Ventricular Arrhythmias Associated with Lidoflazine: Side-Effects Observed in a Randomized Trial •Y

European Heart Journal (1983) 4, 889-893

Ventricular arrhythmias associated with lidoflazine: side-effects observed in a randomized trial •y-

S. P. HANLEY AND J. R. HAMPTON Department of Medicine, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH, U.K. Downloaded from https://academic.oup.com/eurheartj/article/4/12/889/503490 by guest on 29 September 2021

KEY WORDS: Angina, exercise testing, lidoflazine, propranolol, ventricular tachycardia.

Twenty-four patients received either propranolol, lidoflazine (Clinium), or propranolol/lidoflazine com- binations in a study designed to evaluate the effect of these drugs in angina pectoris. Five patients developed ventricular tachycardia when receiving either lidoflazine or lidoflazine and propranolol in combination; one of these patients died. In addition, one patient died suddenly while being treated with propranolol alone. Lidoflazine therapy was associated with a significant prolongation of the QT interval of the electrocardiogram. Lidoflazine either alone or in combination with propranolol, appears to induce ventricular tachycardia.

Introduction patients already being treated with a beta-blocking, Patients with ischaemic heart disease have an whose symptoms were not adequately controlled; increased risk of death and of developing arrhyth- the second protocol was designed for patients who mias: in any clinical trial of a potential therapeutic were receiving no other treatment other than sub- agent for angina, such events are likely to occur by lingual glyceryl trinitrate. None of thqse patients chance. During a study of lidoflazine we detected was in clinical heart failure. In each of these studies an unacceptable incidence of arrhythmias which exercise tolerance was assessed by treadmill testing led us to discontinue the investigation. using a modified Bruce protocol!6!. Patients were Lidoflazine is a member of the group of drugs encouraged to take as many glyceryKtrinitrate tab- that alters calcium flux through myocardial cell lets as necessary, and with the first protocol digoxin, membranes, and it also alters sodium flux!u>, it is diuretics and beta-blockers which the patients were unusual in that a clinically useful effect is thought already receiving before entry were continued. In to take several weeks to appear!3!. This makes it dif- the second protocol, one subject was taking a ficult to design a clinical trial of its effect in angina diuretic, for hypertension and this was continued. because in many patients the severity of angina is The beta-blocker Used was propranolol in all variable. Although lidoflazine has been claimed to patients except one, who was given metoprolol be an effective anti-anginal agent!4-3! it is not known because of intolerance to propranolol. whether the benefit it confers is additional to that Nineteen patients with uncontrolled angina des- obtained by beta-blockade. pite beta-blockade were admitted to the study using the first protocol. Optimum beta-blocker therapy was first obtained by progressively increasing the Study design dose, with the patient's progress being monitored Two separate protocols were designed to investi- by monthly exercise tests; optimal treatment was gate the efficacy in relieving angina of the com- defined as the use of 720 mg of propranolol daily, bination of lidoflazine with a beta-adrenoreceptor or a failure to improve exercise duration by more +- blocking drug. The first protocol was used for than 10% in successive treadmill tests, or by the appearance of undesirable side-effects. If undesir- Received for publication 6 February 1983; and in revised form 29 June 1983. able effects appeared the dose of beta-blocker was reduced, and the patient was maintained on the Requests for repnnts to-DrS. P. Hanley, Department of Medicine, D Floor, South Block, University Hospital, Queen's Medical optimal dose of beta-blocker for the next part of the Centre. Nottingham NG7 2UH. study. In a single (patient) blind fashion, lidoflazine

