Antiarrhythmic and pharmacokinetic evaluation of intravenous recainam in patients with frequent ventricular premature complexes and unsustained ventricular tachycardia

ARRHYTHMIAS AND CONDUCTION DISTURBANCES

Antiarrhythmic and Pharmacokinetic Evaluation of Intravenous Recainam in Patients with Frequent Ventricular Premature Complexes and Unsustained Ventricular Tachycardia Jeffrey L. Anderson, MD, C. Pratap Reddy, MD, Robert J. Myerburg, Harvey L. Waxman, MD, and Philip J. de Vane, MD The pharmacokinetics, antiarrhythmic activity and safety of intravenously administered recainam were evaluated in 15 men and 3 women. All m Gents had frequent (>30/hour) ventricular prem ture complexes (VPCs) and unsustained ventricular tachycardia. Recainam was administered at a loading dose of 4.5 mg/kg/hour over 40 minutes, followed by a maintenance infusion of 0.9 mg/ kg/hour for 23 hours and 20 minutes. Sixteen patients had satisfactory efficacy data. The mean frequency of total VPCs decreased by 92.6% and the mean frequency of runs decreased by 99.9% during the maintenance infusion. Suppressions of 270% of total VPCs and 290% of runs were maim tained over the 23-hour, a&minute maintenance infusion period in 16 of the 16 patients. During the maintenance infusion, hourly group plasma recainam concentrations ranged from mean + SD 2.6 f 0.7 to 3.4 f 0.9 pg/ml. Patients were observed for 24 hours after termination of the infusion. Periodic blood samples were obtained during and after termination of the infusion to determine recainam concentration. Urine specimens were collected over scheduled intervals to determine urinary excretion of recainam. A 2compartment pharmacokinetic model was used to analyze the data. The following phannacokinetic parameters were obtained: terminal elimination hatf-life, 5.0 + 0.6 hours; systemic clearance, 0.27 + 0.06 liter/hour/kg; and central and steady-state volume of distribution, 0.32 + 0.11 and 1.4 f 0.4 liter/kg, respectively. Adverse experiences were reported in 4 of the 16 patients, possibly drug-related in 2; none was considered severe or required discontinuation of recainam. Mean electrocardiographic PR and QRS intervals (but not QTc interval) were prolonged 20 to 25% From the Division of Cardiology, Department of Internal Medicine, University of Utah Medical School, Salt Lake City, Utah, the Division of Cardiology, Louisiana State University Medical Center, Shreveport, Louisiana; the Division of Cardiology, University of Miami School of Medicine, Miami, Florida, the Division of Cardiology, Department of Medicine, University of Medicine and Dentistry of New Jersey, Camden, New Jersey; and WyethAyerst Research, Philadelphia, Pennsylvania. Manuscript received July 24, 1992; revised manuscript received and accepted October 5, 1992. Address for reprints: Jeffrey L. Anderson, MD, Division of Cardiology, Department of Internal Medicine, University of Utah Medical School, c/o LDS Hospital, Salt Lake City, Utah 84143.

686

THE AMERICANJOURNALOF CARDIOLOGY VOLUME71

MD,

(p 10.01) compared with baseline. No proarrhytb mic response to recainam was observed. No clinically significant changes in vital signs or in laboratory test results occurred. This study suggests that intravenous recainam is highly active in suppressing ventricular ectopy and may be safely administered. However, complete safety profiling and determination of its clinical role require additional studies. (Am J Cardiol1993;71:686-694)

P

harmacologic therapy is frequently given to prevent recurrences of malignant tachyarrhythrnias. However, available antiarrhythmic agents frequently have limitations that include a lack of efficacy, proarrhythmia, narrow therapeutic index, adverse effects and unfavorable pharmacokinetics.ld Even agents released within the past 10 years have had these problems, and no new class I agents have been marketed in the U.S. for intravenous therapy of ventricular and atrial arrhythmias in the past decade. The risk of adverse mortality effects of treatment in specific populations (i.e., postinfarction patients) has recently been emphasized by results of the Cardiac Arrhythmia Suppression Trial7 Thus, new antiarrhythmic agents with increased efficacy and reduced side effects are needed. Recainam (Wyeth-Ayerst Research, Philadelphia, Pennsylvania) is a new propylurea antiarrhythmic compound (Figure 1).s9 Microelectrode studies in canine Purkinje fibers indicate that recainam (10 to 20 @I) decreases action potential phase 0 upstroke velocity and depresses membrane responsiveness,8 a class I action. Reduction in upstroke velocity was also found to depend on the frequency of stimulation (use-dependence). l”,ll Onset of use-dependent block was comparable to that of the class Ia agents disopyramide and procainamide, slower than that of the class Ib agent lidocaine, and faster than that of the class Ic agent flecainide.l” In contrast to procainamide,lo recainam shortens action potential duration in canine Purkinje fibers. These findings indicate that recainam’s electrophysiologic profile does not completely conform to those of representative drugs of the class I subgroups. Initial studies with single intravenous and oral doses of recainam in humans have demonstrated its antiarrhythmic potential and yielded preliminary pharmacokinetic information.12 The present study was conducted to MARCH15,1993

