670

Relative efficacy and safety of intravenous drugs for termination of sustained ventricular tachycardia

The relative safety and efficacy of intravenous of administration adenosine, lignocaine, disopyramide, flecainide, and sotalol for termination of stable, induced ventricular tachycardia was assessed in serial trials. Ventricular tachycardia was terminated by pacing if it persisted 10-15 min after the end of drug administration. 24 patients with recurrent ventricular tachycardia were studied. Ventricular tachycardia was terminated by a drug in 35 of 105 trials. In 6 patients no drug terminated the arrhythmia. Adenosine did not terminate tachycardia or have any serious adverse effect in any patient; both flecainide and disopyramide were significantly more effective than lignocaine, but flecainide had significantly more severe adverse effects than lignocaine. Lignocaine was the safest drug and should continue to be used as first-line drug therapy for stable ventricular tachycardia. Disopyramide should be considered as second-line treatment. DC cardioversion is necessary for unstable ventricular tachycardia, and its availability must be ensured before attempted pharmacological intervention.

Introduction How

should

who present with haemodynamically stable ventricular tachycardia? Transthoracic DC cardioversion requires administration of a general anaesthetic and ventricular overpacing generally requires percutaneous transvenous placement of an electrode; both are usually effective, but time-consuming and not without risk. Thus the first choice is often an intravenous antiarrhythmic-a simple and comfortable solution when effective, but for termination of ventricular tachycardia there are few reports on the efficacy and safety of individual antiarrhythmicsl-9and fewer still on the relative efficacy of different drugs in the same patient cohort.1O We examined the relative safety and efficacy with respect to termination of stable ventricular tachycardia of intravenous administration of adenosine, lignocaine, disopyramide, flecainide, and sotalol in serial trials in the same individuals. we

treat

patients

Patients and methods 69 consecutive patients, all of whom had presented with recurrent, sustained ventricular tachycardia, were recruited after admission for electrophysiological assessment between November, 1986, and November, 1988. The trial was approved by the local ethics committee, and full informed written consent was obtained before entry to the trial. All antiarrhythmic drugs, including beta-blockers and calcium antagonists, were withdrawn for at least five half-lives before investigation, except for amiodarone, which was continued. 2 patients were excluded because the time between recurrence of attacks of ventricular tachycardia precluded a drug-free interval, and 7 because of hypotension during episodes of tachycardia. All patients underwent coronary arteriography, and 3 patients who had critical coronary artery disease (left main-stem stenosis or proximal severe triple-vessel disease) or untreated heart failure were excluded.

Electrodes were inserted through the subclavian vein under local anaesthetic and radiographic control. A bipolar atrialJ wire was positioned in the right atrial appendage and a bipolar pacing electrode was placed in the apex of the right ventricle. These electrodes were left in place for the duration of the trial. In the stimulation protocol, based on one previously described,"’" 1,2, and 3 extrastimuli were introduced during sinus rhythm and after 8 beats of ventricular pacing at 100, 120, and 140 beats/min. When sustained ventricular tachycardia had been started the blood pressure was measured and a 12-lead electrocardiogram (ECG) recorded. Infusions were administered through a volumecontrolled infusion pump. The order of drug administration was predetermined, based on pharmacokinetic characteristics of the drugs; the short half-life of adenosine13,14 and the rapid redistribution of lignocaine15 enabled further drug administration on the same day. Patients were withdrawn from the trial at their request, whether because of an adverse effect or because a drug had been identified that was likely to provide effective therapy. However, most patients completed the full trial even after an effective therapy had been identified. On the first day, doses of005 mg/kg, OT5 mg/kg, and 0-25 mg/kg of adenosine were administered, the first after 2 min tachycardia and then at 2-min intervals. These doses encompass the range found to be effective for junctional tachycardias. 13,14 If the tachycardia continued despite the 3 doses of adenosine, lignocaine was administered as a 1 ’55 mg/kg intravenous bolus after the tachycardia had persisted for a total of 8 min. The tachycardia was observed for a further 5 min and if it persisted was terminated by programmed stimulation. After a delay of 20 min the tachycardia was restarted by programmed stimulation as before. 2 min later a disopyramide infusion was started at a dose of 2 mg/kg given over 5 min as a constant infusion to a maximum dose of 150 mg. If the tachycardia was not terminated by the drug within 15 min of the end of the infusion, or earlier if intervention was necessary, it was terminated

