pulmonary wedge pressure from 23.6 2 7.8 to 16.9 r 6.6 mm H g (P < 0.001). Heart rate, cardiac index, and total systemic resistance did not change acutely after ...
Indoramin in heart failure: Possible adverse effects on hemodvnarnics and exercise capacity Indoramin is an a,-adrenergic antagonist vasodilator of potential value in heart failure. We measured hemodynamics and exercise capacity in 1 2 patients with heart failure, before and &er 1week of indoramin dosing, 7 5 mg b.i.d. Maximal hemodynamic effects 2 hours after the first dose of indoramin consisted of reduced mean systemic arterial pressure from 96.0 2 15.3 to 87.9 + 15.3 mm H g (P < 0.05) and pulmonary wedge pressure from 23.6 2 7.8 to 16.9 r 6.6 mm H g (P < 0.001). Heart rate, cardiac index, and total systemic resistance did not change acutely after indoramin, but after 1 week mean systemic arterial pressure was still reduced whereas cardiac index fell from 2.69 2 0.38 to 2.32 f 0.44 L/min/m2 (P < 0.05) and total systemic resistance rose from 20.4 + 2.8 to 21.9 2 4.0 U (P < 0.1). After 1 week maximal exercise oxygen uptake fell from 16.8 2 5.6 to 12.5 & 3.5 ml/min/kg (P < 0.02). This Limited observation suggests that indoramin is a predominant venodilator acutely in patients with heart failure but that despite this effect it may worsen functional capacity and hemodyanmics during continuous dosing THER 1986;40:567-74.) in these patients. (CLINPHARMACOL
Love Seth, M.D., Nazzareno Galit, M.D., Penny Casebolt, R.N., Horacio Girnenez, M.D., Mark Malloy, M.D., and Joseph A. Franciosa, M.D. Little Rock, Ark., and Wilmington, Del.
Although a,-antagonists such as prazosin have been used for vasodilator treatment of congestive heart failure, their clinical use has been limited by the rapid development of tolerance during long-term therapy.' Indoramin (N-[1-(2-indol-3-ylethyl)-4-piperidyl]benzamide hydrochloride) is an a,-antagonist that has been an effective antihypertensive vasodilator and also has antiarrhythmic proper tie^.^," The present study was designed to assess the shortterm effects of oral dosing with indoramin on hemodynamics and exercise tolerance in patients with chronic congestive heart failure.
From the Cardiovascular Division, University of Arkansas for Medical Sciences, Little Rock. Presented in part at the Eighty-seventh Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Washington, D.C., March 22, 1986. Supported by a grant from Wyeth Laboratories, Philadelphia, Pa. Received for publication March 10, 1986; accepted May 29, 1986. Reprint requests: Joseph A. Franciosa, M.D., Director, Cardiovascular Drugs, Stuart Pharmaceuticals, ICI Americas Incorporated, Wilmington, DE 19897.
METHODS Patient selection. The study population consisted of 12 patients with a history of chronic congestive heart failure of at least 3 months duration while taking digitalis and diuretics. Congestive heart failure was diagnosed by a history of exertional symptoms (class 34 by criteria of the New York Heart Association) and the presence of a ventricular gallop sound, jugular venous distention, pulmonary rales, or otherwise unexplained peripheral edema. In addition, patients had to have one of the following obtained within the previous month: (1) a left ventricular ejection fraction below 4 1% by radionuclide or contrast angiography; (2) a cardiothoracic ratio greater than 55% on chest x-ray film; or (3) a left ventricular diastolic dimension greater than 55 mm by echocardiogram. Finally, all patients had to be stable with no change in symptoms, body weight, or medications for at least 2 weeks before the study. The etiology of congestive heart failure was coronary artery disease, diagnosed by a history of documented acute myocardial infarction or coronary arteriography, or idiopathic dilated cardiomyopathy, diagnosed when no other cause of heart failure was apparent. Patients
CI.IK PHAILMACOL. THEK NOVEMBER 1986
568 Seth etal. Table I. Characteristics of patients with congestive heart failure receiving indoramin Patient No.
1 2 3 4 5 6 7 8 9 10 11 12
Mean SD
Age (Y r )
64 49 54 58 57 60 60 60 43 67 62 52 57.2 6.7
Sex
Cause of CHF
CTR Class*
LVDD
LVEF
(mm)
(%)
IDC IDC IDC CAD IDC CAD IDC IDC IDC IDC CAD IDC -
CHF, congestive heart failure; CTR, cardiothoracic ratio; LVDD, left ventricular diabtolic dimension: LVEF, left ventricular ejection fraction; IDC, idiopathic dilated cardiomyopathy; CAD. coronary artery disease. *According to criteria of the New York Heart Association.
