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THERAPY AND PREVENTION
PULMONARY
HYPERTENSION
High-dose calcium channel-blocking therapy for
primary pulmonary hypertension: evidence for
long-term reduction in pulmonary arterial pressure
and regression of right ventricular hypertrophy
STUART RICH, M.D.,
AND
BRUCE H. BRUNDAGE, M.D.
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ABSTRACT In an attempt to produce substantial reductions in pulmonary arterial pressure and
pulmonary vascular resistance in patients with primary pulmonary hypertension, a new treatment
strategy using high doses of calcium channel-blocking drugs was developed. Thirteen patients were
given an initial test dose of 60 mg diltiazem or 20 mg nifedipine followed by consecutive hourly doses
until a 50% fall in pulmonary vascular resistance and 33% fall in pulmonary arterial pressure was
achieved or untoward side effects developed. The initial drug challenges failed to produce significant
reductions in mean pulmonary arterial pressure or pulmonary vascular resistance. In eight of 13
patients, continued hourly doses produced a reduction in mean pulmonary arterial pressure of 48% (61
to 35 mm Hg, pK<.01) and a reduction in pulmonary vascular resistance of 60% (15 to 6 units, p<.01).
These patients were discharged on high-dose (up to 720 mg/day diltiazem or 240 mg/day nifedipine)
calcium channel-blocking drugs as long-term therapy. Five patients have returned for restudy after 1
year. In four of five the reductions in pulmonary arterial pressure and pulmonary vascular resistance
were sustained and were associated with regression of right ventricular hypertrophy as assessed by
electrocardiography and echocardiography. One patient who reduced her dose to a conventional level
had a return of her pulmonary arterial pressure and pulmonary vascular resistance toward previous
levels. We conclude that substantial reductions in pulmonary arterial pressure and pulmonary vascular
resistance that are associated with regression of right ventricular hypertrophy are possible in some
patients with primary pulmonary hypertension by use of calcium channel-blocking drugs. High doses
of these drugs were required to produce marked hemodynamic responses in patients who exhibited
marginal responses to conventional doses. In patients able to tolerate the high-dose therapy sustained
reductions in pulmonary arterial pressure and pulmonary vascular resistance appear to last for a period
of at least 1 year.
Circulation 76, No. 1, 135-141, 1987.
SINCE Rubin and Peter' reported a 52% reduction in
pulmonary vascular resistance from hydralazine in 4
patients with primary pulmonary hypertension (PPH)
in 1980, there have been several published studies on
potential beneficial and adverse effects of vasodilators
for PPH.24 In contrast to their effectiveness in lowering systemic pressure in patients with essential hypertension, however, vasodilators have not generally produced a substantial reduction in pulmonary arterial
pressure in those with PPH. 1-6 In addition, there have
been no reported series providing hemodynamic data
From the Deaprtment of Medicine, Section of Cardiology, the University of Illinois College of Medicine at Chicago.
Address for correspondence: Stuart Rich, M.D., Cardiology Section,
University of Illinois, P.O. Box 6998, Chicago, IL 60680.
Received March 10, 1987; accepted April 9, 1987.
Vol. 76, No.
1,
July 1987
(greater than 1 year) follow-up in patients
who appear to respond favorably.
Based on the contention that a substantial reduction
in pulmonary arterial pressure must accompany the fall
in pulmonary vascular resistance in order for patients
with PPH to have sustained improvement,7'8 we undertook this study using high doses of calcium channelblocking drugs in patients with PPH to see if we could
produce greater reductions in pulmonary pressure than
previously achieved with conventional treatment. In
addition, patients who appeared to respond favorably
were followed with a repeat right heart catheterization
after 1 year to assess long-term efficacy.
on long-term
Methods
Thirteen consecutive patients referred to the University of
Illinois Hospital with unexplained pulmonary hypertension
135
RICH and BRUNDAGE
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were enrolled in the study (reviewed and approved by the University of Illinois Institutional Review Board). There were 10
women and three men (mean ages 36 + 12 years). All of the
patients fulfilled the diagnostic criteria for PPH based on history, physical examination, chest radiograph, lung scan, pulmonary function testing, two-dimensional echocardiography, and
absence of either left-to-right shunting or elevated left heart
pressures on catheterization, according to the protocol of the
National Institutes of Health PPH Registry.9
A diagnostic right heart catheterization was performed in all
of the patients after an overnight fast, and all medications except
for digoxin and diuretics had been discontinued at least 2 weeks
prior to the study. No patient was treated with anticoagulants,
either before or after this protocol. Systemic and pulmonary
arterial pressures were measured and cardiac outputs were determined by the thermodilution technique, with values for pulmonary vascular resistance and systemic vascular resistance
calculated according to standard formulas. The patients were
then transferred to the coronary care unit with a thermodilution
flow-directed catheter in the pulmonary artery and a small arterial cannula in the femoral artery for further drug evaluation.
