Hemodynamic Effects of an Oral Dopamine Receptor Agonist (Fenoldopam) in Patients with Congestive Heart Failure

792 lACC Vol. 6, No.4 October 1985:792-6

Hemodynamic Effects of an Oral Dopamine Receptor Agonist (Fenoldopam) in Patients With Congestive Heart Failure

JAMES B. YOUNG, MD, FACC, CARLOS A. LEON, MD, CRAIG M. PRATT, MD, FACC, JOSE M. SUAREZ, MD, ROBERT D. ARONOFF, MD, ROBERT ROBERTS, MD, FACC Houston, Texas

Dopamine receptor stimulation causes vascular and neu• (p < 0.05) and mean pulmonary artery pressure de• rohumoral responses that may be beneficial in patients creasing from 32 ± 9 to 29 ± 8 mm Hg (p < 0.05). with heart failure. Oral inactivity, emesis and adre• Systemic vascular resistance decreased from 1,987 ± nergic-induced arrhythmias have limited the use of cur• 887 to 1,191 ± 559 dynes-s-cm-s (p < 0.05) with a sub• rently available compounds. Fenoldopam (SKF -82526-J) sequent 55% increase in cardiac index from 2.2 ± 1.1 is anew, orally available, selective, dopamine-receptor to 3.1 ± 1.3 liters/min per m2 (p < 0.05). Heart rate agonist with potent renal vasodilating properties (six times and right atrial pressure did not change (p > 0.05). No that of dopamine) without positive inotropic or adren• emesis or new tachycardia was noted at any dose. Base• ergic activity. Drug efficacy was clinically evaluated in line hemodynamics generally returned within 3 to 4 hours. 10 patients with heart failure after single oral doses of Fenoldopam, therefore, is a short-acting, orally ef• placebo and 50, 100 and 200 mg of medication. Placebo fective drug that decreases systemic vascular resistance produced no changes. Peak efficacy was noted 30 min• and increases cardiac index in patients with heart failure utes to 1 hour after the 200 mg dose with mean blood and represents a new class of oral compounds that may pressure decreasing from 96 ± 15 (mean ± SD) to be useful in treating such patients. 83 ± 8 mm Hg (p < 0.05), pulmonary capillary wedge (J Am Coil CardioI1985;6:792-6) pressure decreasing from 23 ± 6 to 20 ± 8 mm Hg

Early in the last decade, dopamine was introduced for the option to employ during management of patients with treatment of congestive heart failure (1). Hemodynamic ef• congestive heart failure and those with disorders resulting fects observed with different concentrations of dopamine in renal retention of salt and water. Dopamine itself, how• were attributed to the simultaneous activation of both alpha• ever, is only effective when given parenterally and may and beta-adrenergic receptors, as well as the stimulation of induce tachycardia and arrhythmias because of its adrenergic specific dopamine receptors (1,2). Recent research (3) has activity. provided evidence that activation of these dopamine recep• Fenoldopam mesylate (SKF-82526-J) is a novel and po• tors results in a variety of vascular and neurohumoral re• tent benzazepine derivative synthesized with the objective sponses in the cardiovascular system. This has led to the of obtaining enhanced selectivity for the activation of pe• development of newer compounds that selectively activate ripheral vascular dopaminel receptors (5). It is active both the dopamine receptors and have few, if any, other adrener• in the oral and intravenous formulations, a distinct advan• gic sequellae and are orally effective (4). These properties tage over existing dopaminergic compounds, is six times as make dopamine analogs a new and attractive therapeutic potent as dopamine in producing renal vasodilation and POS" sesses no adrenergic activity. This study was designed to evaluate, for the first time, the hemodynamic effects of From the Section of Cardiology, Baylor College of Medicine and Ben Taub General Hospital, Houston, Texas. This study was presented in part fenoldopam in patients with congestive heart failure. at the 57th Scientific Sessions of the American Heart Association, Miami, Florida, November 14, 1984. Computational assistance was provided by the CLINFO Project funded by Grant RR-()()350, Division of Research Methods Resources, National Institutes of Health, Bethesda, Maryland. This project was funded in part by a research grant from Smith, Kline & French Lab• Patients. Using a protocol approved by the Baylor Col• oratories, Philadelphia, Pennsylvania. Manuscript received February 19, lege of Medicine Institutional Review Board for Human 1985; revised manuscript received May 7, 1985, accepted May 24, 1985. Address for reprints: James B. Young, MD, 6535 Fannin MS F-1001, Research, we studied 10 patients with a congestive state Houston, Texas 77030. caused by left ventricular dysfunction. Nine patients (seven