assessthe pharmacokinetics, activity and safety of a 24hour infusion of recainam in hospitalized patients with stable ventricular ectopic activity. Interim results of a portion of this study were previously reported.13,14 METHODS Patient selection: Patients with stable ventricular ectopy, aged between 21 and 74 years, and within 10% of normal weight for height and age, were candidates for this study. A frequency of 230 ventricular premature complexes (VPCs) per hour, occurring as isolated beats, couplets, triplets or unsustained ventricular tachycardia (~12 consecutive beats), was required. Patients were excluded if they had New York Heart Association class III or IV congestive heart failure, hypersensitivity to propylurea derivatives, uncontrolled hypertension (supine diastolic blood pressure>lOO mm Hg), or sustained ventricular tachycardia (>30 secondsduration or causing hemodynamic compromise). Other exclusions were known alcoholism, drug or narcotic abuse, or need for tranquilizers or sedatives.Further exclusions were serum electrolyte abnormalities or clinically significant impairment of hepatic, renal, respiratory, endocrine, central nervous, or cardiovascular systems, myocardial infarction within 3 months, or child-bearing potential. Concurrent antiarrhythmic medications were not permitted; previous antiarrhythmic drugs were discontinued for 25 half-lives before study entry. Alcohol or caffeine was also not permitted, but other necessarymedications were allowed. Institutional review board approval for the study was obtained and all patients gave prior written informed consent. Study plan: This was a 24-hour, open-label, multicenter study designed to evaluate the antiarrhythmic activity, pharmacokinetics and safety of intravenous recainam in hospitalized patients with frequent VPCs and unsustainedventricular tachycardia. The primary goal of the study was to assessthe effects of recainam on ventricular ectopic frequenciesduring the maintenanceinfusion. Effective arrhythmia suppression was delined as 270% reduction in the frequency of total VPCs and 290% reduction in repetitive forms of VPCs during treatment comparedwith the 48-hour baseline recording. Within 3 days before study entry, a complete clinical examination, a 12-lead electrocardiogram, a complete laboratory evaluation, and 48-hour Holter monitoring were performed. Patients were admitted to the hospital for an overnight fast after completion of these baseline evaluations. They consumed 250 ml of water 2 hours before drug infusion the next morning. An intravenous infusion of 0.9% saline solution was started in 1 forearm to permit drug administration and to maintain adequate urinary output. Recainam hydrochloride (126 mg in 2 ml vials) was diluted with 0.9% saline solution. A loading dose of 4.5 m&g/hour was given for 40 minutes by constant infusion. After completion of the loading dose, a maintenance infusion was given at a rate of 0.9 mg/kmour for 23 hours and 20 minutes (total drug administration time, 24 hours). Vital signs were monitored frequently and recorded at 3Ominute intervals during the 2 hours before drug

TABLE I Patient Characteristics Primary Diagnoses

Pt. No.

Age (yr) & Sex

Weight (kg)

1 2 3

54M 48M 71F

99.5 84.0 82.6

VA VA VA

4* 5 6 7 8 9 10 11 12

61F 59M 21M 72M 66F 46M 74M 54M 67M

89.5 82.5 75.5 76.1 56.5 63.0 89.0 96.0 87.0

VA VA VA VA VA VA VA VA VA

13 14 15 16* 17 18

70M 50M 53M 63M 54M 74M

95.0 80.9 105.0 75.5 119.0 83.0

Mean + SD

59 ? 13

85.5 ? 14.6

VA VA AS/Al AP VA VA

Secondary Diagnoses 0 0 Idiopathic cardiomyopathy Urinary infections 0 0 0 0 0 0 0 Hypertension, carotld arteriostenosis, diabetes mellitus Epilepsy, prostatism 0 0 0 Diabetes mellitus Hypertension, claudication, compensated heart failure

*The Halter tapes for these 2 patients on the day of dose admimstration were notavailable for analysis by Cardlo Data; these patients were excluded from the analysis of means for the group, but reported separately here and in text. Al = aortic insufficiency; AP = angina pectoris; AS = aortic stenosis; VA = ventricular arrhythmias.

infusion, at 5, 10, 20, 30 and 40 minutes during the lirst hour of the infusion, and subsequentlyat 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36 and 48 hours after the initiatian of drug administration. Continuous monitoring of electrocardiographic leald II was performed during drug infusion. A 1Zlead electrocardiogram was obtained before drug administration and at 1, 3, 6 and 12 hours after the start of drug infusion. Additional 12-lead and lead II electrocardiographic monitoring was done at the discretion of the investigator. Rhythm strips for PR, QRS and QTc determinations were obtained before the infusion, at 20 and 60 minutes, at hourly intervals until 6 hours after the start of the infusion, and at 2-hour intervals until the end of the infusion. Holter recording was performed 48 hours before and during the recainam infusion and for 2!4 hours after the end of the infusion. The Holter monitoring tapes were analyzed and reported by a central laboratory (Cardio Data Systems, Inc., Haddonfield, New Jersey). Blood sampleswere obtained at 2, 4, 8 and 12 hours after the start of the infusion for laboratory evaluations.

FI NH-C-NH-CH2-CH2-CH2-NH-CH

/

CH3

\ CH3 FIGURE 1. Ch&nical structure phenyHU’&(l-methylethykmino)

CH3 of recainam, [N-2,BdimethyC propylurea] hydrochloride,.

ANTIARRHYTHMIC EFFICACYAND PHARMACOKINETICS OF RECAINAM 6617

6 to 12, 12 to 18,24 to 36, and 36 to 48 hours. All samples were stored at -20°C. Recainam levels were analyzed using high-pressureliquid chromatographywith a sensitivity of 0.06 p&-nl. l5 Recainam plasma concentration and urinary excretion data were analyzed using pharmacokinetic methods described previously.12 Statistical methods: For each patient, total VPC frequencies for the baseline (scheduled to be 48 hours) and the maintenanceinfusion (scheduledto be 23 hours and 20 minutes) periods were determined. In each period (baseline and maintenance)for each patient, the observed VPC count was divided by the actual length of observation to get an hourly frequency. Thus, baseline

These included hematologic analyses,blood chemistries and urinalyses. Phammcokinetic analysis: Blood samples for determinations of recainam plasma concentrations were collected at the following times: 2 to 5 minutes before and 20 minutes after the initiation of loading infusion, at the completion of the drug load (40 minutes), and then at 1, 1.5, 2,4,8, 12, 18,24, 26,28, 30 and 36 hours after the beginning of the loading infusion. All blood sampleswere collected in heparinized tubes and immediately centrifuged. The plasma was separated and frozen. Urine sampleswere collected during the following intervals after the initiation of the infusion: 0 to 6,

TABLE II Patient List of the Frequency of Ventricular Ectopy (total, single and paired WCs, and runs of VP& per hour) at Baseline and Over the 23-Hour, 20-Minute Maintenance Infusion Baseline Pt. No. 1 2 3 5 6 7 8 9 10 11 12 13 14 15 17 18

Total VP&/Hour

Single VPCs/Hour

Mean

581 139

Paired VPCs/Hour

123

127 226 1,362 147 112 1,816 1,056 533 188 1,588 470 292 352 167 397 466

SE:

Maintenance Infusion

217

3 8

1,116

141

137 107 1,416 356 436 172 1,519 444 270 352 145 330 457 475 114

7 4 319 166 76 15 59 23 20 0.0 22 63 9 58 21

Total VPCslHour

Runs/Hour 0.0 0.4 29 1 0.1 26 73 6.9 0.1 3.4 0.7 0.3 0.0 0.3 1.3 0.1 9 5

9 (-93) 0.0 C-100) 3 (-100) 1 (-99) 5 C-95) 5 C-100) 17 C-95) 2 C-100) 2 (-99) 252 C-83) 7 C-98) 9 (-97) 1 C-100) 0.1 C-100) 65 t-80) 288 C-37) 42 t-91) 23

9 c-931* 0.1 C-100) 3 C-100) 1 C-99)

6 5 18 3 2 254 7 9 1 0.1 86 288 43 23

Single VPCs/Hour

t-95) 1-100) C-98) (-100) C-99) C-84) (-99) C-97) C-100) (-100) C-78) t-38) (-93)

Paired VPCs/Hour 0.0 C-100)

0.1 (-100) 1 (-100) 0.0 C-100) 1 C-73) 0.1 (-100) 1 C-100) 0.4 C-100) 0.0 (-100) 2 C-97) 0.0 (-100) 0.1 1-100) 0.0 NA 0.0 C-100) 21 C-67) 0.0 C-100) 2 C-97) 1

Runs/Hour 0.0 (- 100) 0.0 C-100) 0.0

(-100)

0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0

C-100) C-100) (-100) (-100) (-100) C-100) C-99) f-100) (-100)

0.0 NA 0.0 0.0 0.0 0.0 0.0

(-100) (-97) C-100) (-100)

*Values m parentheses represent the percent changes from baseline ectopic frequency. NA = not applicable; VPCs = ventricular premature complexes.

FIGURE 2. Total ventricular premature complex (WC) frequency before, during, and after 24-hour recainam infusion (n = 16).

-------------------------SASiiiE TOTAL VPCs

- ----------

1OO

w

0i ’ -40,,, -40

, -32, , -24,,

-16,

, -6, , 0, I+

No of Observalfms

688

7 11 14 15 1515

9 151616

2b MFIJSICN

TIME ( hours ) 161614 1616

-

16161612

THE AMERICANJOURNALOF CARDIOLOGY VOLUME71

32

40

48

16 16151514

10

1

MARCH15,1993

characteristics are listed in Table I. Age (mean fSID) averaged 59 f 13 years (range 21 to 74), and mean weight was 85.5 + 14.6 kg (range 63 to 119).Primary diagnosesincluded ventricular arrhythmias (n = 16), aortic stenosis/insufficiency (n = 1) and angina pectoris (n = 1). Antianhythmic effect: Sixteen patients had data evaluable for antiarrhythmic effects by a central laboratory. The 48-hour baseline mean frequencies of total, single and paired VPCs and runs of VPCs are listed in Table II. The mean frequency of total VPCs decreased by 92.6% and the mean frequency of runs by 999% over the maintenanceinfusion period (p
and maintenance VPC frequencies, obtained for each patient, were normalized to a “per hour” basis. Mean ventricular ectopic frequencies at baseline and during therapy were determined for patients with paired data (i.e., data at baseline and the interval under consideration). Differences were expressedas percentagesof baseline means. The changesfrom baseline in the ventricular ectopic frequencies were analyzed through the paired t test after logarithmically transforming the data. The mean changesfrom baseline in the vital signs and electrocardiographic parameters were analyzed by a paired t test.

900

800

FIGURE 3. Si@e ventkular

premature complex (WC) frequency before, during and efter 24-hour recainam infusion (n = 16).

-48

40

-32

-24

-18

-8

0

24

I~HFUSlON TIME NoofObsewafkms

7 11 141515159

( bows

32

40

-

MEAN

-

MEAN

- SE.

48

-cl

1

151818181614181818181612181815151410 -

500

250

FIGURE 4. Paired ventricular premature complex (WC) frequency before, during end efter 24-hour recainam infusion (n q 16).

-

MEAN

+ S.IE.

-

MEAN

- Sli.

70% “TFF”” BASEUNE PAIRED WCs

’ 48

NoofObsswatiins

-40

711

-32

141515159

-24

-18

-8

0 1-

INFUSION

-

24 1

32

40

48

TIME ( horn 1 151618161814161616181812181615151410

ANTIARRHYTHMIC EFFICACYAND PHARMACOKINETICS OF RECAINAM

689

able baseline runs of ventricular tachycardia had 100% suppressionof runs, and all 15 patients had >95% suppression of runs. Two patients were excluded from the mean efficacy evaluation becausetheir data were not available for analysis by the central laboratory. For these 2 patients, 1 (patient 16) had 99.95% suppressionof total VPC frequency based on preliminary (investigation site) analysis; no runs were recorded for this patient at baseline or during infusion. The other patient (patient 4) had a baseline total VPC frequency of l,465/hour, which was reported to have remained unchanged (at 1,72O/hour) during the recainam maintenanceinfusion. However, this patient had 99.7% suppressionof runs, and paired VPCs were suppressed96.4%.