Short-term drug protocol. The patients were allowed 2 to 4
hr to become acclimated to the cardiac care unit surroundings
before the drug study was initiated, with measurements of systemic and pulmonary pressures and cardiac outputs made periodically until stable baseline values were achieved, and then
hourly throughout the period of drug evaluation. All patients
received an initial challenge of a conventional dose of nifedipine
(20 mg) or diltiazem (60 mg) and hemodynamic measurements
were made after 1 hr. Consecutive oral doses of either nifedipine or diltiazem were then administered hourly to the patients
until a "break" or positive response (defined as a 50% reduction
in pulmonary vascular resistance and a 33% fall in mean pulmonary arterial pressure) was obtained, or until the patient experienced adverse effects of the drug requiring its discontinuation.
For purposes of this study, 20 mg nifedipine and 60 mg diltiazem were considered to be equivalent oral doses. If there was no
response to multiple consecutive doses of diltiazem, nifedipine
was used in an attempt to minimize side effects while maintaining additive effects with respect to calcium-channel blockade.
Drug challenges were stopped if the systemic systolic blood
pressure fell below 90 mm Hg (one patient), or if gastrointestinal upset precluded further drug administration (four patients).
In patients in whom a positive response was achieved the
cumulative dose of drug deemed effective was then readministered every 6 to 8 hr (depending on the duration of action) over a
24 hr period. If a single large dose produced marked side effects, however, the dose was reduced and given more frequently. For example, if it were determined that nifedipine was effective as 80 mg every 8 hr but produced marked nausea, the dose
would be changed to 60 mg every 6 hr or 40 mg every 4 hr so
that the total daily dose administered (in this case 240 mg)
remained constant. Final hemodynamic measurements were
made 1 hr after the last dose.
Long-term follow-up. Patients having a positive response
were discharged on the drug regimen that was deemed effective.
To minimize side effects, some patients were started on lower
doses (20 mg tid nifedipine or 60 mg tid diltiazem), and then the
dose was titrated gradually upward over 6 weeks until the previously determined effective daily dose was reached. In addition, digoxin was initiated to counteract any negative inotropic
effects of the calcium blockers. After 1 year the patients were to
return and undergo repeat electrocardiography, two-dimensional echocardiography, and right heart catheterization. The catheterization was done on an outpatient basis in the cardiac catheterization laboratory 1 to 2 hr after the last dose of drug was
administered.
136
Statistical analysis. Means and standard deviations were
computed for the variables measured. Comparisons between
control and treated states were made by paired Student's t test.
Differences between the effect of conventional doses and high
doses of drug were evaluated with McNemar's test. Comparisons between responders and nonresponders were made by student's t test for unpaired data.
Results
The clinical characteristics of hemodynamic findings in the 13 patients studied are listed in tables 1 and
2. All of the patients had marked elevations in pulmonary arterial pressure (61 ± 15 mm Hg) and pulmonary vascular resistance (16 ± 7 U), which are characteristic of primary pulmonary hypertension. After a
conventional test dose of either 60 mg diltiazem or 20
mg nifedipine there was a mean 2% (p= NS) fall in
pulmonary pressure and a 3% (p = NS) fall in pulmonary vascular resistance. Further hourly dosing however, produced a mean 36% fall in pulmonary arterial
pressure and a 49% fall in pulmonary vascular resistance in eight of the 13 patients (figures 1 and 2). No
significant change occurred in heart rate (from 82 to 83
beats/min), indicating that the increased cardiac output
was due to an increase in stroke volume. The dose
required to "break" the pulmonary arterial pressure
was then readministered every 6 to 8 hr, with the
effects of the therapy noted to be sustained for 24 hr in
all responding patients. In those in whom the drug
challenge failed, either because of systemic hypotension or other adverse drug effects (nausea, vomiting,
and agitation), the maximum change obtained was a
TABLE 1
Patient characteristics
Number of
Age
Patient No.
