Tocainide for drug-resistant ventricular arrhythmias: Efficacy, side effects, and lidocaine responsiveness for predicting tocainide success

Tocainide fsr drug-resistant arrhythmias: Efficacy, side lidocaine tocainide

responsiveness

ventricular effects, and for

predicting

sulccess

Roger A. Winkle, M.D., Jay W. Mason, M.D., Donald C. Harrison, M.D. Stanford, Calif. Tocainide

therapy

has

recurrent arrhythmias

sustained could

ventricular tachycardia not be managed with

doses averaged concentrations tocainide and and nonresponders.

1,590 from 16

been

evaluated

mg/day 6 to 12

(39%) did Lidocaine

in 38

(range m/ml. not.

patients

and

with

and/or quinidine,

600 to 2,400) and Twenty-two patients

Tocainide was effective

ventricular

fibrillation procainamide,

dose and plasma in 26 patients

and

arrhythmias. 29 required disopyramide,

the majority (61%) had

Thirty-one

of patients had their arrhythmias

concentrations and 16 (63%)

were of these

the Cardiology Stanford, Calif.

From

IDivision,

Stanford

Reprint requests: Roger A. Winkle, ford University School of Medicine,

0002-8703/80/131031

+ 06$00.60/O

University

School

of Medicine,

M.D., Cardiology Division, Stanford, CA 94305.

Q 1.980 The

Stan-

C. V. Mosby

Co.

These Tocainide

plasma controlled

similar for had their

controlled with tocainide. Of 12 patients in whom lidocaine was known to be ineffective been previously treated, only two (17%) had arrhythmias controlled with tocainide (f < 0.02). Side effects occurred in approximately two thirds of patients but required long-term tocainide in only three patients.

Tocainide is a lidocaine analogue that is effective for treating ventricular arrhythmias.‘m6 It has nearly complete bioavailability and a plasma half-life averaging 13.5 hours.‘. 7 Plasma concentration is directly proportional to dose in individual patients and there is a narrow range of intersubject variation of plasma concentration for any dose.’ Electrophysiologically, tocainide resembles lidocaineY-” and its primary hemodynamic effect after intravenous dosing is a modest elevation of vascular resistance resulting in a slight rise in arterial pressure.l’ This study reports our experience with the use of long-term tolcainide in a group of patients with severe ventricular arrhythmias that could not be managed with other generally available antiarrhythmic drugs. We will examine the efficacy and side effects and the value of lidocaine responsive-

had

prior cardioversions. or propranolol.

with

responders arrhythmias

or who

had

discontinuation

ness for predicting tocainide.

not of

arrhythmia

control

with

Methods

Thirty-eight patients with ventricular arrhythmias are the subjects of this report. This report includes and provides further follow-up on the 17 patients reported on in 1978.” Each patient had ventricular arrhythmias that could not be managed adequately with currently available antiarrhythmic drugs. All gave written informed consent and the therapy was approved by the Stanford Human Subjects Committee. For patients with frequent recurrent episodes of sustained ventricular tachycardia or ventricular fibrillation, tocainide therapy was considered successful when control of these severe occurrences was established. For patients with ventricular ectopic activity, tocainide was considered successful when there was nearly complete elimination of ventricular ectopic beats. Initial dosing with tocainide was undertaken for most patients at 400 mg every 8 hours. The

American

Heart

Journal

103

1

Ta I. Respsnse toeainide success

Effective Ineffective NQ. effective/ total

to Bidocaine

16 10

1 3

with

ventricular

arrhythmias

!=

I SUCCESSFUL THERAPV

I LATE ARRHVTHMlA

0 LATE SIDE EFFECTS

1 UNSUCCESSFUL THERAPV

Fig. 2. Mean tocainide plasma concentration over one dosing kterval. Most patients’ plasma concentrations were between 6 and 12 pg/ml. There was no significant difference between the plasma concentrations in those treated successfully and those treated unsuccessfully.

dosage was gradually increased until arrhythmias were controlled or side effects occurred. Frequent blood sampling was performed, and plasma coneentrations’3 given for each patient represent an estimate of the average over a dosing interval. For each patient, assessment was made as to the responsiveness of the arrhythmias to lidocame. Comparison between the success or failure of tocainide in patients responsive or nonrespon-

I

1 7 -

16/26

(63%)

sive to lidocaine was perf0rmed isher exact test.

