338
2
Hemodynamic Responses to Combined Therapy With Captopril and
Hydralazine in Patients With Severe Heart Failure
BARRY M. MASSIE, MD, FACC,* MILTON PACKER, MD, FACC,t
J. TIMOTHY HANLON, MD, FACC,:!: D. THOMAS COMBS, MD, FAcej:
San Francisco, California, New York, New York and Bend, Oregon
The hemodynamic benefitsand safety of combined ther-
apy with captopril and hydralazine were studied during
invasive hemodynamic monitoring in 14 patients with
severe heart failure. In eight patients, the individual
effects of both drugs were evaluated before the admin-
istration of combined therapy, whereas hydralazine was
added to maintenance captopril therapy in the other six
patients. In the first group, captopril alone produced a
marked decrease in pulmonary wedge pressure (28 ± 4
to 18 ± 5 mm Hg) and mean arterial pressure (85 ±
20 to 69 ± 13 mm Hg) (both p < 0.001) without a
significant increase in cardiac index. Hydralazine alone
produced a marked increase in cardiac index (1.6 ± 0.4
to 2.7 ± 0.5 liters/min per m2) (p < 0.001), but with a
minimal decrease in pulmonary wedge pressure (28 ±
4 to 23 ± 4 mm Hg) (p < 0.05) and without a significant
change in mean arterial pressure.
Captopril, an orally active inhibitor of the angiotensincon-
verting enzyme, is of established value in the management
of patients with severe chronic heart failure (1-10). Short-
and long-term captopril administration produces a marked
decrease in left ventricular filling pressure, but only a modest
increase in cardiac output (5-10). In contrast, the direct-
acting arteriolar vasodilator drug, hydralazine, produces a
marked increase in cardiac output, but only a small decline
From the Department of Medicine, Uruversity of California and the
Cardiology Service of the Veterans Adrmnistratron Medical Center, San
Francisco, California; * the Division of Cardiology, Department of Med-
icine, Mount Sinai School of Medicine and Medical Center, New York,
New York;t and the Bend Memorial Clinic, Bend, Oregont. Dr. MaSSIe
is a Clinical Investigator of the Veterans Administration, Washington, D.C
Dr. Packer is the recipient of a Young Investigators' Award (R23-HL
25055) from the National Institutes of Health, Bethesda, Maryland. This
work was also supported by Grant HL 28146 from the National Heart,
Lung, and Blood Institute, Bethesda, Maryland. Manuscript received Jan-
uary 3, 1983; revised manuscript received March 18, 1983, accepted March
30, 1983.
Address for reprints. Barry M. Massie, MD, Cardiology Service (IIIC),
Veterans Administration Hospital, 4150 Clement Street, San Francisco,
California 94121.
© 1983 by the Amencan College of Cardiology
JACC Vol. 2, No.
August 1983:338-44
The combination of captopril and hydralazine
produced an increase in cardiac index similar to that of
hydralazine alone and decreases in pulmonary wedge
pressure and mean arterial pressure similar to those with
captopril alone. Most important, when hydralazine was
added to captopril in the entire group of 14 patients,
cardiac index increased markedly with little additional
decrease in mean arterial pressure and no significant
increase in heart rate. The one patient who experienced
symptomatic hypotension with combination therapy also
had dizziness with captopril alone. Seven of the nine
patients maintained on long-term treatment experienced
symptomatic improvement. Thus, in patients with severe
chronic heart failure, the combined use of captopril and
hydralazine is feasible and produces acute hemodynamic
improvement superior to that from either drug alone.
in left ventricular filling pressure (11-13). These comple-
mentary actions suggest that combined therapy with hy-
dralazine and captopril might produce hemodynamic effects
superior to those of either drug when administered alone.
Furthermore, because long-term therapy with hydralazine
stimulates the renin-angiotensin system (14), which might
lead to attenuation of the vasodilating effects of the drug
by angiotensin-mediated systemic vasoconstriction and al-
dosterone-mediated sodium retention (15-17), the devel-
opment of tolerance to hydralazine might be prevented or
forestalled by concomitant administration of a converting-
enzyme inhibitor. Despite these potential advantages, the
hemodynamic effects of combined captopril-hydralazine
therapy have not been reported.
Because hypotension often occurs after administration of
captopril, the addition of hydralazine has the potential to
produce a clinically detrimental decrease in systemic arterial
pressure. As a result, the hemodynamic and clinical safety
of this approach must be demonstrated before the clinical
application of combined therapy can be recommended. The
present study was conducted to investigate the hemody-
0735-1097/83/$3 00
l ACC Vol 2. No. 2
August 1983 338-44
namic responses to combinedhydralazine and captopril ther-
apy in patients with severe chronic heart failure and to
determine the feasibility of starting and maintaining patients
on this regimen.
Methods
Study patients. We evaluated 14 patients (II men and
3 women) with severe chronic heart failure and a mean age
of 64 ± 13 years. The cause of heart failure was ischemic
cardiomyopathy in nine patients, primary myocardial dis-
ease in three patients and persistent left ventricular dys-