with idiopathic dilated cardiomyopathy and two with coro• parametric, paired value, Wilcoxon signed rank test. Results nary artery disease) had severe, chronic heart failure with were deemed significant if the p value was less than 0.05. New York Heart Association functional class III to IV symp• toms and a mean (± SD) ejection fraction of 20 ± 8% (range 11 to 33). One patient had hypertensive heart disease Results and clinical features of heart failure. Hemodynamic results. All the hemodynamic measure• Study design. The study was random ordered, single ments for the group are summarized in Tables 1 and 2. blinded and placebo controlled. Diuretic drugs and vaso• Figure 1 presents the first 3 hours of data as the mean (± dilators were discontinued for more than 24 hours before SEM) percent change from baseline measurement for heart hemodynamic study. All patients were maintained on a sta• rate, pulmonary capillary wedge pressure, systemic vascular ble dose of digoxin. After obtaining informed consent, right resistance and cardiac index. heart catheterization was performed using a flow-directed, Placebo dosing in each patient did not significantly change triple lumen, balloon-tipped thermodilution catheter in a any of the measured or calculated variables. Heart rate and standard fashion. The catheter was inserted 24 hours before right atrial pressure were unaffected not only by placebo, the study. The mean right atrial, pUlmonary artery and pul• but also by any dose of drug. monary capillary wedge pressures were measured. Cardiac The 50 mg dose caused no dramatic changes. There was output was obtained in triplicate by the thermodilution tech• a tendency for the mean blood pressure (Fig. 1), mean nique using a thermodilution computer with a variation of pulmonary capillary wedge pressure (Fig. 1) and systemic less than 10%. Arterial pressure was measured with a mer• vascular resistance (Fig. 1) to decrease (decreases of 4, 3 cury manometer and cuff over the brachial artery. Calculated and 17% from baseline, respectively); only the decrease in hemodynamic indexes included: systemic vascular resistance was significant (p < 0.05).

5 The 50 mg dose caused no dramatic changes. There was Systemic vascular resistance in dynes.s.cm- : a tendency for the mean blood pressure (Fig. 1), mean Mean arterial pressure - Right atrial pressure pulmonary capillary wedge pressure (Fig. 1) and systemic ------"------"'----...!.....-- x 80; Cardiac output vascular resistance (Fig. I) to decrease (decreases of 4, 3 utes, p < 0.01), systemic vascular resistance (a 35% de• Mean blood pressure in mm Hg: crease at 30 minutes, p < 0.01) and an increase in cardiac ([Systolic blood pressure - Diastolic blood pressure] x 0.33) index (a 42% increase at 30 minutes, p < 0.01). + Diastolic blood pressure; The greatest responses were generally seen with the 200 mg dose (Table 2). As with the 100 mg dose, per.I( effects 2 Cardiac index in liters/min per m : after 200 mg of fenoldopam were noted early (between 30 Cardiac output . minutes and 1 hour) with significant changes persisting at Body surface area' approximately 2 hours. Cardiac and stroke volume indexes, increased significantly from 2.2 ± 1.1 to 3.1 ± 1.3 li• 2 2 2 Stroke volume index in mllm : ters/min per m and 25 ± 16 to 33 ± 15 mllm , respectively Cardiac output/Heart rate (mean ± SD, both P < 0.05). There were no significant Body surface area changes in heart rate (94 ± 12 to 98 ± 11 beats/min) but there was a significant decrease in mean arterial blood pres• 2 Left ventricular stroke work index in g-m/m : sure from 96 ± 15 to 83 ± 8 mm Hg (p < 0.05). Systemic vascular resistance decreased significantly from 1,987 ± Stroke volume index (Mean arterial pressure 5 - Pulmonary wedge pressure) x 0.0136. 887 to 1,191 ± 559 dynes.s-cm- (p < 0.01). A slight decrease was observed in pUlmonary capillary wedge pres• The study was performed during a 4 day period in our sure (23 ± 6 to 20 ± 8 mm Hg, p < 0.05) and mean cardiac care unit. On each study day, patients received a pulmonary artery pressure (32 ± 9 to 29 ± 8 mm Hg, single dose of either placebo or 50, 100 or 200 mg of active p < 0.05). drug in a random order. All patients had an overnight fast Baseline hemodynamics returned 3 to 4 hours after ad• of more than 8 hours and oral intake was allowed approx• ministering the medication. For the 100 mg dose, however, imately 4 to 6 hours after the medication had been admin• systemic vascular resistance did remain lower and cardiac istered. Hemodynamic variables were obtained at baseline index higher (both p < 0.05) at the 4 hour observation point study and repeated 30 minutes and 1, 2, 3 and 4 hours after (Table 2). administering medication. Additional observations. No significant side effects were Data analysis. The statistical analysis, comparing base• noted. One patient developed transient nausea with emesis line hemodynamic values obtained with placebo and the I hour after receiving medication (200 mg dose) and this different medication doses, was performed using the non- resolved spontaneously in 15 minutes. No new tachycardia 794 YOUNG ET AL. JACC Vol. 6, No.4 HEMODYNAMIC EFFECTS OF FENOLDOPAM October 1985:792-6