(yr)
Sex
FC
Duration
(mo)
1
2
3
4
5
6
7
8
9
10
11
12
13
38
52
28
44
22
25
53
22
31
38
18
50
45
F
F
F
F
F
F
M
F
M
F
F
F
M
III
III
II
III
III
III
II
III
IV
II
II
III
III
20
48
24
7
5
60
9
18
18
3
72
36
7
Duration
hourly doses
of drug
until response
or failure
4
3
3
4
4
7
10
7
12
11
12
9
12
duration from first symptom until trial; FC = NYHA.
CIRCULATION
~_
THERAPY AND PREVENTION-PULMONARY HYPERTENSION
TABLE 2
Response to drug treatment
Mean pulmonary
arterial pressure
Patient
No.
C
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Responders
1
77
2
62
3
41
4
60
5
41
6
47
7
77
8
80
Mean 61
±SD 16
Nonresponders
9
67
10
43
11
81
12
59
13
59
Mean 60
±SD 15
Pulmonary vascular
resistance
(mm Hg)
T B F 1 yr
C
T
76
46
42
55
45
51
77
77
59
15
11-
17
14
7
23
8
10
15
29
15
8
15 17 5 4
9 7 5 10
8 3 2 2
19 10 7 5
11 4 5 4
12 6 5
21 8 6
23 13 1215 8 6
6 5 3
67 -6742 - 4177 - 7359 - 63 56 - 4260 - 5713 - 15 -
17
10
23
10
23
17
7
22 - 19
9 - 9
21 - 15
10 - 9
20 - 1816 - 14
6 - 5
48
35
25
39
27
33
49
55
39
11
32 28
39 55
22 28
38 39
32 35
2040 53 -
35-
(units)
B F 1 yr
Systemic systolic
blood pressure
Cardiac output
(1min)
C
T
B
F
1 yr
4.1
4.1
4.9
2.3
3.7
3.9
4.4
2.5
3.7
0.9
3.9
4.4
4.5
2.4
3.5
3.9
3.2
2.6
3.6
0.8
5.9
4.7
6.6
3.6
5.5
4.2
4.6
4.0
4.9
1.0
4.8
6.2
6.8
4.5
5.5
5.4
4.7
4.0
5.2
0.9
5.4
4.7
8.8
7.5
6.1
3.6
3.6
3.1
5.4
2.3
3.6
1.1
2.8
4.1
3.2
5.6
2.5
3.6
1.3
- 3.3
-
-
3.3
- 4.2
- 4.2
- 1.9 - 3.4 - 0.9 -
C
T
(mm Hg)
B F
Mean right
atrial pressure
1 yr
126 122 130
133 126 112
127 120 105
135 121 104
125 128 121
113113120
135 136 120
143 145 126
130 126 121
9 10 15
102
124
102
110
121
111
121
128
115
10
140
134
132
126
127
132
6
97 130
10492 9610315
142
135
120
122
127
129
9
-
-
-
110
120
118
128
120
-
-
(mm Hg)
C T B F 1 yr
11 10 5
6 5 4
3 2 3
13 12 5
2 3 3
0 1 4
17 6 7
10 7 4
7 6 4
5 4 1
7 3
8 7
1 3
4 1
6 3
125
43-
17 15 -26 4 1 - 11 2 - 91 1- 1
6 10- 76 6- 9
7 6 - 10 -
C = control values; T = after conventional drug test; B = values after "break" in pulmonary pressure and resistance; F = final measurements after
24 hr (responders) or maximum effect noted (nonresponders); 1 yr = values in patients restudied after 1 year.
5% fall in mean pulmonary pressure and a 12% fall in
pulmonary vascular resistance, compared with a 48%
fall in pulmonary arterial pressure (p<.01) and a 60%
fall in pulmonary vascular resistance (p<.01) in the
responders after 24 hr. The nonresponders had a fall in
NON - RESPONDERS
RESPONDERS
80k
W
70
U)
a.
z60
a: s
W
40
mean systemic arterial pressure of 22%, compared
with a 12% reduction in the responders (p<.05).
In the responders, a "break" in the level of pulmonary arterial pressure occurred after three consecutive
hourly doses in two patients, four consecutive doses in
three patients, seven consecutive doses in two patients,
and 10 consecutive doses in one patient. In the nonreNON - RESPONDERS
=
24
W
c)
z
20
i3 16
a:
W
z 30
0
4:D
-J 20
12
U
cn
a.
