Cardiovascular Drugs and Therapy 1991;5:719-726 9 Kluwer Academic Publishers, Boston. Printed in U.S.A.
Amiloride Improves Hemodynamics in Patients with Chronic Congestive Heart Failure Treated with Chronic Digoxin and Diuretics Melvin D. Cheitlin, R a n d o l p h Byrd, Neal Benowitz, Eric Liu, a n d G u n n a r d Modin Cardiology Division, San Francisco General Hospital, San Francisco, CA, USA
Summary. Potassium-sparing diuretics have been reported to
decrease the positive inotropic effect of digoxin. We studied the hemodynamic effects of amiloride in patients taking digoxin for chronic heart failure. Eleven men with a history of congestive heart failure were studied in a double blind, cross-over, placebo controlled trial with the patients on digoxin alternating placebo with amiloride. After 7 days on the trial drug, a Swan-Ganz catheter was placed in the pulmonary artery and measurements made at rest and with increasing degrees of supine bicycle exercise. Right-sided and pulmonary artery wedge pressures and systemic arterial pressures, as well as cardiac outputs, were measured. After a 7 day washout period, placebo (P) and Amiloride (A) were switched and after 7 days on the therapy, a second hemodynamic study at rest and varying degrees of supine bicycle exercise was repeated. At rest there were no significant differences in the rightsided, pulmonary arterial wedge pressure or cardiac outputs between the patients on Amiloride (A) versus placebo (P). During exercise there were significant differences between (P) and (A) at the 50 watt-second stage of exercise. Right a t r i a l p r e s s u r e s ( P = 15.0 +- 6.8 mm Hg vs A = 10.5 - 5.4 mm Hg), PA wedge pressure (P -- 28.6 -+ 8.5 vs A -- 22.1 -+ 7.3 mm Hg), PA diastolic pressure (P -- 32.2 -+ 9.9 mm Hg) vs A = 21.6 - 10.0 mm Hg), and mean PA pressure (P = 44.4 + 11.0 vs A --- 38.9 - 12.5 mm Hg), were all lower on (A) than on (P) and the left ventricular stroke work index (LVSWI) (P -- 69.5 --+ 18.0 vs A -- 77.9 --- 22.2 Gm-m/m2), stroke volume index (P -- 44.9 • 8.8 vs A -- 46.2 -+ 11.4) cc/beat/m2 were higher than on placebo. This study clearly demonstrates no decrease in the inotropic action of digoxin when A was added to a regimen of digoxin and diuretics combined, and may possibly improve ventricular performance compared to digoxin and diuretics alone. The mechanism by which the A improves the ventricular function and promptly increases the inotropic effect in patients taking digoxin is unclear. The addition of (A) to digoxin appears to be safe and may provide clinical benefit above and beyond potassium-sparing.
of p a t i e n t s w i t h c o n g e s t i v e h e a r t failure. I n the past, i n t e r a c t i o n s b e t w e e n t h e p o t a s s i u m - s p a r i n g diuretics amiloride a n d s p i r o n o l a c t o n e a n d digoxin have b e e n s h o w n to d e c r e a s e t h e p o s i t i v e inotropic effect of dig o x i n [1-3]. I n view of t h e s e s t u d i e s a n d the wides p r e a d c o n c o m i t a n t u s e of d i g o x i n w i t h p o t a s s i u m s p a r i n g d i u r e t i c s , we s t u d i e d t h e h e m o d y n a m i c effects of amiloride in p a t i e n t s t a k i n g digoxin for chronic cong e s t i v e h e a r t failure.
Me~o~
drugs.