0195-668X/83/120889+05 J02.00/0 © 1983 The European Society of Cardiology 890 S. P. Hanky and J. R. Hampton was introduced, starting with 120mg daily for a second protocol (five received active drugs), but the week, then 240 mg daily for a further week, and study was discontinued before any had completed then 360 mg daily; this dose was maintained for the treatment programme. No useful information nine weeks. In a double-blind fashion the patients about the effect of lidoflazine on exercise duration were then allocated at random either to continue was obtained. treatment with lidoliazine fora further 12 weeks,or to matched placebo tablets; in either case the SIDE-EFFECTS beta-blocker was continued. Finally the beta- The side-effects observed were similar in patients Downloaded from https://academic.oup.com/eurheartj/article/4/12/889/503490 by guest on 29 September 2021 blocker was withdrawn by reducing the dose by treated according to either protocol, and the 50% at each visit, and the patient remained on patients can therefore be considered together. either lidoflazine or placebo. During the course of the study we became suspi- The second protocol involved treatment with cious that lidoflazine might be inducing arrhyth- propranolol and lidoflazine or with matching mias, and during the later part of the study we placebo tablets. After an initial period in which the therefore performed 24-h ECG ambulatory tape patients were given (single-blind) both types of recordings during the third week of any treatment placebo tablets, they were allocated at random that might (because of the double-blind design of (double-blind) to receive either active propranolol part of the study) be lidoflazine. plus placebo lidoflazine or active lidoflazine plus placebo propranolol. After 12 weeks the placebo (a) Side-effects associated with beta-blocker component was substituted by active drugs. therapy -A. Four patients developed complications while OTHER DRUGS ADMINISTERED being treated with propranolol, before lidoflazine All the patients except one received glyceryl therapy was commenced. One patient died sud- trinitrate sublingually as necessary throughout denly at home, one was intolerant of beta-blockade, both studies. In the first study 12 patients received one was admitted to hospital with a myocardial additional treatments throughout the duration of infarction and one developed symptoms of left the study. One subject received clofibrate and ventricular failure; all were withdrawn from the one nifedipine. Six subjects were given diuretics study. (frusemide 1, amiloride hydrochloride—hydrochlorothiazide combination 2, and cyclopenthia- (b) Side-effects associated with lidoflazine therapy zide — potassium chloride combination 3) Four Only 19 of the 24 patients who began treatment other patients received digoxin, three of these according to the trial protocols actually received in combination with diuretics as follows: fruse- lidoflazine. Among these 19 patients five developed i- mide plus slow K.1, frusemide plus amiloride ventricular tachycardia, and one of these patients hydrochloride 1, and amiloride hydrochloride — died. hydrochlorothiazide combination and warfarin 1. One patient was admitted to hospital with severe In the second study one subject received ad- chest pain characteristic of cardiac ischaemia nine ditional treatment with an amiloride hydrochlor- days after starting lidoflazine in addition to pro- ide— hydrochlorothiazide diuretic combination. pranolol. His ECG showed short episodes of ventricular tachycardia; although there were no ECG changes suggestive of recent infarction his plasma Results levels of amino-aspartate transferase and hydroxy- Nineteen patients began the programme of butyric dehydrogenase rose sequentially to more therapy defined by the first protocol, but only eight than four times the upper limit of normal, and it completed it. All these eight patients showed an was considered that he probably had a myocardial increase in exercise duration of the end of the first infarction. Lidoflazine was discontinued and the X- month of lidoflazine treatment, but at the end of the patient made a satisfactory recovery; in retrospect 12 weeks of combined lidoflazine and beta-blocker it is impossible to know whether the infarction therapy, only four of the. eight patients had an exer- caused the arrhythmia, or vice versa. cise duration greater than it has been on beta- The second patient developed shortness of breath blocker alone, and only three had an exercise and episodes of unconsciousness 19 days after start- duration greater than the first month on lidoflazine. ing lidoflazine in addition to propranolol. His ECG Six patients began treatment according to the showed short episodes of severe sinus bradycardia Side-effects associated with lidqflazine 891

