Evidence-based Cardiology – part 7 ppsx

cava. 41,42 Ablation techniques have evolved extremely rap- idly in recognition of these mechanisms and can be divided into those directed at ectopic triggers (focal ablation) and at preventing intra-atrial re-entry (linear ablation). Focal ablation for paroxysmal atrial fibrillation This technique involves transseptal puncture to pass catheters from the right atrium into the left atrium, and the use of multi-electrode catheters in the ostia of the pulmonary veins to identify the conduction pathways into and out of these veins. The superior pulmonary veins are the most common sources of ectopic triggers and form the targets for ablation. 43 Two approaches may be adopted – electrical isolation of the culprit veins identified from spontaneous ectopic beat activity, or the anatomical approach in which as many pulmonary veins as possible are isolated in an attempt to eliminate all ectopic triggers. 44 Initial techniques involved ablation deep within the veins and were associated with a significant incidence of pulmonary vein stenosis. 45 It is now generally accepted that radiofrequency energy should be applied at or close to the ostia to minimize this risk. Success rates for pulmonary vein ablation are currently around 60% in experienced centers, with success defined as lack of symptomatic recurrence of atrial fibrillation in the medium term (few long-term data are yet available). It is now recognized that pulmonary vein ectopic impulses may be involved in the maintenance of atrial fibrillation as well as its initiation. Ablation of these foci in some patients with persistent atrial fibrillation can acutely terminate the arrhythmia. 46 The response to antiarrhythmic drugs may be improved by modi- fying the triggering focus. Recurrences occur because of multiple pulmonary vein triggers, triggers occurring within the atria themselves, or incomplete isolation of veins. Linear ablation Linear ablation procedures are designed to compartmental- ize atrial tissue to prevent intra-atrial re-entry. These procedures owe much to the early experience with the surgical maze and corridor procedures. 47 Current techniques involve the production of linear lesions around the pulmonary vein ostia, across the superior aspect of the left atrium, and connecting the mitral valve annulus to the pulmonary vein ostial lines. Specially designed compliant, multi-electrode ablation catheters have been developed for this purpose. At present linear ablation is still considered an experimental procedure. 48 The pace and ablate strategy For patients with persistent, symptomatic atrial fibrillation, total AV nodal ablation offers a means of controlling heart rate and of regularizing the ventricular rhythm. A physiological (rate responsive) permanent pacemaker is implanted and used to govern heart rate. This technique is effective at improving quality of life in selected patients, especially those with palpitation. Its effectiveness is less clear-cut in patients with non-specific symptoms such as fatigue and dyspnea, in which the underlying cardiac condition may be the main Supraventricular tachycardia: drugs v ablation 571 Table 40.2 Potential problems of drugs and ablation for treatment of SVTs Antiarrhythmic drugs Ablation Proarrhythmia Potentially life-threatening complication Ͻ2% if otherwise normal heart (for example, cardiac tamponade, stroke, myocardial Ͼ4% in other patients (that is, infarction) – very rare structural or coronary disease) No deaths in 1998 NASPE registry Non-cardiac side effects AV block requiring pacemaker 8 to 60% with Class IC drugs 11 0·15% (AVRT) 24% with verapamil 10 to 1% (AVNRT) Failure to control arrhythmia Inability to ablate target up to 30% with 2·6% (AVNRT) short-term follow up 6% (AVRT) up to 28% (atrial tachycardia) 14% (atrial flutter) a Compliance issues Pneumothorax (avoided by coronary sinus cannulation via femoral vein route) Tricuspid regurgitation (rare) Vascular complications (rare) a This figure is likely to improve with the use of large tipped catheters and cooled tip catheters that can produce a larger lesion. cause. Total AV nodal ablation is thus best reserved for patients with atrial fibrillation who have palpitation and for whom AV nodal blocking drugs are ineffective or cause significant adverse effects. Risks of ablation In discussing treatment options with patients, the risks of treatment are an important factor (Table 40.2). The risks of antiarrhythmic drugs, especially proarrhythmia, have already been covered. For catheter ablation there are uncommon but important risks. Most patients worry about the risk of a dis- abling or life-threatening complication. Cardiac tamponade can occur because of transseptal puncture, catheter trauma or ablation in thin-walled tissue. This risk is therefore greatest with