E l e v e n male p a t i e n t s w i t h a h i s t o r y of c o n g e s t i v e h e a r t failure a n d a t l e a s t o n e episode of p u l m o n a r y e d e m a w e r e studied. T h e e t i o l o g y of t h e h e a r t failure was c o r o n a r y a r t e r y d i s e a s e in n i n e a n d cardiomyopat h y in t w o p a t i e n t s . T h e m e a n age of t h e p a t i e n t s was 63 -- 11 (S.D.) y e a r s . F o u r p a t i e n t s w e r e N e w York H e a r t A s s o c i a t i o n Class I I I , a n d s e v e n w e r e Class II. All p a t i e n t s w e r e c o n t i n u e d on digoxin 0.125 or 0.25 m g daily w i t h h y d r o c h l o r o t h i a z i d e 50 or 100 m g p e r d a y t h r o u g h o u t t h e s t u d y . O n e of t h e p a t i e n t s rem a i n e d on his p r e s t u d y t h e r a p y of f u r o s e m i d e 80 m g p e r day. All p a t i e n t s r e c e i v e d s u p p l e m e n t a l p o t a s s i u m chloride t h r o u g h o u t t h e s t u d y to keep s e r u m potass i u m b e t w e e n 3.5 a n d 4.5 mEq/1. T h e s t u d y plan is d i a g r a m m e d i n F i g u r e 1. D u r i n g a 2 - w e e k b a s e l i n e period, t h e p a t i e n t s w e r e s e e n w e e k l y a n d i n s t r u c t e d to c o n s u m e a diet cont a i n i n g 100 m E q s o d i u m a n d 80 m E q p o t a s s i u m . Ser u m a n d u r i n e e l e c t r o l y t e s a n d c r e a t i n i n e w e r e monit o r e d w e e k l y to a s s e s s a d h e r e n c e to t h e diet a n d s t a b i l i t y of l a b o r a t o r y p a r a m e t e r s . A physical examin a t i o n , 12-lead e l e c t r o c a r d i o g r a m , a n d chest r o e n t g e n o g r a m w e r e o b t a i n e d a t b a s e l i n e a n d at follow-up.
D i g i t a l i s is a t p r e s e n t t h e oldest and still the only inotropic a g e n t t h a t is u s e d i n t h e chronic t r e a t m e n t
Address for correspondence and reprint requests: Melvin D. Cheitlin, M.D., Cardiology Division, Room 5G1, San Francisco General Hospital, San Francisco, CA 94110, USA.
Cardiovasc Drugs Ther 1991;5:719-726
Key Words:Digitalis; Potassium-sparing diuretics; Inotropic
7/9
720
Cheitlin, Byrd, Benowitz, Liu, and Modin
{ ~lAM| " L7ORIDE)( GROUP I
2 WEEKS Stable on DIgoxin and Dluretlcs
(1 week)
(§ PLACEBO) / GROUP n
GROUP I (+ PLACEBO)
1 WEEK V~ashout on Placebo
(1 week)
GROUP II (+AMILORIDE)
A=Supine Bicycle Exercise R=Right Heart Cath., Rest and Exercise
Fig. 1. Study plan. The design is a placebo-controlled, double-blind, cross-over study of the hemodynamic effects of amiloride when added to digoxin.
At the end of week 2 of the baseline period, patients w e r e hospitalized overnight at the Clinical Study C e n t e r of San Francisco General Hospital. During this time, a practice, graded, supine bicycle exercise t e s t was p e r f o r m e d at 0 (free-wheeling), 25, and 50 watt-second loads for 3 minutes at each stage. All patients completed the 9 minutes of exercise. At discharge the patients w e r e randomized in a double-blind, cross-over fashion to t r e a t m e n t group I or II. Group I received, in addition to their usual digoxin and diuretic therapy, 5 or 10 m g of amiloride daily, depending on w h e t h e r they w e r e taking 50 or 100 mg or hydrochlorothiazide, for 1 week. Group I I received a placebo instead of amiloride. At the end of the 7-day t r e a t m e n t period, the patients w e r e again hospitalized overnight. R e s t and exercise radionuclide angiography, using a gated equilibrium method with in vivo Tc-99M/pertechnetate-labeled r e d blood cells, was obtained in the 45 ~ left anterior oblique projection to m e a s u r e the left ventricular ejection fraction. Supine bicycle exercise was done at a 50 watt-second load. A f t e r 3 minutes of exercise, the left ventricular ejection fraction was m e a s u r e d again. All m e a s u r e m e n t s were made 4-6 hours a f t e r the morning digoxin and diuretic doses. H e m o d y n a m i c m e a s u r e m e n t s w e r e obtained during right h e a r t catheterization. A Swan-Ganz balloontipped thermodilution c a t h e t e r was inserted percutaneously t h r o u g h an antecubital vein. Hemodynamic m e a s u r e m e n t s w e r e made at r e s t and at t h r e e levels of supine bicycle exercise: 0, 25, and 50 watt-seconds. H e m o d y n a m i c m e a s u r e m e n t s w e r e begun 2 minutes after the onset of the workload at each stage. Pressures, both phasic and mean, w e r e obtained in the right atrium, p u l m o n a r y artery, and pulmonary art e r y w e d g e position, and three thermodilution cardiac outputs w e r e m e a s u r e d and averaged. Systemic blood p r e s s u r e was obtained indirectly b y cuff m e a s u r e m e n t