(heart rate 32 per min) and ventricular tachycardia first study while receiving propranolol alone since of the 'torsade de pointes' type. Temporary trans- exertional dyspnoea became the exercise limiting venous pacing was required, and lidoflazine was symptom. Two subjects who had not completed the discontinued; the patient made a complete recovery second study were withdrawn due to cessation of and there was no evidence suggesting that he had the study because of the incidence of arrhythmias. a myocardial infarction. One of these had only received double placebo. A third patient was admitted to hospital 11 days after starting lidoflazine in addition to propranolol, EFFECTS OF LIDOFLAZINE ON THE QT-1NTERVAL Downloaded from https://academic.oup.com/eurheartj/article/4/12/889/503490 by guest on 29 September 2021 because of breathlessness and syncopal attacks; his Thirteen of the 19 patients who were initially ECG showed sinus bradycardia (heart rate 46 per treated with propranolol in the first study received min) with intermittent ventricular tachycardia of lidoflazine. The QT interval and RR interval (mean the 'torsade de pointes' type. He also developed a or four complexes) and pre- and post-lidoflazine are severe paranoid psychosis. Lidoflazine was discon- shown in Table 1. No correction formulae for QT tinued and he made a satisfactory recovery; there interval have been used. Statistical analyses were was no evidence of a myocardial infarction. performed by paired / test. Subjects 1, 2, and 3 A fourth patient died suddenly at home 21 days developed ventricular tachycardia and correspond after starting lidoflazine. A 24-h ECG tape record- to the first three patients previously described. Sub- ing was being made at the time of his death, and ject 1 was also in atrial fibrillation. Subjects 2 and subsequent analysis of the tape showed that the 3 developed the most prolonged QT intervals and cause of death was 'torsade de pointes' ventricular had ventricular tachycardia of the 'torsade de tachycardia with short episodes of bradycardia pointes' type; subject 1, who had had the possible (heart rate 43-48 per min) around the time of this myocardial infarction and ventricular tachycardia event. This patient had been randomized to receive not of 'torsade de pointes' type developed only a lidoflazine first and had not therefore received small degree of QT prolongation, suggesting per- propranolol. haps that the ventricular tachycardia was due to In a fifth patient, a short run of asymptomatic myocardial infarction rather than the lidoflazine. ventricular tachycardia associated with sinus bradycardia (heart rate 45 per min) was demon- strated by an ambultory ECG tape recording, 21 Table 1 The effect of lidoflazine on the R-R and QT days after starting propranolol; this patient had intervals in patients receiving propranolol already received lidoflazine for 12 weeks. A pre- •A vious 24-h tape recording when the patient was on R-R intervals (s) QTi nterval (s) lidoflazine alone showed no similar episodes of Subject bradycardia or ventricular tachycardia. Pre Post Pre Post All five of these subjects received glyceryl trinitrate; the other daily treatments taken simul- 1 0-73 0-49 0-34 0-38 taneously by these patients were, subject 1 fruse- 2 113 118 0-48 0-56 3 0-88 1-21 0-43 0-69 K mide 80 mg, slow K. 3, digoxin 0-25 mg; subjects 2 and 4 an amiloride hydrochloride—hydro- 4 106 101 0-42 0-39 4 0-88 0-97 0-39 0-44 chlorothiazide combination 2 and I tablets daily, 6 118 1-44 0-45 0-54 respectively, and subject 3 nifedipine 10 mg t.d.s. 7 0-94 0-95 0-43 0-51 Lidoflazine was also associated with other 8 0-92 114 0-37 0-47 side-effects. Two patients discontinued treatment 9 0-96 11 0-36 0-41 because of severe headaches and one because 10 0-86 0-93 0-38 0-40 11 104 109 0-37 0-42 of visual hallucinations; three other subjects 12 112 111 0-42 0-45 reduced their dose of tablets because of dizzi- 13 0-89 111 0-35 0-43 ness, headaches, sleep disturbances, and visual hallucinations. Mean 0-97 1-06 0-40 0-47

OTHER WITHDRAWALS SEM 004 0-06 001 002 Five other patients failed to complete the study. Two subjects withdrew from the first study due to lack of benefit. One subject was withdrawn in the Pre v. Post />>0-05 892 S. P. Hartley and J. R. Hampton

