CONGESTIVE

HEART

FAILURE

Usefulness

of Bucindolol in Congestive Heart Failure

Stewart G. Pollock, MD, John Lystash, MD, Christine Tedesco, BSN, George Craddock, MD, and Mark L. Smucker, MD

The sympathetic hyperactivity of congestive heart failure (CHF) may worsen cardiovascular function by down-regulation of myocardial @-receptors. For this reason, @blockade is proposed to be useful in CHF. Bucinddld is a new @blocker that has intrinsic nonadrenergieally-mediated vasodilation and may be valuable in the treatment of CHF. To test this, 19 patients with CHF were randomized in a double-blind protocol to 3 months of treatment with bucindolol (n = 12) or placebo (n = 7). Significant improvement was seen in the bucindolol group using invasive and noninvasive tests; treadmill time increased from 445 to 530 seconds (p = 0.04), Minnesota Living With Heart Failure Questionnaire score improved from 61 to 40 (p = O.ooOl), cardiac output increased from 4.0 to 4.7 (p = 0.02), and systemic vascular resistance decreased from 1,666 to 1,481 (p = 0.64). Also, peak exercise heart rate and pulmonary capillary wedge pressure decreased significantly with treatment. There were no changes in the placebo group. We conclude that bucinddol may be an effective treatment for CHF when administered chronically and that its nonadrenergic vasodilation may be an important feature. (AmJ Cardiol 1996;66SO3-607)

From the Cardiology Division, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia. This study was funded by Bristol-Myers Corporation, Wallingford, Connecticut. Currently, Dr. Lystash is at Roanoke Memorial Hospital in Roanoke, Virginia. and Dr. Smucker is at St. Joseph’s Medical Center, South Bend , L,7 .,;ana. Manuscript received February 1, 1990; revised manuscript received and accepted April 23, 1990. Address for reprints: Stewart G. Pollock, MD, Division of Cardiology, Box 158, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908.

he heightened sympathetic tone of chronic congestive heart failure (CHF) compromises myocardial function by down-regulating PI receptors and impairing response to exogenous catecholamines.’ It has, therefore, been proposed that pharmacologic P blockade is actually useful in the treatment of chronic CHF.2 Metoprolol has been most widely used for this purpose, but newer agents, with different properties, are being evaluated.3 Bucindolol is a member of a new class of /3 blockers that possess peripheral vasodilating activity.4 Although bucindolol is reported to have mild intrinsic sympathomimetic activity in animals, its vasodilating effect is a direct one and is not due to intrinsic sympathomimetic activity alone. 5,6 Because vasodilation is beneficial in CHF, a p blocker with vasodilation may be especially valuable.7%s We evaluated bucindolol’s usefulness in CHF in a randomized, double-blind trial of 19 patients.

T

METHODS Patients: Patients in this study were referred to the

University of Virginia for evaluation and treatment of CHF. Patients with stable, symptomatic CHF with a dilated cardiomyopathy due to either ischemic or idiopathic causes were selected if they met the following criteria: ejection fraction 16 minutes, on a modified Naughton protocol; no concurrent /?blocker use; no pulmonary contraindication to p blockade; and no concurrent severe illness. Twenty-one patients were enrolled between January and December 1988. One patient died during the prerandomization evaluation and 1 patient randomized to bucindolol was lost to follow-up. Thus, 19 patients completed the trial. Patients received diuretics, digoxin and afterload reduction as deemed appropriate by their primary physician. There were 4 women and 15 men and the mean age was 54 years. Seven patients had an ischemic cardiomyopathy and 12 had an idiopathic dilated cardiomyopathy. Patients were classified as ischemic or idiopathic on the basis of available clinical information, such as recent catheterization, previous myocardial infarction or exercise thallium imaging. No patient’s exercise capacity was limited by angina pectoris and no patient had roentgenographic pulmonary edema at study entry. One in each group had pleural effusions. Study design: Prerandomization evaluation consisted of a history, physical examination, 2 treadmill tests (1 day apart), rest radionuclide ventriculography and pulmonary artery catheterization. Patients were then