in the opposite u p p e r arm. A f t e r the m e a s u r e m e n t s were obtained, the exercise level was increased. The time at each stage varied from 4 to 5 minutes, depending on the t i m e needed to collect the hemodynamic data. All patients completed the t h r e e stages of exercise. A f t e r exercise the patients' legs were t a k e n down off the bicycle pedals. Hemodynamics were also measured at 3 and 6 minutes after the cessation of exercise. The following w e e k was a 7-day washout period, in which both groups I and I I received placebo in addition to the usual digoxin and diuretic therapy. A f t e r this washout week, urine and serum electrolytes, creatinine, and a practice-graded supine bicycle exercise test were obtained as before. The t r e a t m e n t groups were reversed, and in the w e e k following the washout phase group I now received placebo and group I I received amiloride. After 7 days of t h e r a p y , the patients were readmitted to the hospital, and r e p e a t radioisotope ejection fractions at r e s t and with supine bicycle exercise were again obtained. The next day a right heart catheterization with percutaneous Swan-Ganz catheter was repeated, as described previously. Hemodynamic values are presented as m e a n - one standard deviation, except where otherwise mentioned. The mean systemic pressure was calculated as systolic pressure minus diastolic pressure divided b y 3 plus the diastolic pressure. L V S W I = (systolic blood pressure - PAW) SVI x 0.136, w h e r e LVSW
= left ventricular stroke work index (Gm-m/ m 2 b o d y surface area)
PAW
= pulmonary (mmHg)
SVI
= stroke volume index (cc/beat/m e body surface area)
SVR
= m e a n arterial blood pressure-RA/CO x 80, w h e r e
arterial
wedge
pressure
SVR = systemic vascular resistance (dyne-sec cm
- 5)
RA
= m e a n right atrial pressure (mmHg)
CO
= cardiac output (1/min)
Statistical analysis The data for each of the hemodynamic variables w e r e analyzed using a r e p e a t e d measures analysis of variance. Tukey's method was used for posterior analysis. Student's t t e s t was used w h e r e it was appropriate. A significant difference was assessed at a p < 0.05 value.
Amiloride in Chronic Heart Failure
721
Table 1. Summary of hemodynamic data PA (mmHg)
RA (mmHg) Placebo Supine r e s t Exercise 3 min 9 rain Recovery 6 rain
Amiloride
Placebo
Amiloride
Placebo
Amiloride
AOS (mmHg)
AOD (mmHg)
Placebo
Amiloride
Placebo
Amiloride
84.8 • 8.9
5.5 • 3.1
5.5 • 3.0
18.5 • 6.2
17.3 • 4.1
9.9 • 6.2
8.4 • 3.7
126.3 • 10.3
128.6 • 9.3
10.3 -+ 3.9 15.0 • 6.8
7.8 • 2.6 10.5 -+ 5.4
32.8 • 9.3 44.4 +- 11.0
27.0 • 8.0 20.3 • 6.9 38.9 • 12.5 28.6 • 8.5
14.8 • 4.8 22.1 • 7.3
140.6 • 13.3 160.7 • 12.1
139.8 • 14.4 85.8 • 11.9 167.7 • 14.2 98.2 • 10.2
94.1 • 13.6 100.5 • 10.5
6.5 • 2.8
5.5 • 2.5
25.2 • 10.2
20.4 • 7.4
9.5 • 3.4
136.5 • 10.5
135.5 • 12.2 85.2 -+ 8.4
87.5 • 13.0
H R (beats/min) Placebo Supine r e s t Exercise 3 min 9 rain Recovery 6rain
PCW (mmHg)
Amiloride
11.3 • 6.0
CI (1/min/m z) Placebo
S V I ( m l / b e a t / m 2)
Amiloride
Placebo
Amiloride
S V R ( d y n e - s e c / c m -5) Placebo
85.9 • 13.6
L V S W I ( g m - m / m 2)
Amiloride
Placebo
Amiloride
69.0 + 13.2
72.5 • 14.6
2.6 +- 0.4
2.4 • 0.4
39.0 • 7.1
34.9 • 8.5
1570 • 285
1725 • 370
54.6 • 12.6
50.5 • 14.5
80.1 • 14.6 102.9 • 15.5
81.5 • 14.0 101.7 • 17.4
3.5 • 0.7 4.5 • 0.7
3.3 • 0.6 4.6 • 0.8
44.3 • 9.7 44.9 • 8.8
42.1 • 9.3 46.2 • 11.4
1295 • 270 1110 • 205
1360 -+ 223 1145 • 221
62.3 • 19.8 69.5 -+ 18.0
63.3 +- 18.0 77.9 +- 22.2
3.0•
2.7•
40.5•
36.0•
1470•
1585•
60.5•
53.9+-11.1
74.9•
77.2•
A O S = a o r t i c s y s t o l i c p r e s s u r e ; A O D = a o r t i c diastolic p r e s s u r e ; H R = h e a r t r a t e .