by programmed pacing. On day 3, tachycardia

was again started by programmed stimulation. A flecainide infusion was started 2 min later at a dose of 2 mg/kg, to a maximum dose of 150 mg over 10 min. If the arrhythmia persisted for more than 10 min after the end of the infusion the arrhythmia was terminated by programmed pacing. After a further 2 days the procedure was repeated and 2 min after initiation of the tachycardia sotalol was infused, at a dose of 1 mg/kg over 5 min. If necessary, the tachycardia was terminated by programmed electrical stimulation 10 min after the end of the infusion. The induced ventricular tachycardia was deemed "clinical" if it had the same QRS morphology and a similar rate (within 50 beats/min) as the documented spontaneous tachycardia. In the absence of a 12-lead ECG of the documented spontaneous tachycardia, a sustained monomorphic tachycardia which produced the same symptoms as the spontaneous tachycardia was accepted as the clinical tachycardia. A severe arrhythmogenic event was defined as acceleration or change in morphology of the tachycardia with associated haemodynamic collapse. An event was also considered arrhythmogenic if the tachycardia could not be terminated within 1 h of drug administration by pacing or DC cardioversion. A severe hypotensive event was defined as systolic blood pressure of or below 50 mm Hg, unassociated with acceleration or changed morphology

of the

tachycardia.

ADDRESS: Department of Cardiological Sciences, St George’s Hospital Medical School, London SW17 ORE, UK (M J. Griffith, MRCP, N J. Linker, MRCP, C. J. Garratt, MRCP, D. E Ward, FRCP, Prof A. J Camm, FRCP). Correspondence to Dr M. J. Griffith, Department of Cardiology, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK

671

TABLE I-DRUG EFFECTS IN INDIVIDUALS

Continuous variables were compared by use of Student’s t test for paired or unpaired groups as appropriate. The X2 test was used for differences between proportions, unless any of the expected cells had less than 5 members when Fisher’s exact test was used.

Results

completed in 24 patients who had a patients were excluded because their tachycardia was not inducible, was insufficiently sustained (less than 8 min), or was associated with hypotension. All 24 patients had had sustained haemodynamically stable tachycardia and the induced tachycardia was identical to the clinical tachycardia in all but 1, who had multiple morphologies of tachycardia and in whom the induced tachycardia which was tested was of similar rate to the clinical tachycardia and produced the same symptoms. 20 patients (83%) had coronary artery disease, 1 (4%) had idiopathic dilated cardiomyopathy, and 3 (13%) had idiopathic ventricular tachycardia with structurally normal hearts (normal ECG, echocardiogram, and chest radiograph). Amiodarone was continued in 12 of the 24 patients, in whom the mean serum (SD) amiodarone concentration was 1.35 (0-68) mg/1. The 24 patients had failed a mean of 3-25 earlier clinical drug trials (range 1-5) and none was on treatment with a beta-blocker or calcium antagonist. 22 patients received adenosine, 23 received lignocaine, disopyramide was given to all 24, 20 received flecainide, and sotalol was given to 14. 2 did not receive adenosine because of drug supply problems; 5 did not receive all the drugs because effective therapy was found, and 5 because early intervention was necessary. No patient died or suffered serious long-term adverse effects as a 105

drug trials

mean

were

age of 53 years. 45

result of the trial. Drug termination of tachycardia occurred in 35 of 105 trials (table I). Adenosine failed to terminate any tachycardia. Lignocaine terminated ventricular tachycardia in 7 of 23 (30%) patients with no serious adverse effects.