were excluded for primary valvular heart disease, obstructive cardiomyopathy, acute myocardial infarction within 3 months, hypertension requiring more than diuretic treatment, primary lung disease, angina pectoris, or inability to exercise for any reason other than dyspnea or fatigue. The study protocol was approved by the local Human Investigation Committees in August 1983. The above eligibility criteria were adopted because no single measure of left ventricular function, dimensions, or hemodynamics has correlated with symptoms or measured exercise capacity in patients with heart f a i l ~ r e . Thus ~ . ~ all our patients had symptoms of heart failure and at least one indicator of abnormal left ventricular size or function. These same criteria have been applied to recent large multicenter vasodilator trials in patients with heart failure, and there is no evidence that responsiveness of exercise capacity relates to any of these baseline characteristics, including acute hemodynamic responses to test drugs.'.'4 Hernodynamic study. Patients meeting all selection criteria gave written, informed consent and were hospitalized for right heart catheterization. Vasodilators were discontinued at least 24 hours before the day of study. Maintenance doses of digitalis were administered whereas diuretics were withheld on the day of study. After a light breakfast, right heart catheterization was performed with a Swan-Ganz thermodilution catheter. Heart rate was monitored electrocardiographically, systemic arterial pressure was measured by cuff, and cardiac output was measured invasively by thermodilution and noninvasively by carbon dioxide rebreathing, a
method previously validated by us in patients with heart Baseline hemodynamic measurements were repeated in triplicate at 20-minute intervals until they varied by less than 10%. Pulmonary wedge pressure was taken as occluded pulmonary arterial pressure or pulmonary arterial diastolic pressure, and only one of these was used in any given patient. Patients had to have pulmonary capillary wedge pressure equal to or greater than 15 mm Hg or cardiac index by thermodilution equal to or less than 2.5 L/minlm2 to remain in the study. Two of 14 patients who met initial eligibility criteria were excluded for not meeting the hemodynamic criteria. The 12 patients who met all the above criteria were given 75 mg of indoramin by mouth and hemodynamics were measured at hourly intervals until they returned to baseline after a response or up to a maximum of 6 hours if no response occurred. Response was defined as fall in total systemic resistance or pulmonary wedge pressure of at least 20% from control. No other drugs or meals were given during this period of observation. Diuretics were resumed at the end of this period. Follow-up. On completion of this acute hemodynamic study, patients were given indoramin, 75 mg b.i.d., for 7 days. This dosing regimen has been effective in the treatment of hyperten~ion.~." During this week digitalis doses were kept constant, diuretics were adjusted as needed, and no other vasodilators were permitted. At the end of the week, noninvasive hemodynamic measurements were repeated, including cardiac output by the carbon dioxide rebreathing method. Ex-
VOI.UME 40 NUMBER S
Indoramin in heart failure 569 PULMONARY WEDGE PRESSURE (rnrn H g )
HOURS AFTER INDORAMIN A D M I N I S T R A T I O N
Fig. 1. Effects of a single oral dose of indoramin on pulmonary wedge pressure in patients with heart failure. Values = mean and SD. (* = P < 0.05; ** = P < 0.01; *** = P < 0.001.)
ercise testing was performed at baseline and at the end of the week of treatment with indoramin. No attempt was made to perform exercise at a specific time after dosing with indoramin since it is well established that exercise responses are not related to single doses of cardioactive drugs in heart failure but are time dependent after continuous d o ~ i n g . ' ~Exercise ,'~ was performed on an upright bicycle ergometer beginning at work load of 150 kilopond meterslmin (kpmtmin) and increasing by 150 kpmlmin every 4 minutes until symptomatic maximum of dyspnea or fatigue. Exercise was not terminated for any other reason. Expired air was collected during exercise for on-line measurement of oxygen consumption, carbon dioxide production, and ventilatory exchange ratio. The ventilatory exchange ratio was used to indicate the achievement of anaerobic threshold, and a rise during exercise of at least 0.15 or to an absolute value above 1 was required for an exercise test to be considered valid.I9 M-mode echocardiograms were obtained for measurement of left ventricular dimensions and ejection fraction before initiation of therapy and on the last day of treatment with indoramin. Patients were weighed and examined daily. Data analysis. Calculated hemodynamic variables included mean arterial pressure taken as diastolic blood pressure plus one third of the pulse pressure, total systemic resistance (in units) as mean arterial pressure divided by cardiac output, and total pulmonary resistance (in units) as mean pulmonary arterial pressure divided by cardiac output. Right atrial pressure was not included in the calculation of total systemic resistance
because it was not available at follow-up study after 1 week. Statistical analysis was carried out with the Student t tests for paired data. All serial observations were analyzed by ANOVA and t tests were done only if the F statistic was significant.