Results There was no significant difference between the serum digoxin levels at the beginning of the first randomization period in the placebo group (0.92 • 0.20 ng/ml) and the amiloride group (0.96 • 0.21 ng/ml). The effect of adding amiloride on hemodynamics was examined at rest and with exercise (Table 1). Hemodynamically these patients were well controlled by their medications, as can be seen by their resting hemodynamics. At rest there were no significant differences between the placebo and amiloride periods in right atrial pressure, pulmonary atrial pressure, heart rate, pulmonary a r t e r y wedge pressure, systemic atrial pressure, R V S W I , LVSKI, systemic vascular resistance, cardiac index, or stroke volume index (Figure 2). During exercise (Table 1) there were significant differences between the placebo (P) and atolloride (A) periods at the 50 watt-second (or third) stage of exercise. The right atrial pressure (P = 15.0 • 6.8mmHg vs. A = 10.5 • 5.4 mmHg), pulmonary a r t e r y wedge pressure (P = 28.6 • 8.5 m m H g vs. A = 22.1 -- 7.3 mmHg), pulmonary a r t e r y diastolic pressure (P = 32.2 • 9.9 m m H g vs. P = 21.6 • 10.0 mmHg), and mean pulmonary artery pressure (P = 44.4 • 11.0 m m H g vs. A = 38.9 • 12.5 mmHg) were lower on amiloride than on placebo, and the LVSWI (P = 69.5 • 18.0 Gm-m/m 2 vs. A = 77.9 • 22.2 Gm-m/m 2) and, stroke volume index (P = 44.9 • 8.8 cc/beat/m z vs. A = 46.2 • 11.4 cc/beat/m 2) were higher on amiloride than on placebo. There were no significant differences between placebo and amiloride groups at the third stage of exercise in RVSWI, heart rate, aortic pressure, cardiac index, and total sys-
temic vascular resistance. A summary of the multivariate analysis of the amiloride effect at rest and at exercise on the hemodynamics is given in Table 2. The g r e a t e s t differences were seen in the increases from rest to third stage in pulmonary a r t e r y pressure (P = 18.7 • 6.6 m m H g vs. A = 13.7 -- 6 m m H g , p < .001), stroke volume index (P = 5.9 • 30 m m H g vs. A = 11.3 -- 5.4 m m H g , p < .05), and L V S W I (P = 15.0 • 1 0 . 1 m m H g vs. A = 27.4 • 13.3mmHg, p < .005) (Figure 3). There were no statistically significant differences b e t w e e n amiloride and placebo in the change from rest to the third stage of exercise in heart
PLACEBO H E A R T RATE RA PCW AORTIC MEAN PRESSURE
69.0
__+ 1 3 . 2
72.5
+
14.6
3.1
5.5
+
3.0
+ 6.2
8.4
+
3.7
S.S + 9.9
AMILORIDE
97.5
+
10.2
99.1
-t- 14.1
CI
2.6
+
0.4
SVI
39.0
_.+ 7.1
34.9
-t- 8 . 5
LVSWI
54.6
_.+ 1 2 . 6
50.5
+
14.5
SVR
1570
-I- 2 8 5
1725
+
370
2.4 +
0.4
NO SIG. DIFFERENCES
Fig. 2. Resting hemodynamics with patients taking digoxin when on placebo and when on amiloride. Units: heart rate (beats/min), pressures (mmHg), cardiac index (l/min/m2), stroke volume index (cc/beat/m2), LVSWI
(gin-m/m2).
