0

95.5 f 1.0
-7.7 f 1.1

57.2 f 1.6
4.1 f 2.0

  Significance




B + H', N + H+, B + N



B + H+, N + Ht. B + N



B + H+

o p <0.05.
+ " <O.OOl
t b (0.01.

B + H = significance of change after adding hydralazine to bendroflumethiazide (Bendro); N -I H = significance of change after adding hydralazine
to nadolol; B -I N ot H = significance of change after adding hydralazine to the combination of B -i- N.

a previous study.g Although the reason has not been
clarified, it seems likely that the reduction in plasma
volume and tendency to a somewhat low cardiac output
may be important factors.

Although the population was predominantly black,
the randomized group included 142 white patients,
which was sufficient to make valid black-white com-
parisons in responsiveness to the various treatments.
N was significantly more effective as an antihyperten-
sive agent in whites than in blacks. The reverse was
found with B, which was somewhat, although not sig-
nificantly, more effective in blacks than in whites.
Similar black-white differences in the antihypertensive
response to beta blockers and to diuretics were found
in the Veterans Administration Cooperative Study
comparing propranolol with hydrochlorothiazide.g
SeedatlO also observed that a diuretic was more effective
than a beta blocker in blacks.lO Hypertensive blacks are
said to exhibit higher plasma volumes and lower plasma
renin activities than hypertensive whites,11J2 although
other investigators have disputed these claims.13J4
Laragh postulated that patients with high plasma vol-
umes have a "volume-dependent" hypertension that
will respond to reduction of extracellular and plasma
volume with diuretics, while those with high plasma
renin activity and low plasma volumes should respond
to beta blockers.15

Few side effects were noted with either drug in this
trial. The most frequent complaints were impotence,
lethargy, weakness and postural dizziness. These side
effects were encountered more often with B than with
N, although they were uncommon with both drugs. In
the prior trial of propranolol versus hydrochlorothia-
zide,g subjective side effects also were uncommon. The
most frequent hydrochlorothiazide-associated com-
plaints in that study were diarrhea, impotence, consti-
pation and numbness, and the most frequent side
effects among propranolol-treated patients were in-
somnia, swelling of the hands and vivid dreams. How-
ever, as in the present trial, the number of possibly
drug-related complaints was relatively small.

Addition of hydralazine to the patients who failed to
reach goal diastolic BP with B, N or both resulted in a

similar decrement of blood pressure in each of the 3
treatment groups. The average additional reduction was
about 7.5 mm Hg in all 3 treatment groups. This re-
sponse is similar to that achieved in a previous Veterans
Administration Cooperative Study.ls In the latter
study, hydralazine was added to the regimen of patients
who failed to achieve a diastolic BP of <90 mm Hg with
hydrochlorothiazide alone. These patients had an ad-
ditional average decrease in diastolic BP of 8.8 mm Hg
3 months after adding hydralazine. Although these re-
ductions may seem small, the BP had already been re-
duced, although not to goal levels, by the original ther-
apy. Furthermore, the lower the level of BP the less will
be the reduction following an antihypertensive drug.
For example, in phase A of the present trial the reduc-
tion in diastolic BP after B averaged 8.2 mm Hg in pa-
tients with pretreatment baseline levels of 95 to 99 mm
Hg, 11.6 mm Hg with 100 to 104 mm Hg diastolic BP
prerandomization and 18.6 mm Hg with entry diastolic
BP of 105 to 114 mm Hg. If the diastolic BP had not
already been partially reduced by the initial treatment,
the decrease associated with hydralazine might have
been considerably greater.

Side effects during hydralazine administration were
not impressive. The most frequent side effect was
moderately severe to severe headache, which occurred
in 4 patients receiving N and 1 receiving the combina-
tion. Headache of this severity was not noted in the
groups receiving hydralazine and B alone. Although the
incidence of headache was too low to make firm con-
clusions, these results suggest that thiazide diuretics
may prevent hydralazine-induced headache, possibly
by reducing plasma and extracellular volume. Except
for headache, the side effects complained of most fre-
quently during hydralazine treatment were the same as
those present before the drug, including lethargy,
weakness and impotence.