RESULTS Characteristics of the patient population are summarized in Table I. All but two patients were men, and nine patients had idiopathic dilated cardiomyopathy as the cause of heart failure. Only one patient had New York Heart Association class IV symptoms at the time of study, and all the others were class 111. All patients were taking digoxin and diuretics at the time of study, and five patients had also been receiving vasodilators for heart failure (nitrates in four patients and captopril in one). The increased cardiothoracic ratio and left ventricular diastolic dimension for the group as a whole, along with a reduced left ventricular ejection fraction, are indicative of left ventricular dysfunction consistent with chronic left ventricular failure. The major hemodynamic effect of indoramin was to reduce pulmonary wedge pressure (Fig. I). Control pulmonary wedge pressure averaged 23.6 + 7.8 mm Hg, consistent with left ventricular failure, and fell significantly by 1 hour after dosing with the first dose of indoramin. It reached a nadir of 16.9 + 6.6 mm Hg at 2 hours and was still significantly reduced, although returning toward baseline, at 6 hours. Changes in mean systemic arterial pressure paralleled the course of
CLIN PHAKMACOL THER NOVEMBER 1986
570 Seth et al.
MEAN S Y S T E M I C A R T E R I A L PRESSURE (mm Hg)
601
0
I
I
1
I
I
1
1
2
3
4
5
6
1
HOURS A F T E R I N D O R A M I N A D M I N I S T R A T I O N
Fig. 2. Effects of a single oral dose of indoramin on mean systemic arterial pressure in patients with heart failure. Values = mean and SD. (* = P < 0.05; ** = P < 0.01 .)
Table 11. Hemodynamic effects of indoramin in patients with congestive heart failure
Patient No.
1 2 3 4 5 6 7 8 9 10 11
12 Mean SD P
HR (bpm)
C
2 hr
92 86 90 63 113 57 95 67 128 77 74 85
90 96 84 60 99 57 99 90 100 75 75 72
85.6 20.4
MAP (mm Hg)
C
2 hr
CI (L/min/m2) C
2hr
PAM (mm H g )
C
2hr
PWP (mm Hg)
C
2 hr
TSR ( U )
C
2 hr
83.1 15.1 NS
HR, heart rate; C, control; 2 hr, 2 hours after indoramin dosing; MAP, mean systemic arterial pressure; CI, cardiac index; PAM, mean pulmonary arterial pressure; PWP, pulmonary wedge pressure; TSR, systemic vascular resistance.
changes in pulmonary wedge pressure (Fig. 2). No changes in cardiac index or total systemic vascular resistance were significant at any time after the first dose of indoramin. The peak acute hemodynamic effects occurred at 2 hours and are summarized in Table 11. Heart rate was unchanged, pulmonary arterial pressures were significantly reduced, and systemic arterial pressure fell significantly without a change in cardiac index or total systemic resistance. Thus indoramin exerted predominant preload reducing effects acutely.
When the two patients with normal left ventricular ejection fractions (patient Nos. 6 and 8) were excluded from analysis because their cardiac disease and drug responsiveness could be different, results were the same. In the remaining subgroup, pulmonary wedge pressure still fell significantly by 1 hour from 23.1 t 8.2 to 17.7 + 6.1 mm Hg (P < 0.01), reached a nadir of 16.6 + 6.0 mm Hg at 2 hours (P < 0.001), and returned near baseline by 6 hours (2 1.4 + 7.8 mm Hg ; not significant). In this same subgroup, cardiac index
VOLUME 40 NUMBER 5
Indoramin in heart failure CONTROL
571
I NDORAM I N
0 WE l GHT ( k g ) , LVDD (mm) , o r LVEF ( X )
1
'0°1
(P