>8
to
l
CONTROL
TEST
HIGH
DOSE
z
CONTROL
TEST
MAX
DOSE
FIGURE 1. The initial mean pulmonary arterial pressure and the responses to conventional and high-dose treatment are illustrated. All but
one of the responders had falls in their mean pulmonary arterial pressures to 40 mm Hg or lower. The one nonresponder who had reduction
in pulmonary arterial pressure also had systemic hypotension at the
same time.
Vol. 76, No. 1, July 1987
A
-J
J
L
CONTROL
TEST
HIGH
DOSE
CONTROL
TEST
MAX
DOSE
FIGURE 2. The effect of the treatment regimen on pulmonary vascular
resistance, with the patients divided as responders and nonresponders.
In the responders all but one had a reduction in pulmonary vascular
resistance to 7 Wood units or less with high-dose therapy.
137
i?,
RICH and BRUNDAGE
TABLE 3
Results of long-term treatment
Patient Maintenance
No.
(mg/day)
1
2
3
4
5
6
7
8
720
240
120
120
120
180
160
240
dil
dilA
nif
nif
nif
nif
nif
nif
Follow-up QRS axis RV, RVID
(mo)
(degrees) (mm) (mm)
FC
1
11
I
I
1
I
(died)
I
20
19
17
16
13
6
6
4
95--66
115--ll0
98--76
110--78
125- 105
2--1
4--2
4-*1
7-*1
5--3
31--21
32--36
28-*16
40--28
34- 26
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Maintenance = daily dose of drug taken after outpatient readjustments; FC = NYHA functional class at follow-up; Follow-up = current length of follow-up period; QRS axis = initial QRS axis from
electrocardiogram and changes after 1 year; RV, height of R wave
from lead V, initially and after one year; RVID
right ventricular
internal dimension by M mode echocardiogram initially and after 1
year; dil = diltiazem; nif = nifedipine.
APatient who reduced her dose.
sponders, a lack of response and/or untoward effects of
therapy were noted after 9 consecutive hours of treatment in one patient, 1 1 hr in one, and 12 hr in the other
two (table 1).
Long-term follow-up. At the present time, five of the
eight responding patients have been treated for over 1
year and have returned for restudy. Their daily maintenance doses of calcium-channel blocker are shown in
table 3. (One patient [No. 2] experienced unpleasant
side effects from the high dose of medication and vol-
UF
1
1
1: .:
__
_
_ _,
-V-
untarily reduced her dose from 240 to 120 mg diltiazem/day.) Each patient noted an improvement in
symptoms, with every patient but one (see below) improving by at least one New York Heart Association
(NYHA) functional class and all patients falling into
NYHA functional class I or II. In addition, in each
there was an improvement in the electrocardiographic
manifestations of right ventricular hypertrophy, ranging from a reduction in right-axis deviation and R wave
voltage in lead V1 to normalization of the electrocardiogram (table 3; figure 3). All had improvement on
their echocardiograms, with four of five showing a
return to virtual normal cardiac chamber size and normal septal systolic curvature (table 3; figure 4).
The hemodynamic findings after 1 year of therapy
are listed in table 2. In four of the five patients the
reduction in pulmonary arterial pressure and pulmonary vascular resistance achieved over the initial 24 hr
of treatment was sustained for 1 year. In one patient
(No. 2) however, there appeared to be a return of
pulmonary arterial pressure and pulmonary vascular
resistance toward the values recorded 1 year before.
Although she reported an improvement in functional
class and lifestyle, she had the least change noted in
her noninvasively measured variables as well. The two
responding patients who have been followed for less
than 1 year have also reported a sustained improvement in symptoms; of the nonresponding patients, the
conditions of two are unchanged, those of two have
deteriorated, and one has died.
#.-
I
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__
__
F_e <L
lv --t
t-- - -,t.
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__
.,
.-f
t111I -.l
__
_
_. _
_
__
.
t
F::
---I
T
-1
}n ti}
~iiii
s.
__
.¢,-i l
,9
0:::__
C.
__
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__
1
_ .-
___
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__
:m
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__
Tj t
t--i -! 1-
_ -...,.
1- -I
.-
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After I Yeor
FIGURE 3. The electrocardiograms from one patient (No. 4) obtained before drug treatment and after 1 year. A reduction in the
rightward axis from 110 to 78 degrees, as well as a dimunition in R wave voltage in leads V, and V2, suggest regression of right
ventricular hypertrophy.