Figures 2 to 5 illustrate the mean hourly frequency of total, single and paired VPCs, and runs of VPCs in the 16 patients included in the efficacy analyses. The mean frequency of total, single and paired VPCs per hour decreasedfrom baseline by 270% at each hourly reading from the tirst to the 27th hour after the start of infusion. The mean frequency of runs per hour decreased from baseline by 290% at each hourly reading from the tirst to the 28th hours. A greater percentage of repetitive forms than single VPCs was suppressed. Plasma W relation: The relation between plasma concentrations of recainam and suppressionin VPCs and runs is shown in Figures 6 and 7 for individual patients. In general, effective suppres-

55 50 45 40 35 s P 2

30

FIGURE 5. Graphic display of the ventricular tachycadia run Wquency before, during and after 24-hour receinem infusion (II q 16).

25

f

5 90% SUPPRESSION OF-$ BASELINE RUNS -46

-40

-32

?4

-16

-6

0

24

tTIME ( hews NoofObservakms

I

MEAN

-

MEAN

+ S.E.

- S.E.

4.3

1

1

FIGURE 6. Display of each patient categc+ rized for the presence or absence of 70% suppression of total ventricular premb ture complex versus plasma recainam concentration and time since the start of drug infusion (n = 16). A satisfactory response is defined as 270% suppression of total ventricular premature complex frequency at baseline.

0

Satisfactory

0

Unsatisfactory

RECAINAM

f

INFUSION

-I

I

I

I

I

I

I

I

I

213

7

1.5

2

4

8

12

18

TIME

690

40

MEAN

-

711141515159151616161614161616161612161615151410

III3

INFUSION-t

32

-

( hours

I

24

I

I

28

28

I1

30 38

)

THE AMERICANJOURNALOF CARDIOLOGY VOLUME71

MARCHl&l993

effective arrhythmia suppression (270% suppressionof total VPCs and 290% suppressionof runs) in 16 of the 18 patients (89%). Phamacokinetics: Plasma recainam concentrations over time are shown for all 18 patients in Figure 8. The data were best described by a 2-compartment pharmacokinetic model of disposition. Maximal plasma recainam concentration was mean z!zSD 5.02 f 1.64 pg/ ml; there was considerable variation among patients. Pharmacokinetic parametersderived from plasma con-

sion of both total VPCs and runs was observed at recainam concentrations >l t.&nl. The peak plasma concentration of recainam (mean Z!I SD 4.90 + 1.49 pg/ml) was noted at the end of the loading infusion (Figure 8). During the recainam maintenance infusion individual plasma recainam concentrations ranged from 1.32 to 5.73 p.gjml for all 18 patients; the group plasma recainam concentrations ranged from mean f SD 2.63 + 0.72 to 3.39 f 0.90 pg/ml. The observed plasma recainam levels were associatedwith 8

D -

FlGURE 7. Display of each patient ca& gorized for the pwsence or absence of 90% suppmwsion of runs versus plasma recainam concentration and time since the start of drug infusion (n = 3.8). A satisfactory response is defined as 290% suppression of nm frequency at base line.

. .

0 Satisfactory 0 Unsatisfactory

D” I -RECAlNAM I I I l/3 2/3 1

I 1.5

INFUSION I I I I 2 4 8 12 TIME ( hours

10 -

I 18 )

I 24

I 26

I 28

I I 30 36

Infusion Maintenance Discontinued

FIGURE 8. Plasma recainam concentration over time for all 18 patients. All patients received intravenous recainam at a loading dose of 4.5 -hour over +O minutes, fqllowed by a main& nance dose of 0.9 -hour for 23 hours and 20 minutes. Connected so/id @ts, mean plasma concentrations; shark ed (cfvss-hat~) area, observed plasma concentration range.

VRECAINAM I 0 4

I 8

I 12

INFUSION -I I I 16 20

I 24

I

I

I

2s

32

36

TIME ( hours )

ANTIARRHYTHMIC EFFICACY AND PHARMACOKINETICS OF RECAINAM

691

TABLE III Two-Compartment

Pharmacokinetic

Mean * SD

Parameters

5.02 4.95 0.27 0.14 0.32 1.39 1.92 3.39 3.10 0.14

0-m (p&N tl/Z, A2 (hours) CL (liters/hour/kg) CLr (liters/hour/kg) Vc (liters/kg) Vss (liters/kg) VA2 (liters/kg) C24H (kg/ml) Al (hour-l) A2 (hour-l)

