Hemodynamic effects of a new antiarrhythmic agent, flecainide (R-818), in coronary heart disease

Hemodynamic Effects of a New Antiarrhythmic Agent, Flecainide (R-818), in Coronary Heart Disease VICTOR LEGRAND, MD, MICHEL VANDORMAEL, MD, PIERRE COLLIGNON, MD, and HENRI E. KULBERTUS, MD

The hemodynamic effects of flecainide acetate, a new class I antiarrhythmic agent, were studied in 10 patients with coronary heart disease. The drug was injected intravenously at a dose of 2 mg/kg over 30 minutes. The mean drug plasma level achieved was 394 ng/ml (range 329 to 470). The heart rate did not change, but a significant increase (p <0.001) in P-R ( + 1 7 % ) , QRS ( + 1 5 % ) , and Q-T ( + 7 % ) duration occurred after drug administration. Negative inotropic effects also were observed and consisted of an increase (p <0.01 ) in pulmonary wedge pressure ( + 2 7 % ) and a decrease (p <0.01) in stroke index ( - - 1 0 % ) , left ventricular stroke work index (--12%), and left ventricular ejection rate (--11% ). No significant change in mean aortic pressure or

systemic and pulmonary vascular resistance occurred. Left ventriculography performed after drug infusion revealed a significant increase (p <0.01) in systolic volume ( + 9 % ) and a decrease in ejection fraction (--9 %) and mean velocity of circumferential fiber shortening (Vcf) ( - - 1 3 % ) . A progressive and significant decrease of dP/dt was observed during drug infusion, but 15 minutes after the injection, dP/dt had returned to near basal values. Thus, flecainide acetate has slight, but significant negative inotropic effects, particularly conspicuous during drug infusion. The drug should be administered with caution in patients with poorly compensated heart.

Methods

Flecainide acetate is a novel antiarrhythmic drug t h a t has m a n y properties of class I antiarrhythmic agents. It possesses local anesthetic properties and in prelimin a r y clinical trials has markedly or completely suppressed ventricular arrhythmias. 1-s Despite very promising results, b e t t e r knowledge of the hemodynamic effects of flecainide is needed before its wide acceptance for clinical use. Previous studies in animals 9,1° showed a slight negative inotropic effect, whereas noninvasive studies in man yielded controversial results. 4,11 It is particularly i m p o r t a n t to know whether fiecainide has deleterious negative inotropic effects in patients with serious cardiac disorders, especially coronary h e a r t disease. This study was u n d e r t a k e n to examine the hemodynamic effects of flecainide in patients with ischemic heart disease who are theoretically at special risk when this agent is administered intravenously.

Patients: Ten patients with recent acute myocardial infarction submitted to angiographic and hemodynamic evaluation constituted the study group (Table I). All required antiarrhythmic therapy because of ventricular premature beats or tachycardia. The nature of the procedure was explained to the patient and informed consent was obtained. Procedures: The studies were performed in the afternoon. Four patients (Patients 2, 3, 6, and 10) were currently treated by beta blocking drugs; none received calcium antagonists. All previous therapy was withdrawn for at least 12 hours. With the patient in the supine position, a Swan-Ganz and a pigtail catheter were introduced using the Seldinger technique and a femoral approach. Pressure was recorded from the left ventricle, aorta, right ventricle, right atrium, pulmonary artery, and pulmonary wedge by means of a Statham P23 db strain gauge on a Philips photographic recorder, The common zero reference level for all pressures was set at the mid-chest. The mean pressure values and determination of dP/dt maximum were determined electronically by an automatic catheterization system (Philips Physio Cardiopan System PC 5000). Cardiac output was determined in triplicate with thermodilution techniques using an Edwards model 9620 thermodilution cardiac output computer. The systemic (SVR) and pulmonary (PVR) vascular resistance and total pulmonary resistance (TPR) in dynes s cm -5 were obtained using the following formulas: SVR =

From the University of Liege, School of Medicine, Section of Cardiology*Electrocardiology, 66 Boulevard de la Constitution, 4020 Li6ge, Belgium. Manuscript received May 18, 1982; revised manuscript received and accepted August 20, 1982. Address for reprints: Henri E. Kulbertus, MD, Department of Medicine, Section of Cardiology, H6pital de Bavi~re, 66 Boulevard de la Constitution, B 4020 Li6ge, Belgium.