function after successful valve replacement surgery in two
patients. All patients were in New York Heart Association
functional class III (3 patients) or IV (II patients), despite
therapeutic doses of digoxinand diureticdrugs (furosemide,
40 to 480 mg, in each patient plus metolazone or spirono-
lactone in 6 patients).
Hemodynamic determinations. After giving written
informed consent, each patient underwent right heart cath-
eterization with a triple lumen fl ow-directed catheter and
radial arterial cannulation for measurement of right heart
and systemic arterial pressures. All determinations were
made with the zero reference level at the midaxillary line
with the patient in the supine position. Thermodilution car-
diac output was determined in triplicate using a bedside
computer. Heart rate was monitored from a continuously
recorded electrocardiogram. Systemic vascular resistance
(SVR) was calculated by the formula:
MAP - RAP
SVR (dynes-sec-cm r ' ) = CO X 80,
where MAP and RAP are mean arterial and right atrial
pressures (in mm Hg), respectively, and CO is the cardiac
output (in liters/min).
Drug administration. Baseline determinations of mean
arterial pressure, heart rate, left ventricular fi lling pressure,
mean right atrial pressure and cardiac output wereperformed
until hemodynamic stability was achieved. Each patient then
received captopril, 12.5 to 25.0 mg orally, and all hemo-
dynamic variables were redetermined every 30 to 60 minutes
for a minimum of 3 hours. If the first dose of captopril did
not produce excessive hypotension, the dosage was in-
creased progressively to 25 to 100 mg every 8 hours in
patients whose cardiac index remained less than 2.6 liters/
min per m2 or pulmonary wedge pressure continued to be
higher than 15 mm Hg. The hemodynamic effects of cap-
topril were assessed I to 2 hours after drug administration
after a minimum of 24 hours of therapy.
Aft er the effects of captopril alone were assessed. hy-
dralazine therapy was initiated according to two different
protocols. In eight patients (Group I), hydralazine was sub-
stituted for captopril (that is, treatment with hydralazine was
started and administration of captopril was discontinued);
MASSIE ET AL 339
CAPTOPRIL-HYDRALAZINE IN HEART FAILURE
in the other six patients (Group 2), hydralazine was added
to captopril. The initial dosage of hydralazine in both groups
was 25 to 50 mg, and the dosage was progressively increased
to 100 mg every 6 hours if the cardiac index remained less
than 2.6 liters/min per m2 or the pulmonary wedge pressure
continued to be higher than 15 mm Hg and hypotension or
side effects did not supervene. The hemodynamic effects
of hydralazine were assessed I to 2 hours after drug admin-
istration after 24 hours of therapy. In Group I patients, in
whom hydralazine had been substituted for captopril, cap-
topril was then added to hydralazine after a minimum of 24
hours of hydralazine therapy alone, and hemodynamic de-
terminations were performed I to 2 hours after the combined
administration.
All pati ents were maintained on long-term vasodilator
therapy . Thedischarge regimenwasdetermined bythe hemo-
dynamic responses to individual and combined therapy and
the subsequent side effects. Informationon the long-term re-
sults of treatment was obtained by subsequent clinical eval-
uation, either by the authors or by the referring physician.
Data analysis. The effect of adding hydralazine to cap-
topril was examined by combining the data from the 14
patients in Groups I and 2. Hemodynamic measurements
before treatment, with captopril alone, and those with com-
bination therapy were compared by two way analysis of
variance. The significance of the differences between the
regimens was determined by the Newrnann-Keuls multiple
range test. The hemodynamic effects of captopril and hy-
dralazine, individually, and of the two agents in combination
were compared only in Group I, using the same statistical
methods. All data are presented as mean values ± I stan-
dard deviation.
Results
Comparative effects of captopril and hydralazine, alone
and in combination (Group 1). The effects of the three
treatment regimens in patients in Group I are presented in
Table I. The dosages of captopril and hydralazine employed
in these eight patients were 72 ± 29 mg every 8 hours and
8 1 ± 21 mg every 6 hours, respectively.
Cardiac index and stroke index. Captopril did not in-
crease cardiac index significantly ( 1.6 ± 0.4 to 2.0 ± 0.4
liters/min per rrr'), whereas hydralazine and combined ther-
apy increased cardiac index significantly and to a similar
degree (to 2.7 ± 0 .5 liters/min per m' ) (probability [pI <
0.001 versus control and versus captopril alone). Because
captopril produced a signifi cant increase in stroke volume
index (22 ± 5 to 29 ± 6 cc/beat per nr' ) (p < 0.0 1), the
failure of cardiac index to rise was due to a decrease in
heart rate during captopril therapy. However, the increase
in stroke index with hydralazine alone and with combination
therapy was also greater than that seen with captopril (33
± 5 and 35 ± 9 cc/beat per rrr' . respectively) (p < 0 .00 1
340 MASSIE ET AL l ACC Vol 2. No. 2
CAPTOPRIL· HYDRALAZINE IN HEART FAILURE August 1983 338-44

