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

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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 electro- cardiogram. 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—hydro- chlorothiazide 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 ven- tricular 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
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