Fig. 1, Outcome in 38 patients treated with tocainide.

fo’or predicting

114 (25%)

1/8 (12%)

by means of the

ula~~0~. There were 38 patients (23 le) receiving tocainide; the average age was 58 I 1.2 years. Twenty-one had coronary disease, seven had prior valve replacement, four had mitral valve prolapse, three had a cardiomyopathy, and three had an otherwise normal heart. Congestive heart failure played a prominent role in the prior clinical course of 16 patients. The arrhythmia was sustained ventricular tachycardia and/or fibrillatisn requiring pharmacologic or electrical conversion in 31 patients. Twenty-eight patients had experienced more than one episode and 29 had a prior cardioversion. In seven patients the arrhythmia was symptomatic ventricular ectopy. Thirty-six patients had been treated umxnccessuinidine (average daily dsse ef 3, 33 with procainamide (23 rt 1.1 ropranolol (140 + 101 mg), and 11 !a. suits The rzsul.ts of tocainide therapy are shown in Fig. 1. Tocainide therapy was inS5ally effective in 2% 0f the 38 patients (61%). Four had late arrhythmia recurrences, including two who died of ventricular fibrillation after 3% and 4 months of therapy. Eighteen patients had their arrhythmias treated c~~t~~~~us~y and successfully with tocainide. Three of these required discontinuation of the drug after 6, 7, and 27 months because of side effects (see below). The mmaining 15 patients were treated successfully with tocainide (median duration, 13 months). Eight remain on tocainide and an seven it was discontinued for nondrugrelated causes. (One had a s~~~ta~e0~s decline in arrhythmias, two died after coronary bypass sur-

Tocainide

13 PATIENTS LID~DCAINE TESTED DURING EP STUDY AND THEN TRIEATED WITH TOCAINIDE

LIDOCAINE

6 TOCAINIDE EFFECTIVE

1

3 TOC,&lNIDE 1 FAILED

for drug-resistant

arrhythmias

6 PATIENTS TOCAINIDE TESTED DURING EP STUDY AND THEN TREATED WITH TOCAINIDE

NOT

TOCAINIDE

TOCAINIDE

NOT

I 1

Fig. 3. Outcome in 13 patients in whom lidocaine was tested for protection against ventricular tachycardia induced during intracardiac electrophysiologic study. Although the acute response to lidocaine was fairly predictive of the long-term success or failure of ltocainide, the correlation was imperfect.

Fig. 4. Outcome in six patients undergoing a repeat electrophysiologic study to evaluate ventricular tachycardia inducibility on oral tocainide. Although the number of patients is small, there was a perfect correlation between the outcome of the electrophysiology study and long-term therapy.

gery was performed for angina, one died of lung carcinoma, and three died of heart failure.) Sixteen patients failed to have their arrh.ythmia controlled with tocainide despite maximally tolerated dosesof tocainide. The median duration of treatment in these patients was 7 days. Dose and plasma concentration. The total daily dose of tocainide ranged from 600 to 2,400 mg daily. There was no difference between the daily dose of those treated effectively (1,528 * 379 mg/day) as compared to those treated ineffectively (1,514 h 412 mg/day). There was no difference between the plasma concentration for those responding to tocainide (8.9 I+_3.1 gm/ml) and those not responding (9.4 t 2.2 pg/ ml) (Fig. 2).

not protect against ventricular tachycardia in four patients. In three of these patients, tocainide therapy was a failure. Of six patients in whom oral tocainide was tested during a second electrophysiologic study (Fig. 4), four were treated successfully. Both patients for whom tocainide was not prophylactic at the time of electrophysiologic study had subsequent spontaneous recurrences of ventricular arrhythmias. Lidocaine responsiveness during the electrophysiologic study may aid in selecting patients for oral tocainide therapy. However, all patients should be retested with tocainide prior to hospital discharge. Side effects. Two thirds of patients had side effects (Table II). Side effects occurring during chronic oral therapy tended to be infrequent and were usually not a serious limitation to tocainide therapy. Tremor was minimized by taking the drug with food. Three patients had severe side effects during long-term therapy and required discontinuation of tocainide. One had a prior history of idiopathic and procainamide-induced pericarditis. Tocainide was stopped after 7 months because of anemia, fever, and pericarditis.” Another developed severe arthralgias and arthritis involving the hands after 4 months of therapy, which resolved when tocainide was discontinued. There was a slight rise in the antinuclear antibody titer. This patient had undergone a brief treatment with procainamide 2 months earlier. The third patient had an immunologic side effect that seemed best attributed to tocainide. After 27 months the patient presented with gross hematuria and had a rise in creatinine