Table 1. Measured Hemodynamic Effects of Fenoldopam Variable Baseline 30 Minutes I Hour 2 Hours 3 Hours 4 Hours

Heart rate (beats/min) Placebo 96 ± 19 97 ± 18 97 ± 20 95 ± 18 97 ± 16 97 ± 16 50 mg 96 ± 16 98 ± 11 98 ± 13 97 ± 12 94 ± 15 96 ± 13 100 mg 96 ± 11 96 ± 9 97 ± 8 95 ± 10 93 ± 13 93 ± 10 200 mg 94 ± 12 96 ± 8 98 ± 11 96 ± 11 95 ± 10 96 ± 11 Mean arterial pressure (mm Hg) Placebo 94 ± 14 95 ± 13 98 ± 15 97 ± 15 99 ± 17 98 ± 15 50 mg 95 ± 16 91 ± 13 94 ± 10 95 ± 15 99 ± 14 98 ± 15 100 mg 97 ± 14 87 ± 19* 86 ± 15* 87 ± 15* 96 ± 13 93 ± 13 200 mg 96 ± 15 86 ± 12* 83 ± 8* 91 ± 12 93 ± 9 95 ± 15 Mean right arterial pressure (mm Hg) Placebo 14 ± 7 14 ± 7 14 ± 8 14 ± 8 16 ± 8 14 ± 8 50 mg 13 ± 7 12 ± 7 12 ± 8 13 ± 7 12 ± 8 13 ± 6 100mg 13 ± 6 13 ± 6 13 ± 6 13 ± 6 13 ± 8 12 ± 7 200 mg 13 ± 7 13 ± 7 13 ± 8 14 ± 8 14 ± 8 14 ± 9 Mean pulmonary artery pressure (mm Hg) Placebo 36 ± 12 36 ± 12 35 ± II 35 ± 12 37 ± 6 36 ± 12 50 mg 32 ± 12 32 ± 12 34 ± 7 34 ± 7 35 ± 4 36 ± 8 100mg 33 ± 9 30 ± 9* 30 ± 9* 30 ± 10 31 ± 10 30 ± 11 200 mg 32 ± 9 29 ± 8* 29 ± 9 30 ± 9 31 ± 10 31 ± 10 Mean pulmonary capillary wedge pressure Placebo 23 ± 7 25 ± 8 25 ± 9 26 ± 9 25 ± 6 22 ± 7 50 mg 23 ± 7 23 ± 8 23 ± 8 22 ± 7 22 ± 8 23 ± 8 100mg 23 ± 8 21 ± 8* 21 ± 8* 21 ± 7* 22 ± 7 22 ± 6 200 mg 23 ± 6 20 ± 8* 20 ± 8* 22 ± 8 23 ± 7 22 ± 7