722
Cheitlin, Byrd, Benowitz, Liu, and Modin
Table 2. Summary of multivariant analysis of amiloride vs. placebo effect on rest and exercise hemodynamics
RA PAs PA RVSWI PAW AOS AOD
AO HR
CO CI SVI LVSWI SVR
Amiloride baseline value vs. 9-minute exercise p value
Placebo vs. amiloride baseline value to 9-minute exercise p value
Amiloride Improves Hemodynamics in Patients with Chronic Congestive Heart Failure Treated with Chronic Digoxin and Diuretics Melvin D. Cheitlin, R a n d o l p h Byrd, Neal Benowitz, Eric Liu, a n d G u n n a r d Modin Cardiology Division, San Francisco General Hospital, San Francisco, CA, USA
Summary. Potassium-sparing diuretics have been reported to
decrease the positive inotropic effect of digoxin. We studied the hemodynamic effects of amiloride in patients taking digoxin for chronic heart failure. Eleven men with a history of congestive heart failure were studied in a double blind, cross-over, placebo controlled trial with the patients on digoxin alternating placebo with amiloride. After 7 days on the trial drug, a Swan-Ganz catheter was placed in the pulmonary artery and measurements made at rest and with increasing degrees of supine bicycle exercise. Right-sided and pulmonary artery wedge pressures and systemic arterial pressures, as well as cardiac outputs, were measured. After a 7 day washout period, placebo (P) and Amiloride (A) were switched and after 7 days on the therapy, a second hemodynamic study at rest and varying degrees of supine bicycle exercise was repeated. At rest there were no significant differences in the rightsided, pulmonary arterial wedge pressure or cardiac outputs between the patients on Amiloride (A) versus placebo (P). During exercise there were significant differences between (P) and (A) at the 50 watt-second stage of exercise. Right a t r i a l p r e s s u r e s ( P = 15.0 +- 6.8 mm Hg vs A = 10.5 - 5.4 mm Hg), PA wedge pressure (P -- 28.6 -+ 8.5 vs A -- 22.1 -+ 7.3 mm Hg), PA diastolic pressure (P -- 32.2 -+ 9.9 mm Hg) vs A = 21.6 - 10.0 mm Hg), and mean PA pressure (P = 44.4 + 11.0 vs A --- 38.9 - 12.5 mm Hg), were all lower on (A) than on (P) and the left ventricular stroke work index (LVSWI) (P -- 69.5 --+ 18.0 vs A -- 77.9 --- 22.2 Gm-m/m2), stroke volume index (P -- 44.9 • 8.8 vs A -- 46.2 -+ 11.4) cc/beat/m2 were higher than on placebo. This study clearly demonstrates no decrease in the inotropic action of digoxin when A was added to a regimen of digoxin and diuretics combined, and may possibly improve ventricular performance compared to digoxin and diuretics alone. The mechanism by which the A improves the ventricular function and promptly increases the inotropic effect in patients taking digoxin is unclear. The addition of (A) to digoxin appears to be safe and may provide clinical benefit above and beyond potassium-sparing.
of p a t i e n t s w i t h c o n g e s t i v e h e a r t failure. I n the past, i n t e r a c t i o n s b e t w e e n t h e p o t a s s i u m - s p a r i n g diuretics amiloride a n d s p i r o n o l a c t o n e a n d digoxin have b e e n s h o w n to d e c r e a s e t h e p o s i t i v e inotropic effect of dig o x i n [1-3]. I n view of t h e s e s t u d i e s a n d the wides p r e a d c o n c o m i t a n t u s e of d i g o x i n w i t h p o t a s s i u m s p a r i n g d i u r e t i c s , we s t u d i e d t h e h e m o d y n a m i c effects of amiloride in p a t i e n t s t a k i n g digoxin for chronic cong e s t i v e h e a r t failure.
Me~o~
drugs.