Individual experience of patients shown

as

Circles indicate patients in whom tachycardia

Venn

and # indicate the patients

responsible

event

terminated by each

in

whom

an

arrhythmogemc or identify the drug

occurred, respectively, but do

not

TABLE II-CHARACTERISTICS OF PATIENTS IN WHOM DRUG TERMINATED VENTRICULAR TACHYCARDIA (YES) OR WAS

INEFFECTIVE (NO)

diagram.

was

drug hypotensive

Disopyramide terminated tachycardia in 12 of 24 (50%) patients with arrhythmogenic effects in 1 (4%). Flecainide terminated ventricular tachycardia in 11 of 20 (55%) patients, but produced serious adverse effects in 5 (25%; arrhythmia in 4, hypotension in 1), 3 of whom were on amiodarone. In 3 of the 4 patients with an arrhythmogenic effect, resuscitation was difficult and multiple shocks were needed to terminate the tachycardia, and in 2 the tachycardia became incessant and was only terminated 1.5-7 h after flecainide administration. Sotalol terminated tachycardia in 5 of 14 (36%) patients, with hypotensive effects in 2 (14%). Both disopyramide and flecainide were significantly more effective in termination of ventricular tachycardia than was lignocaine (p < 0-05). However, flecainide was significantly more likely than lignocaine to produce serious adverse effects (p < 005). Of the 20 patients given flecainide, tachycardia was terminated by disopyramide in 8 (40%) and lignocaine in 6 (30%). Of the 14 patients given sotalol, the tachycardia was terminated by lignocaine in 5 (36%), by disopyramide in 6 (43%), and by flecainide in 8 (57%). The figure shows individual patient experiences for all 4 effective drugs; there is a large degree of overlap in efficacy, especially between Vaughan Williams class 1 antiarrhythmics. Sotalol caused the greatest mean (SD) fall in blood pressure during tachycardia (8-8 [26] mm Hg), followed by flecainide (6 [35] mm Hg) and disopyramide (1-0 [23] mm Hg); mean blood pressure rose after lignocaine (4-8 [17] mm Hg). Similarly, severe haemodynamic effects were observed with sotalol in 2 of 14 patients, and with flecainide in 1 of 20 patients. Sotalol had the least effect on maximum RR separation (mean [SD] 27 [20] ms); both disopyramide (80 [27] ms) and flecainide (102 [77] ms) had a significantly greater effect (p < 0-01). Table II shows the characteristics of those patients whose tachycardia was terminated or was not terminated by each drug. There were no significant differences in any of the variables for lignocaine or sotalol, although the rate of tachycardia in those patients whose tachycardia was terminated by lignocaine tended to be faster (p = 0-085). The tachycardias which were terminated by disopyramide were significantly faster than those which were not terminated (352 [73] ms vs 429 [103] ms). Patients whose

QRS width SR=w!dth of QRS m sinus rhythm, RR VT=RR interval during ventncular tachycardia, QRS width VT =width of QRS in ventricular tachycardia, QRS VT 2 min=change in width 2 mm after start of drug infusion, Previous drugsnumber of previous antiarrhythmic drugs, Drug concentrationat time of restimulation *p < 0 05 between yes and no groups

672

tachycardias responded to disopyramide were significantly less likely to be on amiodarone treatment (3 of 12 vs 9 of 12 on amiodarone). With flecainide, the only significant difference between responders and non-responders was the change in RR interval 2 min after the start of the flecainide infusion (+ 14 ms in patients where tachycardia was terminated and - 14 ms where tachycardia continued or an arrhythmogenic effect was seen). Drug concentrations of flecainide and disopyramide were not significantly different between patients in whom tachycardia was or was not terminated; the lower mean concentration seen in patients in whom flecainide did not terminate the tachycardia is explained by premature discontinuation of infusion in 5 patients with arrhythmogenic or adverse haemodynamic effects. For the 4 patients without coronary artery disease the tachycardias were all terminated by disopyramide, flecainide, and sotalol; lignocaine stopped the tachycardia in 3 of these 4 patients. No drug was effective in the 3 patients with an inferior ventricular aneurysm. The 5 patients in whom flecainide had a serious adverse effect were compared with the 15 in whom it had no such effect. The only striking differences were QRS width in sinus rhythm, which was greater in the patients with serious arrhythmogenic effects (114 ms vs 94 ms; p 0-06) and the change in rate induced by lignocaine (+ 21 ms vs + 6-3 ms, =