Elevation of serum triglyceride levels after either
thiazide diuretics of beta blockers have been noted
previously by other investigators.17J8 The increase was
especially marked after the combined drugs, when the
increase averaged 47% above baseline values. The
clinical importance of this change is not clear, however,


1236   NADOLOL IN HYPERTENSION

because of the role of triglycerides in the pathogenesis
of atherosclerosis is not well defined. Serum cholesterol
increased modestly after B but not after N. These ob-
servations with respect to serum cholesterol are also
similar to those reported by others.17,`s
In conclusion, as judged by the results of this trial, N
appears to be a safe and effective antihypertensive
agent. Its long action permits once-daily dosage, which
should facilitate compliance and offer an advantage over
shorter-acting beta-adrenergic blocking drugs. The
present results suggest that approximately half of the
patients with mild and moderate hypertension will
achieve a diastolic BP of <90 mm Hg with N alone, a
further one-third with the addition of B and 10% more
with the addition of hydralazine. Thus, approximately
85% of patients can be controlled by a relatively simple
step-care regimen involving once-daily doses of 1 or 2
agents, with the third drug, hydralazine, reserved for the
small percentage of nonresponders. Also, because of the
differing racial response to these 2 agents, it would ap-
pear advisable to initiate treatment with B in blacks and
with N in whites.

References

1. McDevltt DG. Position paper: differential features of beta-adrenoreceptor
blocking drugs for therapy. In: Laragh JH, Buhler FR, Seldin DW, eds.
Frontiers in Hypertension Research. New York: Springer-Verlag, 1981:
473-481.

2. Heel RC, Brogden RN, Pakes GE, Speight TM, Avery GS. Nadolol: a review
of its pharmacological properties and therapeutic efficacy in hypertension
and angina pectoris. Drugs 1980;20:1-23.
3. Frishman WH. Drug therapy. Nadolol: a new fi-adrenoreceptor antagonist.
N Engl J Med 1981;305:678-882.

4. Hollenberg NK, Adams DF, McKinstray DN, Williams GH, Borucki LJ,
Sullivan JM. D-adrenoreceptor-blocking agents and the kidney: effect of
nadolol and propranolol on the renal circulation. Br J Clin Pharmacol
19787:suppl 2:2195-225s.

5. Textor ST, Fouad FM, Bravo EL, Tarazi RC, Vidt DG, Gifford RW Jr. Re-
distribution of cardiac output to the kidneys during oral nadolol adminis-
tration N Engl J Med 1982;307:601-605.
6. Medical Research Council Working Party on Mild to Moderate Hypertension.
Adverse reactions to bendroflumethiazide and propranolol for the treatment
of mild hypertension. Lancet 1981;2:539-543.
7. Berglund G, Anderson 0. Beta-blockers or diuretics in hypertension? A
six-year follow-up of blood pressure and metabolic side effects. Lancet
  1981:1:744-747.

6. Veterans Administration Cooperative Study Group on Antihypertensive
Agents. Propranolol in the treatment of essential hypertension. JAMA
1977:237:2303-2310.

9. Veterans Administration Cooperative Study Group on Antihypertensive
Agents. Comparison of propranolol and hydrochlorothiazide for the initial
treatment of hypertension. Results of short-term titration with emphasis
on radical differences in response. JAMA 1982;248:1996-2003.
10. Seedal YK. Trial of atenolol and chlorthalidone for hypertension in black
  South Africans. Br Med J 1980;281:1241-43.
11. Chrysant SC, Danlsa K, Kent DC, Dlllard BL, Smith WJ, Frohllch ED. Racial
differences in pressure volume and renin interrelationships in essential
hypertension. Hypertension 1979;1:136-141.
12. MHas JA II, Holle R, Levy SB, Stone RA. Racial analysis of the volume-renin
relationship in human hypertension. Arch Intern Med 1979;139:157-
  160.

13. Messerll FH, DeCarvalho JG, Christie B, Frohlich ED. Essential hyper-
  tension in black and white subiects. Hemodvnamic findinos and fluid volume

14.

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16.

state. Am J Med 197"~@`~"' . * '
            J,"I.Lr--JI.
Holland OB, Gomez
          :-Sanchez C. Fairchild C. Kaolan NM. Role of renin
classification for diuretic treatment of black hypertensive patients. Arch
Intern Med 1979;139:1365-1370.
Laraoh JH. Vasoconstriction-volume analvsis for understandino and treatino
hype?ension: the use of renin and aldosterone profiles. Am>-Med 1973;
55:281-274.
Veterans Administration Cooperative Study Group on Antihypertensive
Agents. Comparison of prazosin with hydralazine in patients receiving hy-
drochlorothiazide. A randomized, double-blind clinical trial. Circulation
1981:64:772-779

17. Ames RP, HI8 P. Elevation of serum lipid levels during diuretic therapy of
hypertension. Am J Med 1976;61:748-757.
16. Shaw J, England JD, Hau AS. Beta-blockers and plasma triglycerides
  (letter). Br Med J 1978;1:986.

lg. Grimm AH Jr, Leon AS, Hunninghake DB, Leng K, Hannan Pr Blackburn
H. Effects of thiazide diuretics on plasma lipids and lipoproterns in mildly
hypertensive patients: a double-blind controlled trial. Ann Intern Med
  1981;94:7-11.

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7.

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11.