E l e v e n male p a t i e n t s w i t h a h i s t o r y of c o n g e s t i v e h e a r t failure a n d a t l e a s t o n e episode of p u l m o n a r y e d e m a w e r e studied. T h e e t i o l o g y of t h e h e a r t failure was c o r o n a r y a r t e r y d i s e a s e in n i n e a n d cardiomyopat h y in t w o p a t i e n t s . T h e m e a n age of t h e p a t i e n t s was 63 -- 11 (S.D.) y e a r s . F o u r p a t i e n t s w e r e N e w York H e a r t A s s o c i a t i o n Class I I I , a n d s e v e n w e r e Class II. All p a t i e n t s w e r e c o n t i n u e d on digoxin 0.125 or 0.25 m g daily w i t h h y d r o c h l o r o t h i a z i d e 50 or 100 m g p e r d a y t h r o u g h o u t t h e s t u d y . O n e of t h e p a t i e n t s rem a i n e d on his p r e s t u d y t h e r a p y of f u r o s e m i d e 80 m g p e r day. All p a t i e n t s r e c e i v e d s u p p l e m e n t a l p o t a s s i u m chloride t h r o u g h o u t t h e s t u d y to keep s e r u m potass i u m b e t w e e n 3.5 a n d 4.5 mEq/1. T h e s t u d y plan is d i a g r a m m e d i n F i g u r e 1. D u r i n g a 2 - w e e k b a s e l i n e period, t h e p a t i e n t s w e r e s e e n w e e k l y a n d i n s t r u c t e d to c o n s u m e a diet cont a i n i n g 100 m E q s o d i u m a n d 80 m E q p o t a s s i u m . Ser u m a n d u r i n e e l e c t r o l y t e s a n d c r e a t i n i n e w e r e monit o r e d w e e k l y to a s s e s s a d h e r e n c e to t h e diet a n d s t a b i l i t y of l a b o r a t o r y p a r a m e t e r s . A physical examin a t i o n , 12-lead e l e c t r o c a r d i o g r a m , a n d chest r o e n t g e n o g r a m w e r e o b t a i n e d a t b a s e l i n e a n d at follow-up.
D i g i t a l i s is a t p r e s e n t t h e oldest and still the only inotropic a g e n t t h a t is u s e d i n t h e chronic t r e a t m e n t
Address for correspondence and reprint requests: Melvin D. Cheitlin, M.D., Cardiology Division, Room 5G1, San Francisco General Hospital, San Francisco, CA 94110, USA.
Cardiovasc Drugs Ther 1991;5:719-726
Key Words:Digitalis; Potassium-sparing diuretics; Inotropic
7/9
720
Cheitlin, Byrd, Benowitz, Liu, and Modin
{ ~lAM| " L7ORIDE)( GROUP I
2 WEEKS Stable on DIgoxin and Dluretlcs
(1 week)
(§ PLACEBO) / GROUP n
GROUP I (+ PLACEBO)
1 WEEK V~ashout on Placebo
(1 week)
GROUP II (+AMILORIDE)
A=Supine Bicycle Exercise R=Right Heart Cath., Rest and Exercise
Fig. 1. Study plan. The design is a placebo-controlled, double-blind, cross-over study of the hemodynamic effects of amiloride when added to digoxin.
At the end of week 2 of the baseline period, patients w e r e hospitalized overnight at the Clinical Study C e n t e r of San Francisco General Hospital. During this time, a practice, graded, supine bicycle exercise t e s t was p e r f o r m e d at 0 (free-wheeling), 25, and 50 watt-second loads for 3 minutes at each stage. All patients completed the 9 minutes of exercise. At discharge the patients w e r e randomized in a double-blind, cross-over fashion to t r e a t m e n t group I or II. Group I received, in addition to their usual digoxin and diuretic therapy, 5 or 10 m g of amiloride daily, depending on w h e t h e r they w e r e taking 50 or 100 mg or hydrochlorothiazide, for 1 week. Group I I received a placebo instead of amiloride. At the end of the 7-day t r e a t m e n t period, the patients w e r e again hospitalized overnight. R e s t and exercise radionuclide angiography, using a gated equilibrium method with in vivo Tc-99M/pertechnetate-labeled r e d blood cells, was obtained in the 45 ~ left anterior oblique projection to m e a s u r e the left ventricular ejection fraction. Supine bicycle exercise was done at a 50 watt-second load. A f t e r 3 minutes of exercise, the left ventricular ejection fraction was m e a s u r e d again. All m e a s u r e m e n t s were made 4-6 hours a f t e r the morning digoxin and diuretic doses. H e m o d y n a m i c m e a s u r e m e n t s w e r e obtained during right h e a r t catheterization. A Swan-Ganz balloontipped thermodilution c a t h e t e r was inserted percutaneously t h r o u g h an antecubital vein. Hemodynamic m e a s u r e m e n t s w e r e made at r e s t and at t h r e e levels of supine bicycle exercise: 0, 25, and 50 watt-seconds. H e m o d y n a m i c m e a s u r e m e n t s w e r e begun 2 minutes after the onset of the workload at each stage. Pressures, both phasic and mean, w e r e obtained in the right atrium, p u l m o n a r y artery, and pulmonary art e r y w e d g e position, and three thermodilution cardiac outputs w e r e m e a s u r e d and averaged. Systemic blood p r e s s u r e was obtained indirectly b y cuff m e a s u r e m e n t