Lidocaine rehponsiveness for predicting tocainide success’. Since many of these patients

were referred because their arrhythmia was responsive to lidocaine, we evaluated the value of a good lidocaine response for predicting the successof tocainide. Table I summarizes the results. Tocainide therapy was successful in 63% of patients in wh0.m lidocaine was considered effective. Tocainide was successful in only two (17%) of the other 12 patients in whom lidocaine was ineffective or in whom it was not evaluated. The difference between these groups is statistically significant (P < 0.02). There were 13 patients in whom lidocaine was tested during an electrophysiologic study (Fig. 3). Lidocaine protected against induced ventricular tachycardia in 9 of these 13. Six of these nine had successful oral tocainide therapy. Lidocaine did

American

Heart

Journal

1033

Winkle,

Maeonn, and Harrison

Tremor Nausea Anxiety Rash DiZZiMSS

Decreased mental status Diaphowsis Ataxia Lightheadedness Menthd on lips NjdZ@INlS Increased arrhythmias Visual problems Fatigue Constipation Hot and cold flashes Nightmares Perimrditis Arthritis Gloinerulonephritis

16 142%) 9 (24%) 3 ( 8%) 2( 5%) 2 ( 5%) 2( 5%) 1 ( 3%) 1( 3%) I( 3%) l( 3%) 1 ( 3%) l( 3%) I( 3%) I( 3%) O( 0%) 0 ( QR) Q( 0%) oi 0%) 0 ( 0%) O( 0%)

10 (42%) I ( 4%) Q( 0%) I( 4%) O( 0%) 0; Q%) 3 (12%) 5 (12%) 1( 4%) O( 0%) 0 ( 0%') 0 ( 0%) 1 ( 4%)

a( 070) 1( 4%) 3 (12%) 1 ( 4%) 1: 4%) I ( 4%) 1( 4%)

ts 2.7 mg/dl. A renal biopsy showed an immune complex glomerulonephritis. Thi5 was a nonmembranous glomerulonephritis with immune comeposition in both the mesangium and the basement membranes. ~rn~~n~~~~res~ent stainwas positive f0r IgG, IgM, IgA, and C’3 -was posited in a granular pattern (Fig. 5). There was I[BQ rise in antinuclear antibody titers and antibodies to native DNA were negative. drawal frsm tocainide resulted in a g improvement in renal status.

This report summarizes our experience with tocainide in a group of patients with severe and ~~~e~~br~aten~~g ventricular arrhythmias difficult to manage with standar antiarrhythmic drugs. Conclusions from such studies must be made with caution. It is difficult to standardize therapy and to make carefdly controlled observations with regard ts etEcacy and side e cts. Nonetheless our data suggest that tocainide is a vduable ~nt~~r~hyt~~~c drug for the management of such patients. This study suggests a reasonable correlation between responsiveness to lidoeaine and successful outcome of tocainide therapy. An important unanswered question is the toe&de response

rate of patients not preselected because of lidiDCaine responsfiveness. Oinly one of eig%nt patients in whom the lidocaine responsiveness status was unknown sespcpnded to tocainide. In 0ur study the apparent success of tocainide may in large part be dkle to the fact that patients were preselected because of their lid0caine responsiveness. Nonetheless, the availability of oral tocainide f0r patients responsive to liaOcaine does niqmsent a valuable addition to our list of antiarrhythmi drugs.

Our data suggest that testing intravenous eaine in the eIectrophysi0lsgy laboratory” of value likeiihsod

lidscan be a high

f0r selecting patients who have of arrhythmia control with tocainide.

All patients who respond to lidocaine in the dectrophysiology iabsratory should undergo subsequent electrophysiologie testing on oral tocainide. The range sfphxna concentrations associated with excellent arrhythmia ecsntrol for tscainide was generally from 6 to 12 ,pg/mi. he plasma concerntrations associated with side effects were probably only marginally higher than the therapeutic range since many patients were treated with doses just below those associated with side effects. For most patients the dose -was 400,500, or 600 mg every 8 hours. The doses and plasma concentrations f0r those patients failing tocainide were in the same range as those in patients who had a good respanse. In this study arug plasma concentrations were measure only in retrospect and did not play any role in the management of the patients. For these critically ill patients we preferred to increase the tscainide dose to the point where side effects developed and then diminish it slightly. Such a practice is reasonable with t0caikle since the side effects occurring when patients are under careful observation are minor and resolve promptly, ana there seems to be little danger sf creating serious condncances or potentially lethal arrhythAHthough side effects 0ccurred in two thirds of the patients, they required drug in less than 10% of patients. The commonest side effect was a slight tremor most often noted in the upper extremities. Nausea was the second most common side effect. The three patients requiring discesntinuation during long-term therapy all experienced immunologic side effects. In two of the three it was not certain that tseainide was the