Table 1. Hemodynamic Responses to Captopril , Hydralazine and Combination Therapy in Group I Patients (n = 8)
Significance Levels (p values)
Baseline Captopril Hydralazine Combination
I III IV I vs III I vs IV " vs III " vs IV III vs IV
HR (beats/min) 83 :t 20
"
72 ± 18 84 ± 18 79 ± 18
I vs "
NS NS NS NS NS NS
MAP (mmHg) 85 ± 20 69 ± 13 78 :t 22 65 ± 17 0.01 NS 0.00 1 0 .05 NS 0 .01
Pe W pressure 28 :t 4 18 ± 5 23 ± 4 15 ± 5 0 .00 1 0 .0 1 0 .00 1 0 .0 1 NS 0 .01
(rnmHg)
RA pressure (mm 10 ± 7 7 ± 5 8 ± 5 7 ± 5 NS NS NS NS NS NS
Hg)
Cardiac index t.7 ± 0 .3 2.0 ± 0 .4 2.7 ± 0 .5 2.7 ± 0 .6 NS 0 .001 0. 001 0.00 1 0 .00 1 N
(liters/min per
m' )
Stroke index (mil 22 ± 5 29 ± 6 33 ± 5 35 ± 9 0.01 0. 00 1 0.00 1 NS 0 .05 NS
rrr')
Systemic vascular 2,080 ± 810 1,460 ± 530 1,290 ± 740 1,050 ± 580 0.0 01 0 .001 0 .001 NS 0 .0 1 0 .05
resistance
(dynes -s-crnr ')

Values are mean ± 1 standard deviation.

HR = heart rate; MAP = mean arterial pressure; NS = notsignificant; p = probability; PeW = pulmonary capillary wedge; RA = right atrial.

versus control and p < 0.05 versus captopril alone). All
three regimens significantly lowered systemic vascular re-
sistance, but combined therapy did so to a significantly
greater extent than either agent used alone.
Pulmonary capillary wedge pressure. Captopril alone
reduced pulmonary capillary wedge pressure (28 ::!:: 4 to 18
::!:: 5 mm Hg, p < 0.001 ). Left ventricular filling pressure
also decreased after hydralazine (to 23 ::!:: 4 mm Hg, p <
0.001), but this effect was significantly less marked than
that with captopril. Combined therapy produced a decrease
in pulmonary wedge pressure similar to that seen with cap-
topril alone. Changes in mean right atrial pressure were
similar to those in left ventricular filling pressure, but they
were small in magnitude and not statistically significant.
Arterial pressure. Mean arterial pressure decreased
markedly with captopril alone (85 ::!:: 20 to 69 ::!:: 13 mm
Hg, p < 0.001) ; in contrast, the decline in systemic pressure
with hydralazine alone was modest (to 78 ::!:: 22 mm Hg,
p = not signifi cant [NSJ) and less marked than that seen
with captopril alone (p < 0.05 ). Changes in mean arterial
pressure with combination therapy were similar to those seen
with captopril alone. There were no significant changes in
heart rate.
Hemodynamic effects of the addition of hydralazine
to captopril (Groups 1 and 2). The hemodynamic changes
produced by the addition of hydralazine to captopril in pa-
tients from both Groups I and 2 are illustrated in Figures
I and 2. The mean dosages of captopril and hydralazine
iIIary wedge pressure decreased markedly with captopril
alone (29 ::!:: 5 to 19 ::!:: 5 mm Hg, p < 0.(01 ), and there
was no further reduction with the addition of hydralazine
(Fig. I). Because the directional changes in these variables
were uniform, no difference in response based on the cause
of heart failure could be detected.
Heart rate and arterial pressure. Heart rate decreased
significantly with captopril alone (88 ::!:: 18 to 79 ± 18
beats/min, p < 0.05 ) and increased slightly toward control
values after the addition of hydralazine (Fig. 2). With cap-
topril alone, mean arterial pressure decreased markedly (87
Figure 1. Additive effects of hydralazine when combined with
captopril (Cap) in patients in Groups I and 2. There was little
further decrease in pulmonary capillary wedge pressure (PCW ) for
the group when hydralazine was added to captopril (Comb), but
fi ve patients exhibited an additional decrease of 5 mmHgor more.
The additionof hydralazine, however, produced a marked further
increase in cardiacindex (CI), from 2.0 ± 0.5 to 2.7 ± 0.5 liters/
min per m2 , with each subject showing an increase from the level
with captopril alone. p = probability; pre = before therapy.
,.....- p<.001 ------, ,....-p< .001----,
,p( .OO1.., r: p< .001......p< .001 .,
40 4.0
-.
-.30
E
CI
X c 3.0

were 73 ::!:: 27 mg every 8 hours and 73 ± 22 mg every 6

hours, respectively.
E
.5.20
~
-
E
::!.
(j
Cardiac index and wedge pressure. Cardiac index in- on. 2.0
creased modestly, with captopril alone (1.7 ::!:: 0.4 to 2.0 10
± 0.5 liters/min per m", p < 0.001 ) but increased markedly
with the addition of hydralazine (to 2.7 ± 0.5 liters/min
per nr', p < 0.001 from captopril alone). Pulmonary cap- o 1.0
lACC Vol 2. No 2 MASSIE ET AL. 341
August 1983 338-44 CAPTOPRIL·HYDRALAZINE IN HEART FAILURE