Two patients in the second study received pla- Perhaps a small increase in the dispersion of cebo and then lidoflazine. The QT interval pre- and recovery in this study occurred due to a heart rate post-lidoflazine were 0-42 and 0-34 s for the first reduction caused by propranolol, and this was addi- patient and 0-32 and 0-47 s for the second patient. tive to the effects of lidoflazine on heart rate and on The latter subject then received propranolol in the refractory period. The combination of these addition to the lidoflazine and the QT interval effects may thus explain the high incidence of ven- 4, changed to 0-60 s. This subject also developed a tricular tachycardia that we have observed. We -4 short run of ventricular tachycardia and is the have been unable to find any reported adverse Downloaded from https://academic.oup.com/eurheartj/article/4/12/889/503490 by guest on 29 September 2021 subject 5 previously described. effects of beta-adrenoreceptor blocking drugs in combination with other drugs such as quinidine Discussion which are known to prolong the QT interval and Death, myocardial infarction, and arrhythmias produce torsade de pointes ventricular tachycardia. characterise ischaemic heart disease, and there is no There have been previous reports of an associ- doubt that many of our patients had severe coron- ation between lidoflazine and ventricular tachycar- ary disease. Eleven of the surviving 22 patients dia, but most of these occurred when the drug had underwent cardiac catheterization after completion been tested as an anti-arrhythmic agent in patients of the study; all 11 had severe coronary artery dis- with atrial fibrillation!13141516]. Lidoflazine has ease. Six of these patients had coronary artery vein generally been considered safe in angina although graft surgery. Nevertheless, since episodes of ven- in one patient ventricular tachycardia has been tricular tachycardia occurred within 21 days of described!'7!. addition of lidoflazine to propranolol therapy in Headache, dizziness, and tinnitus have pre- three patients and within 21 days of adding propra- viously been reported as side-effects of lidoflazine nolol to lidoflazine in the fifth patient there seems therapy but hallucinations and paranoid psychosis little doubt that at least some of these episodes were have not been described before!4]. due to lidoflazine and that this may reflect an unex- Since the completion of this study a letter has pected interaction between lidoflazine and propra- been circulated to medical practitioners in the U.K. nolol. However, since the fourth patient who died by the manufacturers of lidoflazine suggesting that -k- with 'torsade de pointes' ventricular tachycardia lidoflazine should not be used in combination with was taking only lidoflazine, combination therapy a beta-blocker. may not be the sole cause of arrhythmias. Bradycardia occurred commonly in patients with Acknowlegements arrhythmias in this study. Bradycardia in associ- The authors acknowledge the help and encouragement ation with tordsade de pointes has been considered of Janssen Pharmaceuticals in this study. 7 to be an important aetiological feature! ) and has References been observed in another study of drug induced [1] Carmeliet E.XhonneuxR. Influence of lidoflazine on tordade de pointes' in the absence of beta- cardiac transmembrane potentials and experimental adrenoreceptor blocking drugsl8). arrhythmias. Naunyn Schmiedebergs Arch Pharma- col 1971; 268: 210-28. Both propranolol and lidoflazine cause a de- 910 [2] Einwachter HM, Kem R, Herb J. Effect of lidoflazine crease in heart rate! ). Slower heart rates have on membrane currents and contraction in voltage been shown to cause a greater temporal dispersion clamped frog atrial fibre. EurJ Pharmacol 1979; 55: of recovery by the ventricle from the refractory 225-32. period and thus theoretically set the stage for the [3] Bloem TJJM, Vermeulen A, Reneman RS. Lido- flazine in the management of angina pectoris. Clin genesis of ectopic beats and re-entry phenome- Cardiol 1979; 2: 407-12. non!"]. Propranolol has no effect on the QT inter- £4] Arvanis C, Counelis E, leremias D. Lidoflazine and val. It decreases the QTC (using Bazett's formula) angina pectoris: A placebo controlled double-blind but does not alter the QT interval during fixed rate study. Curr Ther Res 1973; 15: 285-90. pacing!9!. Lidoflazine has been reported to increase [5] Nordstrom LA, Gobel FL. The effects of lidoflazine on exercise tolerance in patients with angina pectoris. the QT and QTC interval of the electrocardiogram 31012 Chest 1978; 74: 50-4. of man! !, and to prolong the effective refactory [6] Hanley SP, Cowley AJ, Hampton JR. Dangers of period in isolated animal cardiac preparationl1 \ withdrawal of vasodilator therapy in patients with presumably, therefore, the tendency for asynchro- chronic heart failure. Lancet 1980; 1: 735-6. nous recovery of the ventricle from the refractory [7] Krikler DM, Curry PVL. Torsade de pointes, an atypical ventricular tachycardia. Br Heart J 1976; 38: period has been increased. 117-20. Side-effects associated with lidoflazine 893

[8] Khan MM, Logan KL, McComb JM, Adgey AAJ. [13] Miyahara M, Iimura O, Yokoyama M, Hoshikawa Management of recurrent ventricular tachyarrhyth- K. Lidoflazine as an antidysrhythmic drug. Tohoku mias associated with QT prolongation. Am J Cardiol JExpMed 1969; 97: 95-6. 1981; 47: 1301-8. [14] Piessens J, Kesteloot H, De Geest H. Lidoflazine in [9] Brown KF, Zipes DP, Heger JJ, Prystowsky EN. the treatment of chronic atrial fibrillation. Arznei- Influence of the autonomic nervous system on the mittelforsch 1970; 20: 355-S. QT interval in man. Am J Cardiol 1982; 50: [15] Schlepper M, Derro R. Antifibrillatory effect of lido- 1099-103. flazine. Arnzeimittelforsch 1972; 22: 923-7. [10] Piessens J, De Geest H. Long term evaluation of [16] Kennelly BM. Comparison of lidoflazine and lipoflazine in angina pectoris based on exercise quinidine on prophylactic treatment of arrhythmias. Downloaded from https://academic.oup.com/eurheartj/article/4/12/889/503490 by guest on 29 September 2021 tolerance. Cardiology 1972; 57: 135-49. Br Heart J 1977; 39: 540-6. [11] Han J, Millet D, Chizzonitti B, Moe GK. Temporal [17] Batlouni M. Electrocardiographic aspects of lido- dispersion of recovery of excitability in atrium and flazine treatment in patients with angina pectoris and ventricle as a function of heart rate. Am Heart J atrial fibrillation: Practical inferences. Communi- 1966; 71: 481-7. cation presented at Symposium on Lidbflazine, [12] Bernstein V, Peretz Dl. Lidoflazine — A new drug in Beerse, Belgium 1970. the treatment of angina pectoris. Curr Ther Res 1972; 14: 483-95. *

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