THE AMERICAN

JOURNAL

OF CARDIOLOGY

SEPTEMBER

1, 1990

603

I Baseline

TABLE

Characteristics

Mean age No. men No. women No. taking digitalis No. takingvasodilator Election fraction NYHA II NYHA Ill NYHA IV No. idiopathic No. ischemic

Placebo (n = 7)

Bucindolol (f-l = 12)

p Value

50 6 1 5 7 25 1 4 2 5 2

56 9 3 10 8 19 0 10 2 7 5

NS NS NS NS NS NS NS NS NS NS NS

NYHA = New York Heart Assoclatvm

functmm

class, NS = not slgnflcant.

admitted to the hospital, given 2 to 3 test doses of openlabel bucindolol, 12.5 mg orally 12 hours apart and observed for clinical compromise. All patients tolerated this dose and were randomized in a double-blind fashion in a 3:2 ratio to bucindolol or placebo, respectively, at a dose of 12.5 mg orally twice daily. Patients returned weekly for clinical evaluation and dosage was increased to 25 mg twice daily, 50 mg twice daily and finally 100 mg twice daily. All patients tolerated the maximum dose. They were continued on 100 mg twice daily for 8 more weeks (3 months from randomization) and then underwent the same battery of tests as the prerandomization evaluation. The only exception was the treadmill, where only 1 test was performed at 3 months. This study was reviewed and approved by the University of Virginia Health Sciences Center Human Investigation Committee. It was funded by Bristol-Myers Laboratories, who also supplied the bucindolol or placebo tablets. All data were collected and analyzed by the authors. TABLE II Bucindolol-Paired

Treadmill testing: Patients were exercised on a Quinton status 1000 treadmill, using a modified Naughton protocol and a-minute stages. The test was limited by symptoms or upon completion of all stages. No test was terminated due to hypotension, arrhythmias or chest pain. Baseline exercise duration was taken from the second test performed during the baseline examination. Radionuclide angiography: Patients were injected first with pyrophosphate and then 20 &i of technetium. Transit time was measured by the first-pass technique, and ejection fraction by computer calculation of scintigraphic counts obtained by multiple-gated angiography performed in the 45” left anterior oblique “best septal” view. Six-minute walk: Patients were instructed to walk back and forth along a measured corridor at their own pace, according to a previously described protocol.9 Additional encouragement was not given. The distance traveled in 6 minutes of walking was measured in feet. Living With Heart Failure Questionnaire: The Minnesota Living With Heart Failure Questionnaire is a self-administered questionnaire copyrighted by the University of Minnesota that assessesthe patient’s ability to function in everyday life. Twenty-three questions, such as “Did your heart failure prevent you from living as wanted during the last month by making your working around the house or yard difficult?“, are answered by the patient on a scale of 0 (“no”) to 5 (“yes”); higher scores reflect greater impairment. Hemodynamic measu rements: One patient in each group was unable to undergo Swan-Ganz catheterization at 3 months and their hemodynamic data are excluded from analysis. Complete hemodynamic measurements were available in the remaining 6 placebo patients. Of the 11 bucindolol patients undergoing repeat

Comparison 3 Months

Baseline

Noninvasive data Treadmill time(s) 6-minute walk (feet) LHFQ score EF (%) Transit time (s) Rest data HR (beats/min) Mean BP (mm Hg) Pulmonary capillary wedge pressure (mm Hg) Cardiac output (Ilters/min) Systemic vascular resistance (dynes s/cm-“) Exercise data HR (beats/min) Pulmonary capillary wedge pressure (mm Hg) Mean BP (mm Hg) Cardiac output (liters/min) BP = blood

604

pressure;

EF = e]ectlon

THE AMERICAN

Mean

(*SD)