± 16 to 71 ± II mm Hg, p < 0.001), and declined further
after the addition of hydralazine (to 67 ± 15 mm Hg), a
small but significant change (p < 0.001). There was con-
siderable individual variation in blood pressure response,
but with the addition of hydralazine, mean arterial pressure
decreased more than 10 mm Hg in only 3 of 14 patients.
Of the five patients whose mean arterial pressure decreased
more than 60 mm Hg during combined therapy, three pa-
tients had coronary artery disease and two had cardio-
myopathy. It is important to note that heart rate remained
below baseline in four of five patients though it rose by an
average 5 bpm from the captopril alone values. None of
these patients or any other patient experienced ischemic
symptoms or electrocardiographic changes. Only one sub-
ject became symptomatically hypotensive, with dizziness
and extreme fatigue; he also experienced these symptoms
with captopril alone.
Long-term clinical follow-up. The long-term clinical
results in the 14 patients are summarized in Table I. Two
patients were treated with hydralazine alone, one because
of symptomatic hypotension and the other because of a
minimal hemodynamic response . The former was in slightly
improved condition after 2 months of treatment and the latter
died suddenly 8 days later. Three patients were treated with
captopril alone, two because of excellent hemodynamic re-
sponses to this agent and one because of severe nausea with
hydralazine . All three patients have done well and were in
functional class II after 6 to 12 months of treatment.
Figure 2. Individual changes inmean arterial pressure (MAP) and
heart rate (HR) which resulted from the addition of hydralazine.
Heart rate, which had declined slightly during captopril therapy,
did not change significantly, although one patient had an increase
of 20beats/min (bpm). Mean arterial pressure, which had declined
dramatically with captopril therapy alone from 87 ± 16 to 71 ±
II mm Hg, decreased only slightly more with combined therapy,
to 67 ± 15 mm Hg. However, important further declines were
seen inthree patients and five patients had a mean arterial pressure
below 60 mm Hg during combined therapy, although only one
had symptoms . Abbreviations as in Figure I.
~ < .05-i
120 120
The rematntng nine patients received long-term com-
bined captopril-hydralazine therapy. Five of the nine pa-
tients were clinically improved and in functional class II
after 2 to 12 months of treatment. Two others showed some
improvement , but continued to have functional class III
symptoms after I to 4 months. One patient did not show
any benefit. The last patient had a progressive downhill
course despite marked initial improvement and died before
hospital discharge.
Discussion
Rationale for combined therapy. Combined therapy
withcaptopril and hydralazine in the management of patients
withseverechronicheart failure has great theoretical appeal.
Captopril produces a marked decrease in left ventricular
filling pressure but relatively modest improvement incardiac
output (5-10) . Hydralazine producesa pronounced increase
in cardiac output but only a modest decrease in left ven-
tricular filling pressure (11-13). Therefore, combined treat-
ment with both drugs might be expected to produce con-
sistent increases in forward flow and decreases in pulmonary
venous pressures. Our findings confirm the validity of this
approach; thecombination of captopril andhydralazine yielded
additive hemodynamic benefits. Cardiac output and stroke
index increased to a magnitude similar to that with hydral-
azine alone, while pulmonary capillary wedge pressure and
mean arterial pressure declined to the same degree as with
captoprilalone. The addition of hydralazine to captopril thus
resulted in a substantial further increase in cardiac index
and reduction in systemic vascular resistance withoutother
significant hemodynamic changes.
The combination of hydralazine and captopril has the-
oretical advantages in addition to these beneficial hemo-
dynamic effects. The administration of direct-acting vaso-
dilator drugs activates endogenous vasoconstrictor forces
that serve to counteract their pharmacologic actions and
thereby may limit their efficacy (15-17). Prominentamong
the endogenous vasoconstrictor mechanisms is an increase
in the activity of the renin-angiotensin system, which may
also enhance aldosterone secretion and lead to retention of
salt and water. Both of these actions may further diminish
the response to vasodilator agents (18). Activation of the

~
renin-angiotensin system may underlie the development of
.-. 100 E 100 attenuated hemodynamic responses to hydralazine; thus,
Q
Co concomitant therapy with an angiotensin converting-enzyme
:J:
E
.§. 80
--•
.a
80
inhibitor might not only enhance the hemodynamic effects
of hydralazine but also forestall the development of hemo-
Q. ~
c( t:
dynamic and clinical tolerance.

¥ Ourfindings indicate that the combination of hydralazine

:IE III
80 •
:J: 60
and captopril results in hemodynamic improvement com-
parable with that observed with the combination of hy-
40 40 dralazine and nitrates (13). However, captopril may be a
I I I
Pre Cap Comb Pre Cap Comb more appropriate agent to use in conjunction with hydral-
342 MASSIE ET AL JACC Vol 2, No 2
CAPTOPRIL-HYDRALAZINE IN HEART FAILURE August 1983:338-44

Table 2. Long-Term Clinical Follow-Up

NYHA Maintenance Last
Class Regimen Duration of Fol- NYHA
Patient Before Therapy (mg/day) low-up (mo) Class Comment

I 4 C300,H150 14 4 No change
2 4 moo 0 4 Sudden death,
8 days
3 4 C300,HI50 12 2 Marked
improve-
ment
4 4 C300 14 3 Marked
Improve-
ment
5 3 C300,H200 8 2 Marked
Improve-
ment
6 4 C300,H200 9 2 Marked
improve-
ment
7 4 C150,H200 0 4 Continued
deter-
ioration, died
I week
8 3 C300 6 2 Marked
improve-
ment
9 4 C150,H200 2 2 Marked
improve-
ment
10 4 H200 2 3-4 Slight improve-
ment
II 4 C300,H100 3-4 Slight improve-
ment
12 4 C75,H150 2 2 Marked
improve-
ment
13 3 C300 12 2 Marked
improve-
ment
14 4 C150,H200 4 3 Slight improve-
ment