138
CIRCULATION
THERAPY AND PREVENTION-PULMONARY HYPERTENSION
INITIAL
AFTER I YEAR
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FIGURE 4. The two-dimensional echocardiograms obtained from the
parasternal short-axis view before drug treatment and after 1 year in
patient 1. In addition to the reduction in right ventricular chamber size
there was a restoration of the septal curvature during systole from a
reversed to a normal configuration indicative of a reduction in right
ventricular systolic pressure. 25
One patient who responded to the high-dose calcium-blocker regimen has died. By agreement she was
to return to Chicago for a follow-up study after 1 year,
although her follow-up status was kept by phone each
month. After 6 months she and her referring physician
stated that she had become completely symptom free.
She then presented with abdominal pain and vomiting
that was, in retrospect, likely due to viral gastroenteritis. However, the referring physician, uncomfortable
with the amount of nifedipine she was taking, believed
her symptoms possibly due to the drug and reduced her
daily dose from 160 to 40 mg over a short term. Two
weeks later she presented with severe right heart failure and died. A right heart catheterization performed
before her death showed severe pulmonary hypertension with suprasystemic pressures.
Discussion
Much uncertainty has arisen about the definition of a
beneficial response to vasodilator treatment in patients
with PPH. Therapy of essential hypertension has used
a reduction in blood pressure toward normal levels as a
measure of effectiveness. Studies on PPH, however,
have generally regarded reductions in pulmonary vascular resistance of 20% as indicative of a favorable
response.8' ` However, when the effects of long-term
vasodilator therapy were evaluated in patients with
PPH who achieved a 20% fall in pulmonary vascular
Vol. 76, No. 1, July 1987
resistance there was no detectable influence of the
treatment on clinical course or survival.8
In that previous study there was a mean fall in pulmonary arterial pressure of only 3.5% with conventional doses of nifedipine or hydralazine. In this study
the dose of calcium-channel blockers administered
was considerably higher, and was titrated to the patients' hemodynamic response. Had these patients
been limited to a conventional drug challenge their
responses would have also shown a minimal fall in
pulmonary pressure and pulmonary vascular resistance
similar to that in previously published trials. By administering high doses of calcium-channel blockers
reductions in pulmonary arterial pressure of 48% and
in pulmonary vascular resistance of 60% were
achieved in 62% (eight of 13) patients without causing
systemic hypotension. We have previously noted that
spontaneous changes in pulmonary hemodynamics
could result in a lowering of pulmonary arterial pressure by as much as 22%. " The magnitude of changes
observed in this trial, however, make it unlikely that
spontaneous variability was responsible for these
results.
Although the large fall in mean pulmonary arterial
pressure and pulmonary vascular resistance seen was
encouraging, it was felt that demonstration of longterm drug efficacy was necessary in order for these
findings to be truly meaningful. For that reason we
have chosen to wait 1 year until some follow-up hemodynamic studies could be performed to evaluate our
treatment. In four of the five patients restudied there
occurred a sustained reduction in both pulmonary arterial pressure and pulmonary vascular resistance that
was associated with regression of right ventricular hypertrophy documented by electrocardiography, a reduction in right ventricular cavity size documented by
echocardiography, and a return to a nornal, symptomfree lifestyle. In one patient, the short-term effects of
the treatment were not sustained, although she did not
differ from the other responders with respect to the
baseline level or magnitude of reduction in pulmonary
arterial pressure or pulmonary vascular resistance. She
did, however, complain of drug side effects (primarily
leg edema and dizziness) that resulted in a reduction in
the previously determined "effective" dosage.
Data from the five patients who failed to respond to
the high-dose drug challenge were also analyzed.
These patients did not differ from the responders with
regard to their ages, duration of symptoms, baseline
level of pulmonary arterial pressure, or pulmonary
vascular resistance. Rather, they differed only in the
inability of drug challenge to substantially lower their
139
RICH and BRUNDAGE
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pulmonary arterial pressures or in the development of
untoward side effects.
Substantial reductions in pulmonary arterial pressure in patients with PPH have been noted in several case reports by other investigators using a variety of vasodilators, including the calcium-channel
blockers. 2 These patients responded to conventional
doses of the drugs used, suggesting that their disease
was less advanced. That the initial mean pulmonary
arterial pressure was generally less than 50 mm Hg
would support this. Had we limited our assessment of
drug efficacy to conventional testing, however, none
of our responding patients would have been placed on
long-term therapy.