Mean

(*SD)

p Value

12 12 12 12 12

445 1,254 61 19 18.3

142 252 18 7 6.6

530 1.405 40 23 13.7

218 248 24 8 5.2

0.04 0.04 o.ocxl1 0.04 0.02

11 11 11

90 96 27

11 8

21 12 9

4.0 1,888

82 94 20

1.2 524

11 10

127 42

24 15

11 11

109

18 2.1

12 15.3 9

NS NS NS

0.9

0.02 0.04

4.7 1,481

162

96 28

18 12

o.ooo1 0.04

15 1.6

NS NS

i

fraction,

JOURNAL

No. of Patients

5.7

HR = heart rate: LHFQ = Minnesota

OF CARDIOLOGY

VOLUME

Lwmg With Heart Fa~lure Questlonnare,

66

101 5.4

NS = not s,gn,f,cant, SD = standard

dev,at,on

TABLE

III

Placebo-Paired

Comparison Baseline

Nontnvasrve data Treadmrll trme (s) 6-mrnute walk (feet) LHFQ score EF (%) Transrt trme (s) Rest data HR (beats/mm) Mean BP (mm Hg) Pulmonary caprllary wedge pressure (mm Hg) Cardracoutput (liters/mm) Systemic vascular resrstance (dynes s/cmm5) Exercise data HR (beats/mm) Pulmonary capillary wedge pressure (mm Hg) Mean BP (mm Hg) Cardrac output (Irters/mrn) Abbrevmons

3 Months

No. of Patrents

Mean

(&SD)

Mean

(fSD)

p Value

7 6 5 7 7

496 1,132 53 25 13.9

205 392 30 8 3.4

506 1,167 47 29 13.1

234 345 23 10 3.2

NS NS NS NS NS

12 8 11

83 93 23

11 9 14

NS NS NS

6 6 6 6 6

6 6 6 6

90 89 23 5.3

1

1,260

239

118 33 99 8.4

49 1,368

0.8 213

NS NS

10 11

117 32

19 12

NS NS

11 2.7

102

12 2.8

NS NS

8.3

az ,n Table II

Swan-Ganz catheterization, only 10 had baselineand 3month peak exercise pulmonary capillary wedge pressuremeasurementsand 8 had data to calculate systemic vascular resistanceat both times. After overnight fasting, patients had a 7Fr SwanGanz catheter placed from either the brachial or jugular vein. Patients were positioned onto a bicycle ergometer while remaining in the supine position. The catheter was advanced to the pulmonary artery using fluoroscopic guidance. Right atrial, ventricular, pulmonary artery and balloon wedge pressureswere recorded on an Electronics for Medicine strip recorder. Cardiac output was determined by computer calculation of thermodilution curves after the injection of 10 cc of a chilled dextrose solution. Three measurementswere obtained. Brachial artery blood pressurewas measuredwith an automated blood pressurecuff. Patients then exercised, recumbent upon the bicycle ergometer, until limited by symptoms, according to a stepwiseprotocol: 25 watts, 50 watts, 75 watts and up to 100 watts in 3-minute stages. Cardiac output, pulmonary capillary wedge pressureand brachial artery pressure were again measuredat peak exercise. Right atria1 pressurewas not repeated and so systemic vascular resistancewas not calculated at peak exercise. Systemic vascular resistance and mean blood pressure were calculated in the usual way. Statistical analysis: Bucindolol and placebo patients were compared at baselinewith respect to gender, etiology of CHF, useof digitalis and use of vasodilators with a Fisher exact test. New York Heart Association functional class was compared with a nonparametric test (Mann-Whitney) and ejection fraction and age were compared with an unpaired t test. Bucindolol’s efficacy was analyzed in 2 ways. First, bucindolol-treated patients served as their own control

subjects in a comparison of baselineand 3-month values using a paired t test. Then, changeswere compared between placebo and bucindolol-treated patients using an unpaired t test after normalizing data to baselinevalues. All tests were 2-tailed and probability values