422

February 1983 THE AMERICANJOURNAL OF CARDIOLOGY Volume 51

TABLE I

423

Patients' Characteristics

Case

Age (yr) & Sex

1 2 3 4 5 6 7 8 9 10

58M 62M 63M 55F 50M 58M 43M 55M 40M 36M

Electrocardiographic Site of Infarction Inferior Inferior Inferoposterior Inferior Inferior Inferolateral Inferior Inferoposterior Inferior Inferior

Total Delay From MI

Diseased

Peak CK

to Investigation

Vessels

(U/liter)

(days)

(n)

R-818 Injected Intravenously (rag)

873 1,063 1,340 2,418 970 2,850 296 1,380 1,143 1,503

21 43 40 21 26 35 17 20 20 20

2 1 3 2 2 1 1 3 2 1

150 165 140 110 160 140 140 150 165 180

CK = creatine kinase; MI = myocardial infarction.

(MBP - MRA).l.332/CO, PVR = (MPAP - PCWP)1.332/CO; TPR = MPAP-1.322/CO, where MBP = mean aortic blood pressure (ram Hg), MRA = mean right atrial pressure (mm Hg), MPAP = mean pulmonary artery pressure (ram Hg), PCWP = puhnonary capillary wedge pressure (mm Hg), and CO = cardiac output (ml/min). Left ventricular stroke work index (LVSW1) in g.m/m 2 and mean systolic ejection rate (MSER) in ml/s.m 2 were calculated from the following formulas: LVSWI = SVI [MBP LVEDP] ×13.6/100 and MSER = SVI/SEP, where SVI = stroke volume index (ml/m2), MBP = mean aortic blood pressure (ram Hg), LVEDP = left ventricular end-diastolic pressure (ram Hg), and SEP = systolic ejection period (s/ beat). Left ventricular volumes were determined using the Simpson's rule by an automated program. End-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV = EDV - ESV), and ejection fraction (SV/EDV) were calculated for each patient. The mean velocity of circumferential fiber shortening (Vcf) was obtained as follows: Vcf = (dED dES)/(dED.ejection time). In this equation, dED and dES are the left minor axes in end-diastole and end-systole obtained after determination of end-diastolic and end-systolic areas planimetered in the right anterior oblique view (D area and S area) and the corresponding left major axes (lED and 1ES): dED = 4 D area/TriED, and dES = 4 S area/TriES. A qnantitative analysis of segmental wall motion was applied for each ventriculogram according to the technique described by Ingels et al) 2 A point located at 69% of the distance from the anterolateral edge of the aortic valve to the ventricular apex at end-systole served as a fixed reference. Using polar coordinates, regional shortening for all points along the ventricular outline was calculated and displayed by an automated system, which gives an objective and quantitative evaluation of regional contractility. Study protocol: The hemodynamic variables were first measured in basal conditions. Thereafter, a left ventriculogram was obtained in a 30° right anterior oblique view followed by coronary arteriography. Ten minutes were allowed to elapse before the infusion of flecainide was started. Flecainide, 2 mg/kg, was then injected intravenously at a constant rate over 30 minutes. Fifteen minutes after the end of the infusion, hemodynamic measurements were repeated and a second ventriculogram was performed. In the last 6 patients, dP/dt was also recorded using a Millar micromanometer throughout the infusion of the drug and 15 minutes later. At least 55 minutes separated the first and second angiogram: the Pharmacologic effects of contrast medium on myocardial contractility were thus most probably eliminatedJ 3-15

Blood samples for determination of plasma flecainide concentration were obtained during the second hemodynamic measurements, 15 minutes after the end of the infusion. The plasma concentration of flecainide was measured by gas-liquid chromatography.4 Averaged data are presented as mean -4standard deviation. Student's t test for paired observations was used. Statistics are based on the raw data. Results

Heart rate and electrocardiogram (Fig. 1): No significant change in h e a r t rate was observed after administration of the drug. Significant increases in P - R (+16.6%), QRS (+15.2%), and Q - T (+6.6%) (p <0.001) were noted. Pressure and cardiac index (Fig. 2): T h e m e a n pulmonary capillary wedge pressure (PCWP) increased in all but i patient (p <0.01) and the stroke index decreased (p <0.01) in all except 1 (in whom P C W P in-

RR

interval

(msec)

1100

PR p= NS

intervat

( msec ) p < 0 001

225

I 000

900 125

800

Before

QRS d u r o t , o n

After

/

/

Before

QT m t e r v a l

(msec)

After

(msec)

p < 0 001

p < 0 001

125

100

,~00

75

Before

After

Before

After

FIGURE 1. Diagrams showing the individual variations in R-R, P-R, QRS, and Q-T intervals. Changes induced by flecainide infusion (before = before infusion; after = after infusion). The p value indicated is the level of significance of t test for paired data. NS = not significant.