The reason for the apparent selective pulmonary
effects of the calcium-channel blockers in the responders is not obvious. However, it has been shown that
calcium-channel blockers reduce systemic arterial
pressure in patients with essential hypertension but not
in normal controls20 and relieve coronary artery spasm
in patients with Printzmetal's angina while having little effect on either systemic and pulmonary pressures.2` Thus, it appears that, rather than being selective for a specific arterial bed, calcium-channel
blockers work selectively on vascular smooth muscle
that has heightened tone and is vasoconstricted, leaving the other vasculatures largely unaffected. That we
required large doses of calcium-channel blockers in
our patients with PPH suggests that there is a different
sensitivity of the vascular beds or disease states to the
effects of calcium-channel blockade. The nonresponders probably have vascular changes that are too
advanced to permit pulmonary vascular smooth muscle relaxation and vasodilation.22 The drop in systemic
arterial pressure in these patients after the very high
doses of calcium-channel blockers may be related to
both direct effects on systemic vascular tone and other
effects that the calcium-channel blockers can have on
blood pressure through antisympathetic actions at aadrenergic receptors.23
That we have not seen the adverse responses noted
by Packer et al.,24 who administered nifedipine for
PPH, we believe is due to the magnitude of the reduction in pulmonary arterial pressure we noted, which
would offset the negative inotropic properties of the
drug. In addition, we administered digoxin to all of
these patients, although whether this makes a difference clinically is speculative. Finally, the mean right
atrial pressures of the patients in Packer's series were
considerably higher than those of our patients, suggesting they had considerable impairment of right ventricular function. In any case, caution must still be
140
emphasized when administering calcium-channel
blockers to any patient with PPH.
The patient who responded favorably to the highdose calcium channel-blocker regimen but then died
after the reduction in her therapy 6 months later also
supports the notion that active pulmonary vasoconstriction is occurring in these patients. Rebound pulmonary hypertension has been reported on the cessation of vasodilator drugs by others,'6' 19 and should
serve to caution physicians against the sudden withdrawal of therapy in these patients.
We conclude that sustained reductions in pulmonary
arterial pressure and pulmonary vascular resistance
that are associated with regression of right ventricular
hypertrophy are possible in some patients with PPH by
use of calcum channel-blocking drug therapy. The
response to conventional doses appears inadequate,
however, to identify those patients in whom these effects are possible with higher doses. The testing of
high doses of calcium-channel blockers should be done
only with direct hemodynamic monitoring to watch for
adverse hemodynamic effects, be it systemic hypotension or increasing right atrial pressure. Further studies
are also needed to determine why some patients benefit
whereas others do not. In addition, whether patients
with pulmonary hypertension as a result of other forms
of obstructive pulmonary vascular disease will respond
similarly remains untested.
That the reductions in pulmonary pressure and resistance have been maintained for 1 year leads us to
cautious optimism about the medical management of
patients with PPH. Whether or not those patients exhibiting this response to high-dose calcium-channel
blockade will maintain these effects for periods longer
than 1 year can only be answered by continued longterm
follow-up.
We thank Karen Kieras, R.N., for her invaluable assistance
in caring for these patients and Paul Levy, ScD., for his helpful
review of this manuscript.
References
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2. Olivari MT, Levine TB, Weir EK, Cohn JN: Hemodynamic effects
of nifedipine at rest and during exercise in primary pulmonary
hypertension. Chest 86: 14, 1984
3. Packer M, Greenberg B, Massie B, Dash H: Deleterious effects of
hydralazine in patients with primary pulmonary hypertension. N
Engl J Med 306: 1326, 1982
4. Packer M, Medina N, Yushak M: Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension
secondary to obliterative pulmonary vascular disease. J Am Coll
Cardiol 4: 890, 1984
5. Rich S, Ganz R, Levy PS: Comparative effects of hydralazine,
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CIRCULATION
THERAPY AND PREVENTION-PULMONARY
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141
High-dose calcium channel-blocking therapy for primary pulmonary hypertension:
evidence for long-term reduction in pulmonary arterial pressure and regression of right
ventricular hypertrophy.
S Rich and B H Brundage
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Circulation. 1987;76:135-141
doi: 10.1161/01.CIR.76.1.135
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