the mean QTc interval decreasedslightly (2%), but the decreasewas not statistically significant. Changesin vital signs d-&n; treatment are listed in Table I! A small although statistically significaht increasein mean supine heart rate was observed at peak recainam concentration (mean change 7 f 2 beats/min). No statistically significant changesin mean supine systolic and diastolic blood pressureswere found. Moreover, no clinically important changesin vital signs requiring interventions were observed in individual patients. Adverse reactionc Recainam was well tolerated. No patient required dose modification or discontinuatioil becauseof adversereactions.No blood chemistry abnormalities were noted. During the study, adverse experiences were reported in 4 qf the 18 patients. Three adversereactions reported in 2 patients were judged by the investigators to be at least possibly drug related. These included a single occurrenceof headacheand circumoral paresthesiain 1 patient and asymptomaticpersistent left bundle branch block in &e other. Severity was evaluated by the investigator as mild or moderate in all adverseexperiencesexcept the left bundle branch block which was not evaluated.No patient had adverse reactions during recainam treatment that were related to changesin the baseline electrocardiographicintervals or vital signs.

Parameters

e k f a f k r + * 2

I

1.64 0.77 0.08 0.05 0.11 0.37 0.51 0.90 1.13 0.02

C24H = plasma concentration at 24 hours; CL = systemic clearance; CLr = renal clearance; Cmax = maximal plasma concentration; hl = initial phase dlspositian rate constant; A2 = terminal phasedisposition rateconstant; tll2, A2 = terminal half-life; Vc = apparentvolume of distribution of the central compartment; VA2 = apparent termmal volume of distribution; Vss = apparent steady-state volume of distribution.

1

centrations after the infusion are listed in Table III. The terminal elimination half-life of mean & SD 5.0 f 0.8 hours and a systemic clearance of 0.27 f 0.08 liters/ hour/kg were obtained. Electrocardiographic interval measurements and vita! signs: Electrocardiographic intervals for the drug-

free baseline and recainam treatment periods are presented in Table IV The mean electrocardiographic PR and QRS intervals were prolonged 20 to 25% (p lO.001) from baseline values at the end of the 24-hour infusion;

TABLE IV Summary of Electrocardiographic (ECG) Measurements at Baseline and at the End of the 24-Hour Recainam Infusion (n = 18) Scalar ECG Interval PR QRS QTc

Baseline Mean + SD bed 0.190 0.093 p.445

i 0.024 f 0.011 +- 0.054

Changefrom Baseline Mean 2 SE bed

Recainam* Mean f SD (set) 0.234 0.115 0.435

+ 0.039 z 0.029 2 0.038

0.044 0.023 -0.009

2 0.005 2 0.006 f 0.010

Percent Change from Baseline

P Value

+23.4 i24.3 -2.1


*Values were determined at the end of the 24.hour infwon.

TABLE V Summary of Vital Signs Data Before Dosing, at 40 Minutes (peak mean plasma recainam level) and 4 Hours After the Start of the Infusion, and at the End of the Infusion (24 @rs) (n = 18)

Time/Vital

Signs

40 minutes Supine heart rate (beats/min) Supine systolic BP (mm Hg) Supine i(jastolic BP (mm Hg) Supine mean BP (mm Hg) 4 hours Supine heart rate (beats/min) Supine systolic BP (mm Hg) Supine diastolic BP (mm Hg) Supine mean BP (mm Hg) 24 hours Supine heart rate (beats/min) Supine systolic BP (mm hg) Supine diastolic BP (mm Hg) Supine mean BP (mm Hg)

Pre-Dose Mean + SD

Recainam Mean f SD

Mean Absolute Change c-t SE)

THE AMERICAN JOURNAL OF CARDIOLOGY

P Va!ue

67 132 84 100

2 f k -t

14 16 12 10

75 128 87 100

k + rt 2

10 16 11 11

+7.2 k -4.9 k +3.1 + +0.4 2

2.4 2.6 2.7 2.2

+10.6 -3.7 +3.6 +0.4

0.009 0.071 0.273 0.863

67 132 84 100

k & k *

14 16 12 10

77 129 86 100

* f f f

13 16 13 13

+9.7 -3.9 +2.0 0.0

f -t k *

2.1 3.0 2.6 2.2

f14.4 -3.0 2.4 0.0


67 132 84 100

k 14 Y!Z16 f 12 2 10

77 130 82 98

-t f -+ 2

12 14 9 8

+9.4 -2.2 -1.4 -1.7

* -c f k

2.2 3.4 2.6 2.5

f14.0 -1.7 -1.7 -1.7


BP = blood Rressure.