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16.
17.

18.


19.
20.


21.

22.

23.
24.

Appendix

Exclusions

Known adverse reactions to hydrochlorothiazide, beta-
blocking agents or hydralazine
Malignant hypertension including hypertensive neuro-
retinopathy
Hypertensive retinopathy (K-W scale) greater than grade
II

Acute hypertensive encephalopathy
Cerebral or subarachnoid hemorrhage
Atherosclerotic stroke within the past six months
Myocardial infarction within 6 months or angina pectoris
greater than New York Heart Association class II
Patients currently taking "digitalis-like" preparations
Patients with primary valvular heart disease (e.g., rheu-
matic or congenital)

Atria1 fibrillation

Heart block greater than 1st degree or Wolff-Parkin-

son-white syndrome or, if not currently receiving beta-
blocking agent, sinus bradycardia (<60 beats/min)
Patients with Raynaud's disease or symptomatic and
objective peripheral vascular disease
Asthma

Cor pulmonale due to obstructive lung disease
Obstructive lung disease with asthmatic wheezes
Diabetes requiring treatment other than diet
Collagen vascular disease
Surgically curable forms of hypertension-pheochro-
mocytoma, primary aldosteronism, Cushing's disease or
renovascular hypertension
History or evidence of psychiatrically documented
nonsituational, clinically important mental depression
Malignancy including leukemia and lymphoma
Drug abuse, severe organic brain damage or severe alcohol
abuse

Patients on adrenergic augmenting psychotropic drugs
including monoamine oxidase inhibitors, amphetamine
and its derivatives

Patients regularly using transcendental meditation,
biofeedback relaxation and/or similar techniques
Serum creatinine >2.0 mg/dl
Congestive heart failure as evidenced by at least 2 of the
following:
A. Recent dyspnea or orthopnea not of pulmonary
. .

origin

B. Ventricular diastolic gallop (Ss)
C. Basal pulmonary rales
D. Cardiothoracic ratio greater than 0.5 on x-ray
25. Patient unreliable
26. Patient unable or unwilling to participate or refuses to
sign the informed consent

Participants

Co-Chairmen: Edward D. Freis, MD (Washington, D.C.)
and J. R. Thomas, MD (Memphis, TN)
Principal Investigators: Frederick N. Talmers, MD (Allen
Park, MI); William C. Cushman, MD (Jackson, MS); Harold
Schnaper, MD (Birmingham, AL); Thomas J. White, MD
(Memphis, TN); Orlando Fernandez, MD (Miami, FL); Eli
A. Ramirez, MD (San Juan, PR); Ibrahim Khatri, MD
(Washington, D.C.)

Nurses: Barbara Gregory, RN, and Madeline Metcalfe, RN
(Washington, D.C.); Chris Grant, RN, and Julie Pawelak, RN
(Allen Park, MI); Pauline Derrington, RN (Jackson, MS);


December 1. 1983 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 52    1237

Anita McKnight, RN, Susan Reece, RN, and Kristina
Grossman, RN (Memphis, TN); Mary H. Smith, RN, and
Eileen Haran, RN (Miami, FL); Maria Natal, RN (San Juan,
PR); William Hackett, RN, and Donald Quinn, PA (Bir-
mingham, AL)

Biostatistician: Thomas J. Tosch, PhD
Forms Reviewers: Janice Ivie (Memphis, TN); Mary Ellen
Vitek and Jane Foregger (Hines, IL)
Central Research Pharmacist: Larry Young, RPh
Operations Committee: Walter Kirkendall, MD, James
C. Gunnels, MD, C. Mort Hawkins, DS
Consultants: Barry J. Materson, MD, John C. Alexander,

MD, Joseph Meyer, PhD, Dionisio L. Caloza, Jr, MD

Hines Cooperative Studies Program Coordinating
Center Human Rights Committee: Jennie McKay; Patrick
Moran; Mary Davidson, PhD, Kenneth Elmer, Rev. Martin
Feldbush

Cooperative Studies Program Central Administration:
James A. Hagans, MD, PhD, and Ping Huang, PhD (VA
Central Office, Washington, D.C.); William G. Henderson,
PhD, Janice Ivie, Mary Ellen Vitek (Cooperative Studies
Program Coordinating Center, Hines, IL); Mike Sather, RPh,
MS (Cooperative Studies Program Research Pharmacy
Coordinating Center, Albuquerque, NM)

Reprinted from the December 1 issue of The American Journal of Cardiology, A Yorke Medical Journal. Published by Technical Publishing,
a Division of Dun-Donnelley Publishing Corporation, a Company of The Dun & Bradstreet Corporation, 875 Third Avenue, New York, N.Y. 10022
Copyright 1983. All rights reserved. Printed in the U.S.A.