respectively; p < 0 05). For patients in whom lignocaine did not terminate their ventricular tachycardia (lignocaine-resistant tachycardia), sotalol was effective in 2 of 9 (22%), with hypotension in 2; flecainide terminated ventricular tachycardia in 6 of 14 (43%), with adverse effects in 4; and disopyramide was effective in 5 of 16 (31 %) with no adverse effects. Discussion This

study re-emphasises the differences between antiarrhythmic drugs with respect to their relative safety and efficacy in the termination of ventricular tachycardia. Flecainide was the most effective drug (55%) but also had the most severe and the greatest number of serious adverse effects. Most studies of flecainide describe arrhythmogenic effects in about 10% ;18-22 the higher proportion that we have observed may be the result of intravenous administration, although this was not observed in earlier studies. v Because of its rate-dependent binding kinetics to the sodium channel, flecainide is likely to have a greater effect in tachycardia than during sinus rhythm.23 Morganroth et ap2 examined 1330 patients treated with flecainide and showed that serious arrhythmogenic effects were most common in 391 patients treated for sustained ventricular tachycardia (6-8%, half of which were fatal) compared with 0-9% in 931 patients treated for ventricular ectopy; they suggested that arrhythmogenic effects of flecainide were related to poor left ventricular function. Our data do not give clear indications as to which patients are likely to have adverse effects with flecainide. A widened QRS in sinus rhythm (not necessarily available at presentation) or an early (2 min after the start of flecainide infusion) increase in rate and width of the tachycardia may be pointers, but did not reach significance in this trial. Decreased rate of tachycardia at 2 min after the start of flecainide infusion was associated with eventual termination of the arrhythmia. Disopyramide was the second most effective drug, with termination of tachycardia in 12 of 24 patients (50%) and proarrhythmic effects in 1, in whom the accelerated tachycardia required cardioversion-achieved with a single DC shock. This efficacy accords with previous

experience.4-6 Disopyramide

was

significantly

more

effective in termination of ventricular tachycardia in patients with faster tachycardias or those not on amiodarone; Lerman and colleagues23 also found disopyramide to be more effective in suppression of ventricular tachycardia in patients with faster tachycardias, but the reason for this selective effect is not known. Fast tachycardias may be more sensitive to drugs that also prolong circuit refractoriness, such as disopyramide, compared with drugs that predominantly slow conduction, such as flecainide. Sotalol was less effective (36%) than disopyramide or flecainide, even if only the 14 patients given sotalol are considered. Severe hypotension that required intervention occurred in 2, but sotalol was not arrhythmogenic. Lignocaine was the safest drug with no serious adverse effects, but with relatively low efficacy (30%)-which compares well with previous reports.1,24 Harrison and colleagues1 terminated sustained ventricular tachycardia after cardiac surgery in 6 of 7 patients with doses of up to 600 mg lignocaine and found few adverse haemodynamic effects, in contrast to procainamide. A review by Frieden24 recommended lignocaine over quinidine and procainamide on the basis of incidence of reported side-effects. The rapid redistribution of lignocaine should enable a second drug to be given if lignocaine fails to terminate the tachycardia.15 In our trial, drugs were used on the assumption that the patient was "drug free". In practice a second drug-if requiredwould be given much earlier; thus on the one hand our results are not strictly comparable to usual practice, but on the other the rapid clearance of an ineffective antiarrhythmic would assume greater importance. For patients whose tachycardia was not terminated by lignocaine, disopyramide had the best combination of safety and efficacy; ventricular tachycardia was terminated in 30% of these patients, with no serious adverse effects. Both efficacy and arrhythmogenic effects appeared to be directly related to the drug’s ability to block sodium channels.25 Lignocaine, with the most rapid dissociation kinetics, had the lowest efficacy and lowest arrhythmogenic effects. Flecainide, with the longest dissociation kinetics, had the greatest efficacy and most arrhythmogenic effects. Disopyramide, with intermediate dissociation kinetics, was intermediate in both respects. Perhaps drugs with shorter dissociation kinetics for the sodium channel are better able to discriminate between normal and partly depolarised tissue, and so improve the therapeutic index. The risk/benefit ratios in this trial, calculated as a ratio of the number of patients with adverse effects and the number in whom tachycardia terminated, were 0/7 for lignocaine, 1/12 (8%) for disopyramide, and 5/11 (45%) for flecainide. We could not attempt to test all available antiarrhythmic drugs in this trial. Even with the limited numbers tested, 10 of 24 patients dropped out before the end of the trial. Lignocaine, disopyramide, and flecainide were selected because they are widely used class I agents for which comparative data are freely available. Sotalol was selected because it combines class II and class III properties. Although beta-blockers (class II) have not been very successful in the termination of ventricular tachycardia, amiodarone (class III) is widely used; we did not study amiodarone because of its long infusion time (30 min) and long half-life. No class IV drug was tested but adenosine terminates some ventricular tachycardias that are sensitive to verapamil,26 and its short half-life made it simple to include in the protocol. While adenosine did not terminate