692

Mean Change I%)

VOLUME 71

MARCH 15,1993

DISCUSSION

Therapy of ventricular (and atrial) arrhythmias with currently marketed antiarrhythmic agentscontinues to be problematic.1-7 Additional antiarrhythmic agents effective and well tolerated-both intravenously and orally are needed for the treatment of symptomatic or potentially life-threatening ventricular arrhythmias. The results of our study suggestthat recainam may be an effective and well-tolerated ant&rhythmic agent for suppression of complex, symptomatic ventricular arrhythmias when administered intravenously. The initial loading infusion of recainam was well tolerated and resulted ‘in a rapid onset of antiarrhythmic activity. During the maintenance infusion of recainam, 15 of the 16 (94%) evaluable patients responded satisfactorily. The mean frequencies of total VPCs and runs for all 16 evaluable patients decreased by 92.6 and 99.9%, respectively. Efficacy results were tirmly established for total ventricular ectopy. Conclusions for unsustainedventricular tachycardia should be temperedby the fact that only 7 patients had 21 episode per hour. The observed antiarrhythmic effect of intravenously administered recainam is clearly excellent and is similar to the reported efficacy of intravenous flecainide.16 Within 1 to 2 hours after recainam was discontinued, ventricular ectopy (total and single VPCs) began to recur. Repetitive VPCs remained suppressedfor a longer period of time than single VPCs. Ventricular ectopy (total, repetitive and single VPCs) returned to frequencies similar to those before infusion at approximately 8 hours after termination of the infusion. A secondary decrease in ventricular ectopic frequency was observed 16 to 20 hours after stopping the infusion that was more pronounced for repetitive (pairs, runs) than isolated VPCs. These variations are likely due, at least in part, to circadian variations associatedwith sleep.” In studies of oral recainam in patients with chronic nonlife-threatening arrhythmias, more effective suppression of paired VPCs and unsustainedventricular tachycardia than of single VPCs was also demonstrated.18This differential effect probably also potentiated the normal circadian variation in density of VPC pairs and runs. During the 24-hour infusion period, plasma recainam concentrations were >l p,g/ml for all patients. The observed range of plasma concentrations (1.3 to 8.7 p&ml) was associated with successful suppression of VPCs in most patients. These data suggestthat recainam concentrations achieved with the intravenous regimen used in this study are effective in suppressingVPCs in this study population. The pharmacokinetic disposition of recainam in patients with stable ventricular ectopy in this study was similar to that found in normal volunteers (Wyeth Laboratories, Capuzzi DM, unpublished data). In that study, 6 healthy male volunteers were administered recainam by a loading infusion of 4.5 mg/kg/hour over 40 minutes, followed by a continuous maintenanceinfusion of 0.5, 0.75 or LO mg/kg/hour for 23 hours and 20 minutes. ‘Systemic clearance of recainam averaged 0.32 liter/kg/hour, and terminal half-life was 4.6 hours. These values are similar to those seen in the current study. However, the terminal half-life obtained in the present .1

study could be somewhatunderestimatedbecauseof the relative insensitivity of the assay(minimum quantifiable level of 0.06 p&ml) and the suboptimal number of measurable data points in the terminal phase. Recainam produced moderate effects on electrocardiographic PR and QRS intervals. At the end of th.e infusion, both intervals increased significantly from baseline. In contrast, no significant changesin the QTc interval were noted. Becauseaverageplasma concentration exceededby two- to threefold the estimatedthreshold of about 1 pg/ml, the magnitude of the effects (20 to 25% increases) may exceed those associated with (lower) drug doses sufficient to achieve efficacy. A small and statistically significant increase in mean supine heart rate (7 beats/nun) was observedat the time peak plasma levels occurred. A slight increase (3 mm Hg) in the mean supine diastolic blood pressurealso was observed at this time but did not reach statistical significance. The data demonstratethat the acute effects of intravenous recainam on heart rate and blood pressure, in doses needed to achieve efficacy, are generally not clinically significant. Recainam was exceptionally well tolerated in the present study.Adverse experienceswere reported in only 4 of the 18 patients, and none of the reported adverse experiences ‘was considered severe or required dose modification despite the relatively high blood levels comparedwith the efficacy threshold. No proarrhytbmic responses to recainam were seen. However, the observation period was short, the study group was small, and patient groups at high risk for adverseevents were excluded by design (i.e., heart failure, recent myocardial infarction, history of sustained ventricular tachycardia). Thus, adequate safety profiling will require additional experience. Because the benefit/risk ratio of therapy may differ substantially for these important patient groups often needing therapy,s-7recainam will need to be carefully tested in future studies in these patient groups. Als’o, given results of the Cardiac Arrhythmia Suppression Trial? it should be emphasized that suppression of asymptomatic ventricular ectopy may not be associated with mortality benefits, and use of at least some class 1 antiarrhythmic agents may -actually increase risk in certain settings (i.e., after myocardial infarction).3 Thus, the clinical role of recainam must be determined by further studies. REFERENCES 1. Anderson JL. The new antimhythmic drugs. How to put them to the best use. f’ostgrad tieied’1988;83:181-193. 2. V&bit V, P&id P, Lawn B, Cohen BH, Graboys TB. Aggravation and provecation of ventricular arrhythmias by antiarthythmic drugs. Circulation 1982$5: 88&894. 3. Anderson JL. Clinical implications of new studies in the treatment of benign, potentially malignant and malignant ventricular arrhythmias. Am .i Cardiol 1990$5: 36B-i2B. 4. Morganroth J, Bigger JT. Pharmacologic management of ventricular arrhythmias after the cardiac mhythmia suppression trial. Am .I Cardiol 1990;65: 1497-1503. 5. Pratt CM, Eaton T, Francis M, Woolbert S, Mahmaim .J, Roberts R, Young JB. The inverse relationship between baseline left venbicular ejection fraction and outcome of antimhyttmic therapy: a dangerous imbalance in the risk-benefit ratio. Am Heart J 1989;118:43%440. 6. Morganroth J, ‘Anderson JL, Gentzkow GD. Classification by type of ventricular arrhythmia prqlicts frequency of adverse cardiac events from flecainide. J Am Cdl Cardiol 1986;8:607-615.