424

HEMODYNAMICEFECTS OF FLECAINIDE

TABLE II

Plasma Flecainide Concentrations and Relative Changes in Main Electrocardiographic Hemodynamic and Angiographic Variables

Patient

Plasma Level (ng/ml)

Change in P-R Duration (%)

Change in QRS Duration (%)

Change in PCWP (%)

Change in SI (%)

Change in LVSWl (%)

Change in LVER (%)

Change in EF (%)

Change in Mean Vcf (%)

1 2 3 4 5 6 7 8 9 10 Mean

470 388 425 390 361 413 329 397 394 373 394 4- 38

+9 +22 +27 +16 +20 +21 +22 +11 +8 +17 +17

+14 +10 + 16 +12 +18 +25 +26 +18 +10 +11 +15

+25 +7 +50 +37 0 +57 +50 +56 --7 +25 +27

--10 --13 -- 15 --12 --12 --14 +4 --6 --13 --2 --10

-7 --9 -- 12 -18 --19 --1 --14 --16 --24 0 -12

--7 --14 --20 --12 --11 --9 +1 --7 --12 --8 --11

--11 --3 -- 10 --16 --9 --5 +4 --7 --23 --8 --9

--10 -5 --27 --17 --9 --22 --9 0 --16 --18 --13

All changes express the variation in percentage after flecainide infusion compared with the basal value. EF = ejection fraction; LVER = left ventricular ejection rate; LVSWl = left ventricular stroke work index; mean Vcf = mean velocity of circumferential fiber shortening; PCWP = pulmonary capillary wedge pressure; SI = systolic index.

creased from 12 to 18 mm Hg). No significant change in mean aortic pressure was noted. A significant increase in mean pulmonary pressure (p <0.001) was also observed, whereas mean right atrial pressure did not change. Vascular resistance and cardiac performance index (Fig. 3): Slight but insignificant increases in systemic and puhnonary vascular resistance were noted. The left ventricular stroke work index was reduced in 9 patients (p <0.01). The left ventricular ejection rate also decreased in all but 1 patient (p <0.001). The dP/dt was measured during flecainide infusion in 6 patients. Although significant changes were not demonstrated

PCWP

MAP (mrnHg)

( nimHg )

p =NS

100 / "/5

-T Before

MPAP

Before

After

After

Stroke index { n i l / s y s t / r n

(mmHg}

2}

p<001

p < 000t 50

Discussion

~0

30

Before

After

by an analysis of variance, individual variations in dP/dt showed a progressive decrease which became significant 15 minutes after the beginning of infusion as compared with basal value (paired t test). Fifteen minutes after the end of the injection, d P / d t had returned to near basal values (Fig. 4). Ventricular volumes (Fig. 5): No significant changes were noted to diastolic volume after flecainide injection. However, systolic volume increased in all patients (p <0.01), causing a significant decrease in stroke volume (p <0.01) and ejection fraction. Mean velocity of circumferential shortening also decreased significantly (p <0.001). Regional wall motion: All patients had regional disorders of left ventricular contractility. In each, the area of asynergy was supplied by a critically narrowed coronary artery and corresponded to the electrocardiographic site of infarction. After flecainide injection, segmental wall motion analysis indicated a slight diffuse decrease in wall movement with no new areas of asynergy. Plasma drug concentrations: Plasma drug levels obtained 15 minutes after the infusion of 2 mg/kg of flecainide over 30 minutes varied from 329 to 470 ng/ml. Within this drug level range, there was no relation between drug concentration and changes in individual electrocardiographic, hemodynamic, and angiographic variables (Table II). Side effects: Apart from the cardiac effects just described, there were no complications or patient's complaints during or after the study.

Before

After

FIGURE 2. Diagrams showing the individual variations in pulmonary capillary wedge pressure (PCWP), mean aortic pressure (MAP), mean pulmonary arterial pressure (MPAP), and stroke index induced by fiecainide infusion (before = before infusion; after = after infusion). The p value indicated is the level of significance of Student's t test for paired data. NS = not significant.