in the opposite u p p e r arm. A f t e r the m e a s u r e m e n t s were obtained, the exercise level was increased. The time at each stage varied from 4 to 5 minutes, depending on the t i m e needed to collect the hemodynamic data. All patients completed the t h r e e stages of exercise. A f t e r exercise the patients' legs were t a k e n down off the bicycle pedals. Hemodynamics were also measured at 3 and 6 minutes after the cessation of exercise. The following w e e k was a 7-day washout period, in which both groups I and I I received placebo in addition to the usual digoxin and diuretic therapy. A f t e r this washout week, urine and serum electrolytes, creatinine, and a practice-graded supine bicycle exercise test were obtained as before. The t r e a t m e n t groups were reversed, and in the w e e k following the washout phase group I now received placebo and group I I received amiloride. After 7 days of t h e r a p y , the patients were readmitted to the hospital, and r e p e a t radioisotope ejection fractions at r e s t and with supine bicycle exercise were again obtained. The next day a right heart catheterization with percutaneous Swan-Ganz catheter was repeated, as described previously. Hemodynamic values are presented as m e a n - one standard deviation, except where otherwise mentioned. The mean systemic pressure was calculated as systolic pressure minus diastolic pressure divided b y 3 plus the diastolic pressure. L V S W I = (systolic blood pressure - PAW) SVI x 0.136, w h e r e LVSW
= left ventricular stroke work index (Gm-m/ m 2 b o d y surface area)
PAW
= pulmonary (mmHg)
SVI
= stroke volume index (cc/beat/m e body surface area)
SVR
= m e a n arterial blood pressure-RA/CO x 80, w h e r e
arterial
wedge
pressure
SVR = systemic vascular resistance (dyne-sec cm
- 5)
RA
= m e a n right atrial pressure (mmHg)
CO
= cardiac output (1/min)
Statistical analysis The data for each of the hemodynamic variables w e r e analyzed using a r e p e a t e d measures analysis of variance. Tukey's method was used for posterior analysis. Student's t t e s t was used w h e r e it was appropriate. A significant difference was assessed at a p < 0.05 value.
Amiloride in Chronic Heart Failure
721
Table 1. Summary of hemodynamic data PA (mmHg)
RA (mmHg) Placebo Supine r e s t Exercise 3 min 9 rain Recovery 6 rain
Amiloride
Placebo
Amiloride
Placebo
Amiloride
AOS (mmHg)
AOD (mmHg)
Placebo
Amiloride
Placebo
Amiloride
84.8 • 8.9
5.5 • 3.1
5.5 • 3.0
18.5 • 6.2
17.3 • 4.1
9.9 • 6.2
8.4 • 3.7
126.3 • 10.3
128.6 • 9.3
10.3 -+ 3.9 15.0 • 6.8
7.8 • 2.6 10.5 -+ 5.4
32.8 • 9.3 44.4 +- 11.0
27.0 • 8.0 20.3 • 6.9 38.9 • 12.5 28.6 • 8.5
14.8 • 4.8 22.1 • 7.3
140.6 • 13.3 160.7 • 12.1
139.8 • 14.4 85.8 • 11.9 167.7 • 14.2 98.2 • 10.2
94.1 • 13.6 100.5 • 10.5
6.5 • 2.8
5.5 • 2.5
25.2 • 10.2
20.4 • 7.4
9.5 • 3.4
136.5 • 10.5
135.5 • 12.2 85.2 -+ 8.4
87.5 • 13.0
H R (beats/min) Placebo Supine r e s t Exercise 3 min 9 rain Recovery 6rain
PCW (mmHg)
Amiloride
11.3 • 6.0
CI (1/min/m z) Placebo
S V I ( m l / b e a t / m 2)
Amiloride
Placebo
Amiloride
S V R ( d y n e - s e c / c m -5) Placebo
85.9 • 13.6
L V S W I ( g m - m / m 2)
Amiloride
Placebo
Amiloride
69.0 + 13.2
72.5 • 14.6
2.6 +- 0.4
2.4 • 0.4
39.0 • 7.1
34.9 • 8.5
1570 • 285
1725 • 370
54.6 • 12.6
50.5 • 14.5
80.1 • 14.6 102.9 • 15.5
81.5 • 14.0 101.7 • 17.4
3.5 • 0.7 4.5 • 0.7
3.3 • 0.6 4.6 • 0.8
44.3 • 9.7 44.9 • 8.8
42.1 • 9.3 46.2 • 11.4
1295 • 270 1110 • 205
1360 -+ 223 1145 • 221
62.3 • 19.8 69.5 -+ 18.0
63.3 +- 18.0 77.9 +- 22.2
3.0•
2.7•
40.5•
36.0•
1470•
1585•
60.5•
53.9+-11.1
74.9•
77.2•
A O S = a o r t i c s y s t o l i c p r e s s u r e ; A O D = a o r t i c diastolic p r e s s u r e ; H R = h e a r t r a t e .