Tocainide

Fig. 5. Immunofluorescent irregular “lumpy-bumpy”

stains pattern

from renal of immune

biopsy of the patient complex deposition

precipitating factor. One patient had immune complex glomerulonephritis without a rise in the antinuclear antibody titer, suggesting that the antibodies formed may not cross react with nuclear proteins. One potential advantage of tocainide may be its minimal arrhythmogenic potential. Although one patient in our series may have had ventricular irritability increased by tocainide, the drug seemed remarkably free of aggravation of serious arrhythmias. Tocainide slightly diminishes the right ventricular effective refractory period and has no significant effect on Q-T interval. It would not be expected to cause the usual type of Although many drug-induced torsade de pointe. of our patients had severe heart failure, the drug was well tolerated. However, the hemodynamic effects of tocainide after oral therapy have not been well studied and the drug should be used with caution in patients with uncontrolled heart failure. We did not observe worsening of conduc-

American

Heart

Journal

for drug-resistant

who developed glomerulonephritis. in the glomerulus.

There

arrhythmias

is an

tion disturbances, but caution should be exercised in patients with severe conduction abnormalities. In summary, tocainide is a useful addition to the group of drugs avaiiable to treat severe refractory ventricular arrhythmias. We had a reasonable success rate in a group of patients predominantly selected for tocainide because of known responsiveness to lidocaine. Further studies will be required to evaluate the drug’s effect in less critically ill patients, in patients not necessarily responsive to lidocaine, and in those who have been treated successfully with other antiarrhythmic drugs. The drug requires careful individual patient titration to achieve optimal antiarrhythmic effect and to minimize the occurrence of side effects. Most side effects are mild and respond to minor dose adjustments. Occasionally the drug must be discontinued because of immunologic side effects during long-term theraPY.

1035

Coltart DJ, Berndt TB, Kernoff R, Harrison DC: Antiarrhythmic and circulatory effects 0f Astra W36095, a new Iidocaine-like agent. Am J Cardiol Winkle RA, Meffin Pd, Fitzgerald JW, Harrison DC: Clinical efficacy and pharmacokinetics of a new orally effective antiarrhythmic, tocainide. Circulation 64:884, 1936. Winkle RA, Meffin PJ, Rarrison DC: L0ng-term toscainide therapy f0r ventricular arrhythmias. Circulation 57:1008, 1978. W00sley RL, McDevitt IX, Nies AS, Smith RF, Wilkinson CR, Oa.tes JA: Suppression of ventricular ectopic depolarizations by tocainide. Circulation SB:%O, 1977. McDevitt DC, Nies AS, Wilkinson CR, Smith RF, Woosley RL, Oates JA: Antiarrhythmic effects of a lidocaine congener, tocainide, 2-amino-2’,6’-;propionnxylidide, in man. Clin Pharmacol Ther 19:396, 1976, Engler R, Ryan W, LeWinter M, Bluestein H, Karliner JS: Assessment of long-term antiarrhythmic therapy: Studies on the long-term efficacy and toxicity of tocainide. Am J Cardbl 43:612, 1979. Lalka D, Meyer MB, Duce RR, Elvin AT: Kinetics of the oral antiarrhythmic lidocaine congener, tocainide. Clin Pharmacol Ther ‘I 9:X7, 1976. MeKin PJ, Winkle RA, Blaschke TF, Fitzgerald J,

9.

10.

11.

12.

13.

14.

Harrisen DC: Response optimization of drug d0sage: Antiarrhythmic studies with tocainide. Clin Pharmacol l-her +%?:42, 1977. Anderson JL, Mason JW, Winkle RA, Meffin PJ, Fowles RE, Peters F, Miarrison DC: Clinical electrophysiologic effects 0f tocainide. Circulation 673685, 1978. Moore EN, Spear JF, Norowitz LN, Feldman HS, Moller RA: Electsophysi0logic properties of a new antiarrhgtbmic drug-tocainide. Am J Cardi 4’8 :703, 1978. Schnittger X, Griffin JC, Hall RJ, Meffm PJ, Winkle Rh: Effects 0f tocainide on ventricular f%rillation threshold, comparison with lidocaine. Am J Cardiol 4.2:76, 1378. Winkle RA, Anderson JL, Peters F, Me& $9, Fowles RE, Harrisun DC: The nemodynamic effects of intraven0us tocainide in patients with heart disease. Circulation 57587, 1978. M&n PJ, Rarapat SR, Harrison DC: High-pressure liquid chr0matograplric analysis of drugs in biological fluids. II. Determination of an antiarrhvthmic drug, tocainide, as its dansyl derivative using a fluoresce&e detector. J Pharm Sci 66:583, 1977. Mason JW, Wmkle RA: Electrode-catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia.