Cardiovascular Drugs and Therapy 1991;5:629-634 9 Kluwer Academic Publishers, Boston. Printed in U.S.A.

Hemodynamic Evaluation of Bisoprolol After Coronary Artery Surgery in Patients with Altered Left Ventricular Function Marcelo Goldstein, Jean-Louis Vincent, Jean-Louis Le Clerc, A l a i n d'Hollander, Christian Melot, Robert J. K a h n Department of Intensive Care, Erasme UniversiW Hospital Free University of Brussels, Belgium

Summary. Bisoprolol is a n e w cardioselective betal adrenergic blocking agent w i t h o u t intrinsic s y m p a t h o m i m e t i c activity but with minimal effects on myocardial contractility. Bisoprolol w a s compared to propranolol in 24 patients after cardiac surgery for coronary artery bypass graft (CABG). Each patient had been treated preoperatively with betablocking agents and had a cineangiographic left ventricular ejection fraction between 35% and 55%. Patients were randomized to receive orally either 10 mg o f propranolol three times a day or 5 mg o f bisoprolol once a day. Both drugs resulted in a significant and similar decrease in heart rate. This was associated with significant decreases in cardiac index, stroke index, and thermodilution right ventricular ejection fraction 6 hours after administration o f propranolol, but not after bisoprolol. Systolic function measured by Doppler techniques significantly increased in the 10 postoperative days in patients under bisoprolol but not significantly after propranolol. Each drug w a s well tolerated during the 10 postoperative days, and the recovery was uneventful in each patient. These results indicate that in patients with altered systolic function after CABG, bisoprolol is susceptible to reduce heart rate with less cardiovascular alteration than propranolol. Cardiovasc Drugs Ther 1991;5:629-634

Key Words. bisoprolol,

coronary artery bypass graft, propranolol, left ventricular function

A f t e r cardiac surgery for coronary artery bypass graft (CABG), patients commonly develop supraventricular tachyarrhythmias that can be largely prevented by beta-blocking therapy [1-3]. Even though relatively small doses are usually sufficient, betablocking agents might depress myocardial function in the early postoperative period [4]. Bisoprolol is a new highly cardioselective betaadrenoceptor antagonists that seems to produce a minimal cardiodepressant effect [5-7]. Different studies showed that bisoprolol is a potent beta-blocking drug in patients with angina pectoris [8-10]. It has a long half-life (of approximately 12 hours), so that it

can be administered only once a day. It can be administered either intravenously or orally. The present study was therefore designed to evaluate the hemodynamic effects of bisoprolol and to compare them to those of propranolol, a nonselective beta-blocking agent, in patients after CABG. In addition to the conventional hemodynamic techniques, we measured right ventricular ejection fraction (RVEF) by the thermodilution technique [11,12], and we assessed systolic left ventricular function by Doppler measurements. Drug tolerance was also evaluated during the 10 first postoperative days.

Patients and Methods The ethics committee of our hospital approved the aim of the methodology of this study. On the day before CABG, details of this study were discussed with the patients and informed consent was obtained. We selected 24 patients prior to CABG who were currently under beta-blocking therapy and had a left ventricular ejection fraction (LVEF) measured by cineventriculography, between 35% and 55%. The clinical data are shown in Table 1. In addition to beta blockers, treatment consisted in nitrates (N = 10 patients), calcium antagonists (N = 11 patients), and dipyramidole (N = 15 patients). These drugs were interrupted 24 hours before CABG. On the preoperative day, a first Doppler study was performed to evaluate the systolic cardiac function. On the operative day, after induction of anesthesia, we inserted a pulmonary artery catheter equipped with a fast-response thermistor (Swan-Ganz catheter, model 93A-431H7.5F, Edwards Laboratories) and an arterial (radial)

Address for correspondenceand reprint requests: Jean-LouisVincent, MD, PhD, Departmentof Intensive Care, Erasme University Hospital, Route de Lennik808, B-1070Bruxelles, Belgium. 629

630

Goldstein, Vincent, Le Clerc, d'Hollander, Melot and Kahn

Table I. Trial population--clinical and surgical data

Sex (M/F) Age (years) LVEF (%) Duration of bypass (min) Duration of aortic cross-clamping (min) No of CABG

Bisoprolol (N = 12)

Propranolol (N = 12)

11/1 59 --- 1 45 -+ 2 105 +- 10 62 -+ 16

11/1 60 - 1 47 -+ 2 102 -+ 8 58 + 15

2.7 -+ 1

2.8 + 1

catheter. On the first postoperative day, 2 hours after extubation, each patient was randomly assigned to receive either bisoprolol or propranolol. Patients were not included if they had bronchospasm, bradycardia (heart rate below 60 beats/min), intraventricular or atrioventricular conduction defect, heart failure (cardiac index 15 mmHg), or acute myocardial infarction (significant elevation of CPK-MB or suggestive alteration in the electrocardiogram), or if t h e y were currently treated with adrenergic agent, digoxin, or pacemaker. Three patients had transient arterial hypertension treated with sodium nitroprusside until a few hours prior to the study. The patients were randomly assigned to receive orally either 10 mg three times a day of propranolol or 5 mg of bisoprolol, both doses being considered as equipotent [13]. The two groups were similar in age, sex, L V E F , duration of cardiopulmonary bypass or aortic cross-clamping, and n u m b e r of CABG (Table 1). Hemodynamic measurements were performed before and 1, 2, and 6 hours after the first dose of the beta-blocking agent. They included the determinations of heart rate (HR), arterial pressure (AP), pulmonary artery pressure (PAP), pulmonary artery balloon-occluded pressure (PAOP), right atrial pressure (RAP), cardiac output (CO), and R V E F . CO was measured by three to five successive injections of 10-ml aliquots of cold D5W and a closed system (COset system, Edwards Laboratory). R V E F was determined together with the CO ( R E F 1, Edwards Laboratory) using an algorithm based on building exponential curves in lieu of recognition of plateaus [11]. Normal thermodilution R V E F is around 45% [12]. Derived hemodynamic variables were calculated by standard formulas. Ultrasonic measurements taken both before and after CABG (before and 2 hours after the administration of the beta-blocking agent) were obtained by two-dimensional (2DE) 84~ phased array sector scanner (depth 4-24 cm) using a 2.5-MHz transducer

(Hewlett-Packard model 77020 A) with scan converter and pulsed Doppler and another 1.9-MHz probe for continuous Doppler. The 2DE and Doppler images were stored on videotape (Panasonic AG-6200). Doppler measurements of peak aortic blood velocity continuous (PABVC), peak outflow blood velocity pulsed (POBVP), and peak outflow blood acceleration pulsed (POBAP) were obtained by previously described techniques [14]. After the hemodynamic and 2DE-Doppler observations, the t r e a t m e n t was continued for 10 days, either with the administration of 5 mg of bisoprolol daily or 10 mg of propranolol three times a day. Echo-Doppler measurements were performed before surgery, within hours after CABG, on the first and the 10th postoperative days. Statistical analysis was performed by analysis of variance for repeated measures design. When the ratio of variance was above the critical value of 0.05, a modified t test was used to compare two means [15]. Results are presented as means --- SEM. Results

Patients treated with bisoprolol had initially slightly lower values of cardiac index, stroke index, and R V E F than patients treated with propranolol (differences not significant). The administration of bisoprolol or propranolol produced a comparable and significant decrease in heart rate (Table 2, F i g u r e 1). Mean arterial pressure, mean pulmonary arterial pressure, and mean cardiac filling pressure did not change significantly during this acute period (Table 2). During the 2 hours following the administration of either drug, cardiac index, stroke index, and R V E F diminished moderately (Table 2). Six hours after the administration, these parameters decreased further after propranolol, but not after bisoprolol (Figure 1). Right ventricutar end-diastolic volume indexes were identical in the two groups of patients. Systemic vascular resistance increased significantly 6 hours after the administration of propranolol but not after bisoprolol (Table 2). On the first postoperative day prior to the administration of beta-blocking agent, PABVC, POBVP, and POBAP were slightly lower in the bisoprolol group (differences not significant). Between the first and the 10th day after CABG, these p a r a m e t e r s increased in patients treated with bisoprolol but not in patients treated with propranolol (Table 3). The t r e a t m e n t was completed in all patients, and no complication occurred during the study. In particular, kidney and liver functions remained stable in all patients. No patient had angina or significant ECG