673

tachycardia in any patient, it had no severe adverse effects. What conclusions can be drawn from our study? While disopyramide was significantly more effective than lignocaine and caused adverse effects in only 1 of 24 patients, we feel that lignocaine should remain the first-line drug for attempted termination of haemodynamically stable ventricular tachycardia because of its known safety and its rapid redistribution, which allows a second drug to be given if it is ineffective. As a second choice we recommend disopyramide, which terminated lignocaine-resistant tachycardia in 5 of 16 (31 %) patients and was relatively safe. Sotalol was neither more effective nor more safe than lignocaine. Flecainide, while the most effective individual drug in this study, had an unacceptably high rate of serious adverse effects. It must be emphasised that DC cardioversion, with general anaesthesia if necessary, remains the first-line treatment of ventricular tachycardia associated with hypotension, and its availability should be ensured before attempts to terminate any form of ventricular tachycardia with any drug.

20. Flecainide Tachycardia Study Group. Treatment of resistant ventricular tachycardia with flecainide. Am J Cardiol 1986; 57: 1299-304. 21. Sellers TD, DiMarco JP. Sinusoidal ventricular tachycardia associated with flecainide acetate. Chest 1984; 84: 647-49. 22. Morganroth J, Anderson JL, Gentzkow G. Classification by type of

ventricular arrhythmia predicts frequency of adverse cardiac events from flecainide. J Am Coll Cardiol 1986; 8: 607-15. 23. Lerman BB, Waxman HL, Buxton AE, Josephson ME. Disopyramide: evaluation of electrophysiologic effects and clinical efficacy in patients with sustained ventricular tachycardia or fibrillation. Am J Cardiol 1983; 51: 759-64. 24. Frieden J. Antiarrhythmic drugs, VII. Lidocaine as a an antiarrhythmic drug. Am Heart J 1965; 70: 713-15. 25. Hondeghem LC. Antiarrhythmic agents modulated receptor applications. Circulation 1987; 75: 514-20. 26. Lerman BB, Belardinelli L, West A, Berne RM, DiMarco JP. Adenosine-sensitive ventricular tachycardia: evidence suggesting cyclic AMP-mediated triggered activity. Circulation 1986; 74: 270-72.