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7. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. F’reliminary report: effect of encainide and flecainide on mortality in a randomized hial of anhythmia suppression after myocardial infarction. NEnglJMed 1989;321:40&412. 8. Bergey JL, Sulkowski T, Much DR, Wendt RL. Ant&rhythmic, hemodynamic, and cardiac electrophysiological evaluation of N-(2,6-dimethylphenyl)-N-(3-[ 1. methylethylamino]-prophyl) urea (Wy+“2,362). Arzneimittelforschung 1983;33: 1258-1268. 9. Kimmel HB. Phamacokinetics of Wy-42,362 in dogs given single 15 mgikg imragastric and intravenous doses of Wy-42,362 tosylate or hydrochloride. General Technical Report #7471, Wyeth Laboratories, Philadelphia, PA: 1979. &O. Colatsky TJ, Bird LB, Jurkiewicz NK, Wendt RL. Cellular electrophysiology of the new ant&rhythmic agent recainam (WY-42,362) in canine cardiac Pwkinje fibers. J Cardiovasc Phannacol 1987:9:435444. 11. Takikawa R, Kamiya K, Kate R, Singh BN. Electrophysiologic effects of a new ant&rhythmic agent, recainam, on isolated canine and rabbit myocardial fibers. JAm Coil Cardiol 1988;11:875-881. 12. Davies RF, Lineberry MD, Funck-Brcntano C, Echt DS, Lee JT, Capuzzi DM, Roden DM, Woo&y RL. Recainam dose titration and phannacokinetics in patients with resistant arrhythmias. Clin Pharmcol Ther 1989;46:324-334.

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13. Anastasiou-Nana MI, Anderson JL, Hampton EM, Nanas JN, Heath BM. Recainam, a potent new ant&rhythmic agent: effects on complex ventricular arrhytlmiss. J Am Co11 Cardiol 1986;8:427435. 14. Hampton EM, Anastasiou-Nana MI, Nanas JN, Nappi JM, Capuzzi DM, Anderson JL. The disposition of recainam hydrochloride during and after intravenous loading and maintenance infusion in cardiac patients. J Clin Pharmcol 1987;27:951-956. 15. Kimmel HB. A high performance liquid chromatographic method for the determination of Wy-42,362 in biological fluids. General Technical Report #X469, Wyeth Laboratories, Philadelphia, PA: 1981. 18. Somani P. Antiarrhythmic effects of flecainide. Chin Phmmcol The-r 1980;27:4w70. 17. Morganroth J. Evaluation of antiarrhythmic therapy using Halter monitoring. Am J Curdiol 1988;62:18H-23H. 18. Dose-ranging and long-tam efficacy of orally administered recainam (Wy42,362) in patients with frequent premature ventricular contractions (PVCs): final report on open dose-ranging and placebo-controlled double-blind a-ossover phases. General medical reports #154&i (protocol 519B-206) and #15525 (protocol 519B207), Wyeth-Ayerst Research, Philadelphia, PA: 1988.

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