*p < 0.05. or acute rhythm disturbances were noted during bedside pam results in a significant reduction of arterial blood pres• electrocardiographic monitoring while the drug was given. sure and subsequent augmentation of stroke volume without any significant change in heart rate. This suggests that impedance to left ventricular ejection is reduced. A modest Discussion decrease in mean pulmonary capillary wedge and mean pul• Fenoldopam description. Fenoldopam mesylate is a monary artery pressures and no significant change in right benzazepine derivative that appears to act primarily by stim• atrial pressures were noted. The reduction in pulmonary ulation of the dopamine, receptors (6). It is orally effective, wedge pressure without concomitant decrease in right atrial more receptor specific and more potent than dopamine in pressure probably reflects improvement in left ventricular the renal vascular bed. Its vasodilating effects are selectively dynamics rather than venodilation with subsequent preload blocked by bulbocapnine and metoclopramide. The effects reduction. Significant venodilation may not occur with this of fenoldopam are independent of alpha- and beta-adrenergic drug because of the reduced number of dopamine, receptors receptors, as well as cholinergic or histaminic receptors. in the venous circulation (8). This drug does not cause prostaglandin or endogenous cate• Previous studies with dopamine in patients with heart cholamine release. In addition, administration of fenoldo• failure have shown that its beneficial actions are primarily pam does not significantly activate central dopaminergic due to positive inotropic effects mediated by beta,• receptors, indicating that it does not readily cross the blood• adrenergic receptors and, to a lesser degree, activation of brain barrier; thus, it might not cause nausea or vomiting, dopamine receptors. This results in either a modest reduction a problem with other dopaminergic compounds. It does not or no change in the total peripheral resistance. This study inhibit monoamine oxidase, but can inhibit norepinephrine shows, for the first time in patients with heart failure, re• uptake in vitro in concentrations greater than those necessary producible and significant reduction in systemic vascular to dilate renal blood vessels. It has been given orally in resistance with concomitant increase in cardiac output by a patients with essential hypertension, lowering arterial blood drug that selectively stimulates vascular dopamine, recep• pressure and reducing systemic and renal vascular resistance tors only. If the vasodilatory effect of this drug is not subject (7). to tachyphylaxis, potentially detrimental reactive hypertro• Fenoldopam in heart failure. The present study sug• phy may be prevented and symptoms ameliorated (9,10) gests that, at least acutely, oral administration of fenoldo- during chronic administration. JACC Vol. 6, No.4 YOUNG ET AL. 795 October 1985:792-6 HEMODYNAMIC EFFECTS OF FENOLDOPAM

Table 2. Derived Hemodynamic Effects of Fenoldopam

Variable Baseline 30 Minutes 1 Hour 2 Hours 3 Hours 4 Hours

Stroke volume index (mllm2) Placebo 24 :!:: 13 23 :!:: 13 24 :!:: 13 24 :!:: 13 21 :!:: II 25 :!:: 12 50 mg 25 :!:: 12 28 :!:: 12 25 :!:: 13 24 :!:: 9 27 :!:: 16 23 :!:: II 100 mg 22 :!:: 10 30 :!:: 13* 29 :!:: 13* 26 :!:: 11* 27 :!:: 14 26 :!:: 14 200 mg 25 :!:: 16 33 :!:: 15* 30 :!:: 13* 30 :!:: 13* 26 :!:: 12 27 :!:: 14 2 Cardiac index (liters/min per m ) Placebo 2.1 :!:: 0.8 2.0 :!:: 0.7 2.1 :!:: 0.7 2.1 :!:: 0.8 1.9 :!:: 0.9 2.3 :!:: 0.8 50 mg 2.2 :!:: 0.7 2.6 :!:: 1.1 2.3 :!:: 0.9 2.1 :!:: 0.7 2.2 :!:: 1.0 2.1 :!:: 0.8 100 mg 2.0 :!:: 0.8 2.8 :!:: 1.2* 2.8 :!:: 1.1* 2.4 :!:: 0.8* 2.3 :!:: 0.9* 2.3 :!:: 0.9* 200 mg 2.2 :!:: 1.1 3.1 :!:: 1.3* 2.8 :!:: 1.2* 2.7 :!:: 0.9* 2.4 :!:: 0.8 2.3 :!:: 0.9 Systemic vascular resistance (dynes.s.cm - 5) Placebo 1,983 :!:: 860 1,987 :!:: 850 1,925 :!:: 627 1,861 :!:: 657 2,003 ± 833 1,721 ± 517 50 mg 1,730 :!:: 537 1,430 :!:: 473* 1,681 :!:: 485 1,802 :!:: 653 1,897 :!:: 817 1,987 :!:: 912 100 mg 2,069 ± 815 1,335 :!:: 653* 1,237 :!:: 352* 1,485 :!:: 496* 1,726 :!:: 602* 1,776 :!:: 620* 200 mg 1,987 :!:: 887 1,191 :!:: 559* 1,205 :!:: 356* 1.366 :!:: 457* 1,628 :!:: 628 1,694 :!:: 520 Stroke work index (g_m1m2) Placebo 23 :!:: 13 23 :!:: 16 26 :!:: 19 25 :!:: 18 20 :!:: 12 27 :!:: 18 50 mg 26 :!:: 20 28 :!:: 16 26 :!:: 18 24 :!:: 11 29 :!:: 22 24 :!:: 13 100 mg 23 :!:: 16 28 :!:: 20 28 :!:: 20* 25 :!:: 17 28 :!:: 19* 26 ± 18* 200 mg 27 :!:: 24 30 :!:: 20 27 :!:: 16 29 :!:: 19 26 :!:: 17 27 :!:: 21