Results There was no significant difference between the serum digoxin levels at the beginning of the first randomization period in the placebo group (0.92 • 0.20 ng/ml) and the amiloride group (0.96 • 0.21 ng/ml). The effect of adding amiloride on hemodynamics was examined at rest and with exercise (Table 1). Hemodynamically these patients were well controlled by their medications, as can be seen by their resting hemodynamics. At rest there were no significant differences between the placebo and amiloride periods in right atrial pressure, pulmonary atrial pressure, heart rate, pulmonary a r t e r y wedge pressure, systemic atrial pressure, R V S W I , LVSKI, systemic vascular resistance, cardiac index, or stroke volume index (Figure 2). During exercise (Table 1) there were significant differences between the placebo (P) and atolloride (A) periods at the 50 watt-second (or third) stage of exercise. The right atrial pressure (P = 15.0 • 6.8mmHg vs. A = 10.5 • 5.4 mmHg), pulmonary a r t e r y wedge pressure (P = 28.6 • 8.5 m m H g vs. A = 22.1 -- 7.3 mmHg), pulmonary a r t e r y diastolic pressure (P = 32.2 • 9.9 m m H g vs. P = 21.6 • 10.0 mmHg), and mean pulmonary artery pressure (P = 44.4 • 11.0 m m H g vs. A = 38.9 • 12.5 mmHg) were lower on amiloride than on placebo, and the LVSWI (P = 69.5 • 18.0 Gm-m/m 2 vs. A = 77.9 • 22.2 Gm-m/m 2) and, stroke volume index (P = 44.9 • 8.8 cc/beat/m z vs. A = 46.2 • 11.4 cc/beat/m 2) were higher on amiloride than on placebo. There were no significant differences between placebo and amiloride groups at the third stage of exercise in RVSWI, heart rate, aortic pressure, cardiac index, and total sys-
temic vascular resistance. A summary of the multivariate analysis of the amiloride effect at rest and at exercise on the hemodynamics is given in Table 2. The g r e a t e s t differences were seen in the increases from rest to third stage in pulmonary a r t e r y pressure (P = 18.7 • 6.6 m m H g vs. A = 13.7 -- 6 m m H g , p < .001), stroke volume index (P = 5.9 • 30 m m H g vs. A = 11.3 -- 5.4 m m H g , p < .05), and L V S W I (P = 15.0 • 1 0 . 1 m m H g vs. A = 27.4 • 13.3mmHg, p < .005) (Figure 3). There were no statistically significant differences b e t w e e n amiloride and placebo in the change from rest to the third stage of exercise in heart
PLACEBO H E A R T RATE RA PCW AORTIC MEAN PRESSURE
69.0
__+ 1 3 . 2
72.5
+
14.6
3.1
5.5
+
3.0
+ 6.2
8.4
+
3.7
S.S + 9.9
AMILORIDE
97.5
+
10.2
99.1
-t- 14.1
CI
2.6
+
0.4
SVI
39.0
_.+ 7.1
34.9
-t- 8 . 5
LVSWI
54.6
_.+ 1 2 . 6
50.5
+
14.5
SVR
1570
-I- 2 8 5
1725
+
370
2.4 +
0.4
NO SIG. DIFFERENCES
Fig. 2. Resting hemodynamics with patients taking digoxin when on placebo and when on amiloride. Units: heart rate (beats/min), pressures (mmHg), cardiac index (l/min/m2), stroke volume index (cc/beat/m2), LVSWI
(gin-m/m2).
722
Cheitlin, Byrd, Benowitz, Liu, and Modin
Table 2. Summary of multivariant analysis of amiloride vs. placebo effect on rest and exercise hemodynamics
RA PAs PA RVSWI PAW AOS AOD
AO HR
CO CI SVI LVSWI SVR
Amiloride baseline value vs. 9-minute exercise p value
Placebo vs. amiloride baseline value to 9-minute exercise p value