REVIEW ARTICLE Recurrent miscarriage I: definition and epidemiology

REFERENCES

G. M. STIRRAT

1. Harrison DC,

Sprouse JH, Morrow AG. The antiarrhythmic properties of lidocaine and procainamide. Circulation 1963; 28: 486-91. 2. Nathan AW, Camm AJ, Bexton RS, Hellestrand KJ. Intravenous flecainide for the clinical management of paroxysmal tachycardias. Clin Cardiol 1986; 10: 317-22. 3. Ward DE, Cheesman M, Dancy M. Effect of intravenous and oral flecainide on ventricular tachycardia. Int J Cardiol 1986; 10: 251-62. 4. Vandenbosch R, Lisin N, Andriange M, Gach J, Carlier J. Experimentation clinique du disopyramide par voie intraveineuse. Acta Cardiol 1975; 30: 267-78. 5. Vogel M, Desoutter P, Bellanger P, Motte G, Welti JJ. Action du sur les arythmies ventriculaires et sur la conduction auriculo-ventriculaire. Arch Mal Coeur 1976; 4: 395-406. 6. Hulting J, Rosenhamer G. Anti-arrhythmic and haemodynamic effects of intravenous and oral disopyramide in patients with ventricular tachycardia. J Int Med Res 1976; 4: 90-95. 7. Llewellyn MJ, Ramsdale DR. Termination of refractory ventricular tachycardia by a combination of intravenous sotalol and overdrive ventricular pacing, Clin Cardiol 1987; 10: 416-18. 8. Ramsdale DR, Peterson C. Successful termination of combined rapid atrial flutter/fibrillation and ventricular tachycardia by intravenous sotalol. Postgrad Med J 1987; 63: 579-80. 9. Santinelli V, Chiariello M, Stanislao M, Condorelli M. Intravenous mexiletine in management of lidocaine resistant ventricular tachycardia. Am Heart J 1982; 105: 680-85. 10. Green AGH. Disopyramide—an effective treatment for lignocaine resistant ventricular dysrhythmias. Scot Med J 1979; 24: 21-24. 11. Wellens HJ, Schuilenburg RM, Durrer D. Electrical stimulation of the heart in patients with ventricular tachycardia. Circ 1972; 46: 216-26. 12. Brugada P, Green M, Abdollah H, Wellenns HJJ. Significance of ventricular arrhythmias initiated by programmed ventricular stimulation: the importance of the type of ventricular arrhythmia induced and the number of extrastimuli required. Circulation 1984; 69: 87-92. 13. Munoz A, Leenhardt A, Sassine A, Galley P, Puech P. Therapeutic use of adenosine for terminating spontaneous paroxysmal supraventricular tachycardia. Eur Heart J 1984; 5: 735-38. 14. Garratt CJ, Linker NJ, Griffith MJ, Ward DE, Camm AJ. Comparison of adenosine and verapamil for termination of paroxysmal junctional tachycardia. Am J Cardiol 1989; 64: 1310-16. 15. Mason JW, Winkle R. Accuracy of the ventricular tachycardia induction study for predicting long-term efficacy of antiarrhythmic drugs.

disopyramide injectable

N Engl J Med 1980; 303: 1073-77. KK, Harte M, Horgan JH. Sotalol infusion in the treatment of supraventricular tachyarrhythmias. Chest 1985; 87: 113-18. 17. Senges J, Lengfelder W, Jaurenig R, et al. Electrophysiological testing in assessment of therapy with sotalol for sustained ventncular tachycardia.

On epidemiological evidence, the definition of recurrent miscarriage should be three or more consecutive pregnancy losses. Data should be collected to 28 weeks’ gestation but analysis up to 20-22 weeks’ or 500 g fetal weight should also be possible. General practitioners and gynaecologists should do what they feel is suitable for couples whose history does not meet these criteria but a diagnosis of recurrent miscarriage should not be made. Women meeting the definition can be subdivided into primary and secondary groups, respectively consisting of those who have lost all previous pregnancies and those who have had one successful pregnancy followed by consecutive losses.

introduction

Although the term spontaneous abortion is medically exact, many women are distressed by the term, and therefore the word miscarriage is preferred. Miscarriage is broadly defined as the expulsion of the embryo or fetus before viability has been achieved. The World Health Organisation1 definition is "the expulsion or extraction from its mother of an embryo or fetus weighing 500 g or less". The weight criterion was chosen because it corresponded to a gestational age of roughly 20-22 weeks, which was considered to be below the irreducible minimum for viability, and because it was thought to provide some discrimination between pathological causes.

Incidence of

16. Teo

Circulation 1984; 69: 577-84. 18. Anderson JL. Experience with electrophysiologic guided therapy of ventricular tachycardia with flecamide: summary of long-term followup. Am J Cardiol 1984; 53: 79-86B. 19. Flowers D, O’Gallagher D, Torres V, Miura D, Somberg JC. Flecainide: long term treatment using a reduced dosing schedule. Am J Cardiol

1985; 55: 79-83.

miscarriage

The

reported early loss rate among clinically recognised pregnancies is between 12% and 15% (table I). Higher figures in some older studies are flawed by the inclusion of ectopic pregnancies, the lack of rigorous exclusion of induced abortions, and biased selection of patients. ADDRESS Department of Obstetrics and Gynaecology, Bristol Maternity Hospital, Bristol BS2 8EG, UK (Prof G M Stirrat,

FRCOG)