Intrinsic m y o c a r d i a l d e p r e s s a n t effect: Intravenous flecainide in doses recommended for the treatment of arrhythmia (2 mg/kg) exerts mild but significant adverse hemodynamic effects in man. In our patients without overt left heart failure, stroke index and index of cardiac contractility (LVSWI and LVER) decreased 10% (p <0.01). The ejection fraction, which is considered one of the most sensitive indexes of global ventricular performance, decreased 9% (p <0.01). No significant

February 1983

PVR ( d y n - s e c - c m "5 I

SVR (dyn-se c - c m - 5 ) 2 500

p= NB

150

1500

100

Volume 51

425

ct P/dt

mmh, /~ec 3000

200

2 000

THE AMERICAN JOURNAL OF CARDIOLOGY

2000 I000

50 Before

After

Before

'1111i

After

"°° LVSWI ( g m / m

LV ejection rate ( m l l s e c )

2 } p
70

Iooo

.p(OO5 •.p (,OOl

p
t75

i

6O

125

100

30 Before

After

1

,

i

i

,

i

i

+#5

m/n

FIGURE 4. Mean variations in dP/dt observed during flecainide infusion and 15 minutes after the end of injection. The p value indicated is the level of significance of Student's t test for paired data; comparison is made with the basal values before flecainide infusion.

@

~o

T

i

0 *E +fO *15 ~20 *25 +30

150

Before

After

FIGURE 3. Diagrams showing the individual variations of systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), left ventricular stroke work index (LVSWI), and left ventricutar (LV) ejection rate induced by flecainide infusion (before = before infusion; after = after infusion). The p value indicated is the level of significance of Student's ttest for paired data. NS = not significant.

changes in systemic and pulmonary vascular resistance were noted, which suggests the absence of vascular effects. Pulmonary wedge pressure, mean pulmonary arterial pressure, and total pulmonary resistance significantly increased as a consequence of depressed left ventricular function. Thus, flecainide, exerted a direct negative inotropic effect on myocardial fiber but failed to exhibit any significant peripheral vasoconstrictive action. Although similar hemodynamic side effects were reported with all class I antiarrhythmic drugs, 16 comparative studies are required to evaluate the importance of myocardial depression induced by flecainide as compared with that induced by other class I antiarrhythmic drugs. Previous hemodynamic studies showed that the negative inotropic effect produced by tocainide or encainide is comparable to that observed in our study with flecainide. 17,1s Dose-related myocardial depression: The plasma concentration of flecainide in our patients ranged from 329 to 470 ng/ml, a value similar to that achieved by others after I to 2 mg/kg administered intravenously or orally and recognized to have antiarrhythmic effects.2,4,19 Interpatient comparison did not reveal any relation between plasma level and cardiac effects of the drug; however, the range of drug concentration was rather small. This observation suggests that within the therapeutic range achieved, the cardiac response to fiecainide is individual and cannot be predicted from the plasma drug level. Experimental studies in pigs have shown a dose-related negative inotropic effect during infusion of the

drug. 1° The individual response of dP/dt during drug infusion in 6 of our patients confirmed those observations. As the drug was infused, the contractility index dP/dt exhibited a progressive decrease; however, improvement in myocardial contractility appeared after the end of infusion and dP/dt returned to near basal values within 15 minutes. Plasma levels were not studled throughout drug infusion; however, one may hypothesize that intravenous administration of flecainide results in high plasma levels of the drug which rapidly

Diastolic

index ( m l / m 2 )

p=NS

t25

SystolTc

index (ml / m 2 ) p
75

tO0

75

--------------/

Before

25

After

Stroke index

Before

(ml / m 2)

60

p < CLOI

After

mean VCF (circum / s a c } p <0001

1 7S I SO

50

1 25 100

&O

0 75 30 Before

After

Before

After

FIGURE 5. Diagrams showing the individual variation in diastolic volume

index, systolic volume index, stroke volume index, and mean velocity of circumferential fiber shortening (VCF) induced by flecainide infusion (before = before infusion; after = after infusion). The p value indicated is the level of significance of Student's t test for paired data.

426

HEMODYNAMIC EFECTS OF FLECAINIDE

decrease during the first 10 minutes after administration, as shown in animal studies. 1° T h e r a p e u t i c implications: Flecainide acetate administered intravenously exerts a negative inotropic effect that may be of clinical importance in patients with congestive heart failure. This effect is particularly marked during infusion. Therefore, in patients with an uncompensated or poorly compensated heart, the drug should be administered with caution and the infusion interrupted if any deterioration of cardiac function occurs. In such cases, an initial primary dose of only 1 mg/kg or slower administration over 60 minutes may be preferred. References 1. Duff HJ, Roden DM, Woosley RL. Abolition of resistant ventricular arrhythmias by twice daily dosing with flecainide (abstr). Circulation 1980; 62:Suppl Iih111-81. 2. Somani P. Antiarrhythmic effects of flecainide. Clin Pharmacol Ther 1980;27:464-470. 3. Hedges M, Haugland JM, Granrud G. Asinger RW, Mikell FL, Krejci J. Flecainide acetate, a new antiarrhythmic agent: dose ranging and efficacy study (abstr). Am J Cardiol 1981;47:482. 4. Anderson JL, Stewart JR, Perry BA, Van Hamersveld DD, Johnson TA, Conard GJ, Chang SF, Kvam DC, Pitt B. Oral flecainide acetate for the treatment of ventricular arrhythmias. N Engl J Med 1981;305:473-477. 5. Seipel L, Abendroth RR, Breithardt G. Electrophysiological effects of fiecainide R 818 in man (abstr). Ear Heart J 1981;2A:115.

6. Granrud G, Krejcl J, Coyne T, Hedges M. Sustained el!minat~n of Ventricular arrhythmias during chronic flecainide dosing ~aestr). C-irculation 1981;64:Suppl IV:IV-316 7. Van Hamersveld DD, Stewart JR, JohnsonTA, AndersonJL. Oral flecainlde acetate for long term treatment of ventricular arrhythmias in man (abstr). Circulation 1981;64:Suppl IV:IV-316. 8. Campbell RWF, Henderson A, Bryson LG, Reid DS, Sheridan DJ, Rawlins MD, Julian DG. Intravenous flecainlde: pharmacokinetlca and efficacy. Circulation 1981;64:Suppl IV:IV-265. 9. WeHer AN, Schmid JR, Kvam C. Cardiovascular profile of R 818, fleeainide, a new antiarrhythmic (abstr). Fed Proc 1977;36:1003 10. Verdouw PD, Dekers JW, Conard GJ. Antiarrhythmic and hemodynarnic actions of flecainide acetate (R 818) in the ischemic porcine heart. J Cardiovasc Pharmacol 1979; 1:473-486 11. Hedges M, Hoback J, Graham E, Erlien D, Asinger R, Mikell F. Cardiac function after oral dosing with flecainide acetate (abstr). Clin Pharrnacol Ther 1981;29:251. 12. Ingels NB Jr, Daughters GT, Stinson EB, Alderman EL. Evaluation of methods of quantitative left ventracular segmental wall motion in man using myocardial markers as a standard, Circulation 1980;61:966-972. 13. Mulllns CB, Leshin SJ, Miersziak DS, Alsobrook HD, Mitchell JH. Changes in left ventricular function produced by the injection of contrast media. Am Heart J 1972;83:373-381. 14. Hamby RI, Aintablian A, Wilsoff BG, Hartstein M L Effects of contrast medium on left ventricular pressure and volume with emphasis on coronary artery disease. Am Heart J 1977;93:9-18. 15. Fischer HW, Thomson KR. Contrast media m coronary artenography: a review. Invest Radlol 1978;13:450-459. 16. JewiU DE. Hemodynamic effects of newer antiarrhythmic drugs, Am Heart J 1980;100:984-989. 17. Winkle RA, Anderson F, Peters F, Meffin PG, Fowles RE, Hainson DC. The hemodynamlc effects of intravenous tocainide in patients with heart disease. Circulation 1978;57:787-792. 18. Harrison DC, Winkle R, Sami M, Mason J. Encainide: a new and potent antiarrhythmic agent. Am Heart J 1980; 100:1046-1054. 19. Conard GC, Carlson GL, Frost JW, Ober RE. Human plasma pharmacokinet~cs of flecainide acetate (R 818), a new antiarrhythmic following single oral and intravenous dose (abstr). Clin Pharmacol Ther 1979;25:218

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