*p < 0.05. Clinical implications of dopamine analogs. The de• velopment of dopamine analogs that selectively stimulate Figure 1. Mean (± SEM) percent change from baseline of heart rate, pulmonary capillary wedge pressure, systemic vascular re• dopamine I receptors is important because these receptors sistance and cardiac index for the study group (n = 10) after subserve smooth muscle relaxation in the renal (11-13), placebo and 50, 100 and 200 mg fenoldopam dosing. mesenteric (13-15), femoral, coronary (16,17) and cerebral

HEART RATE eo CARDIAC INDEX *

50 .PLACEB. 70 0 50 • 0 40 &0 ~100 30 0200.0 50 *

*,1<0.01 COMPARED TO BASELINE 20 t 11<0.05 COMPAIIED TO BASELINE 40

10 30 i' ...11.1 20 tI Z :i -10 10 !. ~ -20 :::; ...11.1 -10 C ID ; PULMONARY CAPILLARY WEDGE PRESSURE SYSTEMIC VASCULAR RESISTANCE ... 50 30 UI Z C 40 20 Z u '#. 30 10

20 0

10 -10

-20 t

-10 -30 t " -20 -40 * " 30 MIN I HOUR 2 HOURS 3 HOURS -50 30 MIN I HOUR 2 HOURS 3 HOURS 796 YOUNG ET AL. lACC Vol. 6, NO.4 HEMODYNAMIC EFFECTS OF FENOLDOPAM October 1985:792-6

(18,19) vascular beds. This is in contradistinction to agents receptors: physiological, pharmacological and therapeutic implica• activating dopamine2 receptors, which are located on the tions. J Auton Pharmacol 1982;3:189-215. postganglionic sympathic nerve terminal and may lead to 4. Weinstock J, Ackerman DM, Wilson JW, et al. Dopaminergic ben• zazepines with divergent cardiovascular profiles. In: Kaiser C, Ke• an inhibition of norepinephrine release (20,21). These latter babicen J, eds. Dopamine Receptors. Washington DC: American receptors are also present in the central nervous system and Chemical Society, 1983:157-169 (American Chemical Society Sym• at ganglionic sites where they appear to reduce sympathetic posium Series; vol 224). tone. 5. Weinstock J, Hahn R, Wilson JW, et al. Separation of potent central and renal dopamine agonist activity in substituted 6-chloro-2,3,4,5,• Fewer data are available regarding the use of selective tetrahydro-7,8-dihYdroxy-l-phenyl-IH-3-benzazepine. J Med Chem dopamine analogs in congestive heart failure. We first re• 1980;23:973-5. ported the hemodynamic effects of an n-dialkyl substituted 6. Hahn RA, Wardell JR, Jaran HM, Ridrely PT. Characterization of dopamine analog, n-propyl-N-n-butyldopamine, in con• the peripheral and central effects of SK&F 82526, a novel dopamine receptor agonist. J Pharmacol Exp Ther 1982;223:305-13. scious dogs, normal human volunteers and patients with 7. Ventura HO, Messerli FH, Frohlich ED, et al. Immediate hemody• depressed ventricular function (22). This analog activates namic effects of a dopamine receptor agonist (fenoldopam) in patients both dopaminel and dopamine2 receptors without beta• with essential hypertension. Circulation 1984;69: 1142-5. adrenergic stimulation and little or no alpha-adrenergic vaso• 8. Miller RR, Fennell WH, Young JB. Differential systemic arterial and constrictor activity (23). In dogs, this analog lowered blood venous action and consequent cardiac effects of vasodilator drugs. Prog Cardiovasc Dis 1982;24:353-75. pressure without reflex tachycardia, increased renal blood 9. Pfeffer JM, Pferrer MA, Mirsky I, Braunwald E. Regression of left flow and decreased renal vascular resistance. In normal hu• ventricular hypertrophy and prevention of left ventricular dysfunction man volunteers, renal blood flow was doubled with the by captopril in the spontaneously hypertensive rat. Proc Nat! Acad administration of propylbutyldopamine and, in the subset Sci USA 1982;79:3310-4. of patients with heart failure, we found that increasing doses 10. Unverferth DV, Mehegan JP, Magorien RD, Unververth BJ, Leier CV. 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