C = captopril; H = hydralazine; NYHA class = New York Heart Association functIonal class.

azine because it is more likely to facilitate diuresis by re-
ducing plasma aldosterone and thereby delay the develop-
ment of drug tolerance.
Potential disadvantages of combined
Captopril is usually well tolerated in patients with chronic
heart failure, but severe symptomatic hypotension may oc-
cur during the initiation of therapy and may be great enough
to limit long-term treatment with the drug (1,3,4,9). Be-
cause hydralazine may also lower blood pressure, albeit less
frequently (19,20), concomitant therapy with these two agents
could produce severe symptomatic hypotension. Thus, it is
particularly important that our patients generally did not
experience additive hypotensive effects with combined ther-
apy. The decrease in blood pressure was similar to that seen
with captopril alone. However, in five patients, mean sys-
temic blood pressure did decline with combined therapy to
less than 60 mm Hg, which is a potentially dangerous level.
Reflex tachycardia did not generally occur. This may reflect
therapy. blunting of the baroreceptor reflex by the underlying disease
process or by a sympatholytic effect of captopril. This blood
pressure response diminished during continued treatment so
that only one patient could not tolerate the combination of
both drugs because of hypotension-related symptoms; he
was also unable to continue on captopril alone. Importantly,
eight patients received combined therapy with captopril (75
to 300 mg daily) and hydralazine (100 to 200 mg daily) for
as long as 14 months without experiencing symptomatic
hypotension,
The lack of significant hypotension in patients in this
study might be the result of several precautions that we
JACC Vol 2. No 2
August 1983 338 -44
observed in undertaking combined treatment , All patients
were hospitalized and kept under close observation. Hy-
dralazine was initiatedat a low dosage, which was increased
only after careful observation of the hypotensive effects of
previous doses. The doses of hydralazine that produced
marked hemodynamic effects in this study were lower than
those that have generally proved necessary in patients re-
ceiving hydralazine without captopril (21). This supports
the hypothesis that the renin-angiotensin system may limit
the hemodynamic responses to direct-acting vasodilators (16).
Limitations of the present study. This study was de-
signed as an acute trial to determine whether the hemody-
namic effects of combined therapy were advantageous com-
pared with individual drugtreatment and whether thisapproach
was clinically feasible. Although these questions have been
answered in the affirmative, several additional questions
need to be addressed. With many drug regimens for heart
failure, acute hemodynamic improvement at rest may not
be translated into long-term clinical improvement (22,23).
Although many patients appeared to benefit from combined
therapy, this study did not include long-term hemodynamic
measurements or objectiveassessmentsof exercise capacity.
Furthermore , no attempt was made to compare the clinical
efficacy of combined therapy with that of individual long-
term therapy with these same agents or with other vasodi-
lator regimens. Controlled studies designed to evaluateclin-
ical status and survival, necessarily involving large numbers
of patients, are needed.
Clinical implications. Our findings indicate that com-
bined treatment with captopril and hydralazine produces
marked hemodynamic improvement superior to the effects
seen with either agent used alone. The combination is gen-
erally well tolerated and possesses little additional hypo-
tensive effect above that seen with captopril alone; long-
term treatment produces considerable symptomatic relief.
Further objective trials are needed to determine whether
combination therapy produces improvement in exercise tol-
erance superior to that of either drug alone. Until such
information becomes available, we would recommend add-
ing hydralazine to the therapeutic regimen of those patients
who remain significantly symptomatic despite therapy with
captopril alone. Although the addition of hydralazine is
unlikely to produce a marked decrease in blood pressure,
arterial pressure should be monitored carefully when com-
bination therapy is initiated.
We thank Nina TOPIC, Norma Medina and Madeline Yushak for their
Invaluable assistance In the completion of this study. and Penny Reynolds
for her secretarial assistance
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