Bisoprolol After Coronary Artery Surgery

651

Table 2. Effects of bisoprolol and propranolol on hemodynamic parameters and systemic vascular resistance Bisoprolol Baseline HR (beats/min) CI (1/min/m2) S I ( m l / m i n / m 2) R V E F (%) MAP (mmHg) MPAP(mmHg) PAOP(mmHg) RAP(mmHg) SVR (dyne.sec.cm -5)

95 • 2.8 • 34• 43 • 94 • 22 • 13• 13 • 1266 •

1 hour 3 .2 3 3 1 1 88

Propranolol

2 hours

91 -3 • 31• 42 • 94 • 21 • 14 • 14 • 1305 •

3 .1 3 3 2 1 1 112

85 • 2.6 • 30• 40 • 92 • 20 • 15• 14 • 1371 •

6 hours 2b .1

83 • 2.6 • 32 • 41 • 94 • 20 • 13 • 13 • 1334 •

3 3 1 1 1 102

Baseline 25 .1 3 3 1 1 1 115

94 • 3.2 • 36• 46 • 98 • 21• 14• 13 • 1194 •

1 hour 4 .2 3 3 1 1 1 103

88 • 3 • 34 • 45 • 100 • 20 • 14 • 13 • 1307 •

2 hours 3 .2 2 3 1 1 1 103

86 3 • 34• 41 • 100 • 22 • 14 • 13 • 1354 •

6 hours 3b .2 3 4 1 1 1 114

82 2.4 • 30• 38 • 101 • 20• 14 • 15• 1497 •

3b .2 5

a 3b

4 1 1 1 135a

ap < 0.05.; bp < 0.01. HR = heart rate; CI = cardiac index; SI = stroke index; RVEF = right ventricular ejection fraction; MAP = mean arterial pressure; MPAP = mean pulmonary artery pressure; PAOP = pulmonary artery balloon-occluded pressure; RAP = right arterial pressure; SVR = systemic vascular resistance.

Table 3. Systolic function evaluation by Doppler measurements Bisoprolol

PABVC (cm/s) POBVP (cm/s) POBAP (cm/s/s)

Before CABG 87 - 7 87 -- 6 804 • 70

Propranolol

Baseline

After CABG Day 5

78 -- 5 73 • 6 686 • 101

75 - 9 68 • 7 565 • 68

day 10

Before CABG

91 -- 8b 91 • 4b 935 -- 57a

102 -- 7 90 • 6 849 - 100

Baseline

After CABG day 1

day 10

89 • 5 82 -- 7 956 • 185

84 • 7 84 • 11 853 - 83

88 - 9 99 • 8 936 -+ 85

~p < 0.05; bp < 0.01. PABVC = peak aortic blood velocity continuous; POBVP = peak outflow blood velocity pulsed; POBAP = peak outflow blood acceleration pulsed.

changes. No arrhythmia was detected, except for one HEART RATE

% 110'

STROKE INDEX

patient under propranolol treatment transient atrial fibrillation.

100'

+

80

a f t e r C A B G in p a t i e n t s w i t h a l t e r e d c a r d i a c f u n c t i o n . 6 hours

% 11o

Discussion The present study evaluated the effects of bisoprolol

7O

CARDIAC INDEX

who developed

RIGHT VENTRICULAR EJECTION FRACTION

B i s o p r o l o l h e m i f u m a r a t e is a n e w b e t a ] - a d r e n o c e p t o r antagonist that has a high degree of cardioselectivity [16,17] a n d m i n i m a l c a r d i a c d e p r e s s a n t e f f e c t s [ 5 - 7 ] . D u r i n g c o r o n a r y l i g a t u r e i n d o g s , H a r t i n g e t al. [18] demonstrated that bisoprolol protected left ventricul a r c o n t r a c t i l i t y d u r i n g i s c h e m i c d a m a g e . A l s o in p a -

90

=

tients, myocardial contractility does not seem to be

8O

a l t e r e d b y b i s o p r o l o l a s m u c h a s b y o t h e r d r u g s [5,6]. T h i s d r u g h a s a l r e a d y b e e n s h o w n t o i n c r e a s e t h e ef-

70 0

1 9

2 ,

f o r t c a p a c i t y in p a t i e n t s w i t h c o r o n a r y i n s u f f i c i e n c y

6 hours BISOPROLOL

~ --

PROPRANOLOL

9p