left-sided accessory pathways and with ablation of focal atrial arrhythmias, at around 0·7%. For other tachycardias the risk is significantly less. Fatalities were reported par- ticularly during early experience with catheter ablation but in the 1998 NASPE prospective catheter ablation registry there were no deaths reported in more than 3300 procedures. This registry was voluntary and open to reporting bias, but nonetheless death is a very uncommon complication. Other reported complications included myocardial infarction, pneumothorax, pericarditis, tricuspid regurgitation, and femoral artery pseudoaneurysm. AV block requiring pacemaker implantation affected 1 in 100 patients treated for AVNRT, 1 in 650 patients treated for AVRT, and 1 in 150 patients treated for atrial flutter. Complication rates for focal and linear ablation techniques are less well reported but there is concern about the potential for thromoembolic complication when multiple radiofrequency applications are made in the left atrium. References 1.Frishman WH, Cavusoglu E. Beta-adrenergic blockers and their role in the therapy of arrhythmias. In: Podrid PJ, Kowey PR, eds. Cardiac arrhythmia: mechanisms, diagnosis and management. Baltimore, Maryland: Williams and Wilkins, 1995. 2.Gill J, Heel RC, Fitton A. Amiodarone. An overview of its phar- macological properties, and review of its therapeutic use in cardiac arrhythmias. Drugs 1992;43:69–110. 3.Estes NAM, Garan H, Ruskin JN. Electrophysiologic properties of flecainide acetate. Am J Cardiol 1984;53(Suppl. B): 26B–9B. 4.Hellestrand KJ, Bexton RS, Nathan AW et al. Acute electrophysiological effects of flecainide acetate on cardiac conduction and refractoriness in men. Br Heart J 1982;48:140–8. 5.Pritchett ELC, Datorre SD, Platt ML et al. Flecainide acetate treatment of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation – dose response studies. J Am Coll Cardiol 1991;17:297–303. 6.UK Propafenone PSVT Study Group. A randomized, placebo- controlled trial of propafenone in the prophylaxis of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation. Circulation 1995;92:2550–7. 7.Chimienti M, Cullen Jr MT, Casadei G for the Flecainide and Propafenone Italian Study Investigators. Safety of flecainide versus propafenone for the long-term management of symptomatic paroxysmal supraventricular tachyarrhythmias. Report from the Flecainide and Propafenone Italian Study (FAPIS) Group. Eur Heart J 1995;16:1943–51. 8.Hellestrand KJ. Efficacy and safety of long-term oral flecainide acetate in patients with responsive supraventricular tachycardia. Am J Cardiol 1996;77:83A–8A. 9.Weindling SN, Saul JP, Walsh EP. Efficacy and risks of medical therapy for supraventricular tachycardia in neonates and infants. Am Heart J 1996;131:66–72. 10.Dorian P, Naccarelli GV, Coumel P et al. A randomised comparison of flecainide versus verapamil in paroxysmal Evidence-based Cardiology 572 Recommendations Evidence Grade ● Propafenone and flecainide are effective antiarrhythmic drugs for the prophylactic management of paroxysmal supraventricular tachycardia. ● Sotalol and amiodarone are effective prophylactic therapies for paroxysmal atrial flutter. ● Potential proarrhythmic complications and other adverse effects of antiarrhythmic therapy should be considered when choosing antiarrhythmic therapy. ● The choice between ablation and antiarrhythmic drug therapy for the initial treatment of paroxysmal supraventricular tachycardia is dependent on patient preference. ● Verapamil is a safe first-line treatment for pSVT but has a relatively high rate of failure and side effects. ● Flecainide and propafenone reduce symptoms from pSVT in most cases and should be considered for individuals who do not have underlying coronary artery disease. ● RF ablation should be offered as first-line treatment for individuals with pSVT. ● RF ablation is the treatment of choice in individuals who present with pre-excited atrial fibrillation. ● RF ablation should be offered as first-line treatment for individuals with paroxysmal or persistent atrial flutter. ● Pulmonary vein ablation should be considered a second-line treatment for paroxysmal atrial fibrillation in the absence of structural heart disease in selected individuals, where antiarrhythmic drug therapy has failed. ● The “ablate and pace” strategy should be used to pal- liate symptoms in patients with atrial fibrillation in whom rate control is not achieved using drugs. Grade B Grade C Grade B Grade C Grade B Grade B Grade B Grade C Grade C Grade B Grade A supraventricular tachycardia. The Flecainide Multicenter Investigators Group. Am J Cardiol 1996;77:89A–95A. 11.Hopson JR, Buxton AE, Rinkenberger RL et al. Safety and utility of flecainide acetate in the routine care of patients with supraventricular tachyarrhythmias: results of a multicenter trial. The Flecainide Supraventricular Tachycardia Study Group. Am J Cardiol 1996;77:72A–82A. 12.Aliot E, Denjoy I. Comparison of the safety and efficacy of flecainide and propafenone in hospital out-patients with symptomatic atrial fibrillation/flutter. The Flecainide AF French Study Group. Am J Cardiol 1996;77:66A–71A. 13.Orejarena LA, Vidaillet H Jr, DeStefano F et al. Paroxysmal supraventricular tachycardia in the general population. J Am Coll Cardiol 1998;31:150–7. 14.Gooselink AT, Crijns HJ, Van Gelder IC et al. Low-dose amiodarone for maintenance of sinus rhythm after cardioversion of atrial fibrillation or flutter. JAMA 1992;267:3289–93. 15.Chung MK, Schweikert RA, Wilkoff BL et al. Is hospital admis- sion for initiation of antiarrhythmic therapy with sotalol for atrial arrhythmias required? Yield of in-hospital monitoring and prediction of risk for significant arrhythmia complications. J Am Coll Cardiol 1998;32:169–76. 16.Stanton MS, Prystowsky EN, Fineberg NS et al. Arrhyth- mogenic effects of antiarrhythmic drugs: a study of 506 patients treated for ventricular tachycardia or fibrillation. J Am Coll Cardiol 1989;14:209–15. 17.Falk RH. Proarrhythmia in patients treated for atrial fibrillation or flutter. Ann Intern Med 1992;117:141–50. [Published erra- tum in Ann Intern Med 1992;117:446.] 18.Friedman PL, Stevenson WG. Proarrhythmia. Am J Cardiol 1998;82:50N–8N. 19.Echt DS, Liebson PR, Mitchell LB et al. Mortality and morbidity in patients receiving encainide, flecainide or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–8. 20.Reiffel JA. Impact of structural heart disease on the selection of class III antiarrhythmics for the prevention of atrial fibrillation and flutter. Am Heart J 1998;135:551–6. 21.Pritchett E, Wilkinson WE. Mortality in patients treated with flecainide and encainide for supraventricular arrhythmias. Am J Cardiol 1991;67:976–80. 22.Nathan AW, Hellestrand KJ, Bexton RS et al. Proarrhythmic effects of the new antiarrhythmic agent flecainide acetate. Am Heart J 1984;107:222–8. 23.Bathina MN, Mickelsen S, Brooks C et al. Radiofre- quency catheter ablation versus medical therapy for initial treatment of supraventricular tachycardia and its impact on quality of life and healthcare costs. Am J Cardiol 1998; 82:589–93. 24.Weerasooriya HR, Murdock CJ, Harris AH et al. The cost- effec- tiveness of treatment of supraventricular arrhythmias related to an accessory atrioventricular pathway: comparison of catheter ablation, surgical division and medical treatment. Aust NZ J Med 1994;24:161–7. 25.Ikeda T, Sugi K, Enjoji Y et al. Cost effectiveness of radiofrequency catheter ablation versus medical treatment for paroxysmal supraventricular tachycardia in Japan. J Cardiol 1994; 24:461–8. 26.Jackman WM, Beckman KJ, McClelland JH et al. Catheter ablation of accessory pathways (Wolff–Parkinson–White syndrome) by radiofrequency current. N Engl J Med 1991; 324:1605–11. 27.Sathe S, Vohra J, Chan W et al. Radiofrequency catheter ablation for paroxysmal supraventricular tachycardia: a report of 135 procedures. Aust NZ J Med 1993;23:317–24. 28.Scheinmann MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol 2000; 23:1020–8. 29.Fitzsimmons PJ, McWhirter PD, Peterson DW et al. The natural history of Wolff–Parkinson–White syndrome in 228 military aviators: a long-term follow-up of 22 years. Am Heart J 2001;142:530–6. 30.Keim S, Werner P, Jazayeri M et al. Localization of the fast and slow pathways in atrioventricular nodal re-entrant tachycardia by intra-operative ice-mapping. Circulation 1992; 86: 919–25. 31.Inoue S, Becker AE. Posterior extensions of the human com- pact atrioventricular node: a neglected anatomic feature of potential clinical significance. Circulation 1998;97:188–93. 32.Jackman WM, Beckman KJ, McClelland JH et al. Treatment of supraventricular tachycardia due to atrioventricular nodal re- entry by radiofrequency catheter ablation of slow pathway conduction. N Engl J Med 1992;327:313–18. 33.Kugler JD, Danford DA, Deal BJ et al. Radiofrequency catheter ablation for tachyarrhythmias in children and adolescents. The Pediatric Electrophysiology Society. N Engl J Med 1994; 330:1481–7. 34.Cosio FG, Lopez-Gil M, Goicolea A, Arribas F, Barroso JL. Radiofrequency ablation of the inferior vena cava-tricuspid valve isthmus in common atrial flutter. Am J Cardiol 1993; 71:705–9. 35.Chen SA, Chiang CE, Wu TJ et al. Radiofrequency catheter ablation of common atrial flutter: comparison of electrophysio- logically guided focal ablation and linear ablation technique. J Am Coll Cardiol 1996;27:860–8. 36.Jaïs P, Hocini M, Gilet T et al. Effectiveness of irrigated tip catheter ablation of common atrial flutter. Am J Cardiol 2001;88:433–5. 37.Anderson JL, Jolivette DM, Fredell PA. Summary of efficacy and safety of flecainide for supraventricular arrhythmias. (Review). Am J Cardiol 1988;62:62D–6D. 38.Hoffman E, Reithmann C, Nimmermann P et al. Clinical experience with electroanatomic mapping of ectopic atrial tachycardia. Pacing Clin Electrophysiol 2002;25:49–56. 39.Poty H, Saoud N, Haissaguerre M et al. Radiofrequency catheter ablation of atrial tachycardias. Am Heart J 1996;131:481–9. 40.Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn 1962;140:183–8. 41.Haïssaguerre M, Jaïs P, Shah DP et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659–66. 42.Tsai CF, Tai CT, Hseih MH et al. Initiation of atrial fibrillation by ectopic beats originating from the superior vena cava. Electrophysiological characteristics and results of radiofrequency ablation. Circulation 2000;102;67–74. 43.Haïssaguerre M, Jaïs P, Shah DC et al. Right and left atrial radiofrequency catheter therapy of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol 1996;7:1132–44. 44.Hassiguerre M, Jais P, Shah DC et al. Electrophysiolo- gical end-point for catheter ablation of atrial fibrillation initiated from multiple pulmonary venous foci. Circulation 2000;101: 1409–17. Supraventricular tachycardia: drugs v ablation 573 45.Robbins IM, Colvin EV, Doyle TP et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation. Circulation 1998;98:1769–75. 46.Pappone C, Oreto G, Rosanio S et al. Atrial electroanatomic remodelling after circumferential radiofrequency pulmonary vein ablation. Circulation 2001;104:2539–44. 47.Cox JL, Boineau JP, Schuessler RB, Kater KM, Lappas DG. Five year experience with the maze procedure for atrial fibrillation. Ann Thorac Surg 1993;56:814–24. 48.Maloney JD, Milner L, Barold S, Czerska B, Markel M. Two- staged biatrial linear and focal ablation to restore sinus rhythm in patients with refractory chronic atrial fibrillation: procedure experience and follow-up beyond 1 year. Pacing Clin Elecrophysiol 1998;21:2527–32. Evidence-based Cardiology 574 575 Part IIId Specific cardiovascular disorders: Ventricular arrhythmias, bradyarrhythmias and cardiac arrest A John Camm, Editor 576 Grading of recommendations and levels of evidence used in Evidence-based Cardiology GRADE A Level 1a Evidence from large randomized clinical trials (RCTs) or systematic reviews (including meta-analyses) of multiple randomized trials which collectively has at least as much data as one single well-defined trial. Level 1b Evidence from at least one “All or None” high quality cohort study; in which ALL patients died/failed with conventional therapy and some survived/succeeded with the new therapy (for example, chemotherapy for tuber- culosis, meningitis, or defibrillation for ventricular fibrillation); or in which many died/failed with conventional therapy and NONE died/failed with the new therapy (for example, penicillin for pneumococcal infections). Level 1c Evidence from at least one moderate-sized RCT or a meta-analysis of small trials which collectively only has a moderate number of patients. Level 1d Evidence from at least one RCT. GRADE B Level 2 Evidence from at least one high quality study of non- randomized cohorts who did and did not receive the new therapy. Level 3 Evidence from at least one high quality case–control study. Level 4 Evidence from at least one high quality case series. GRADE C Level 5 Opinions from experts without reference or access to any of the foregoing (for example, argument from physiology, bench research or first principles). A comprehensive approach would incorporate many different types of evidence (for example, RCTs, non-RCTs, epidemiologic studies, and experimental data), and examine the architecture of the information for consistency, coherence and clarity. Occasionally the evidence does not completely fit into neat com- partments. For example, there may not be an RCT that demon- strates a reduction in mortality in individuals with stable angina with the use of ␤ blockers, but there is overwhelming evidence that mortality is reduced following MI. In such cases, some may recommend use of ␤ blockers in angina patients with the expecta- tion that some extrapolation from post-MI trials is warranted. This could be expressed as Grade A/C. In other instances (for example, smoking cessation or a pacemaker for complete heart block), the non-randomized data are so overwhelmingly clear and biologically plausible that it would be reasonable to consider these interventions as Grade A. Recommendation grades appear either within the text, for example, and or within a table in the chapter. The grading system clearly is only applicable to preventive or therapeutic interventions. It is not applicable to many other types of data such as descriptive, genetic or pathophysiologic. Grade A1aGrade A Introduction Arrhythmic death and risk stratification Epidemiologic studies and carefully conducted clinical trials have consistently demonstrated that deaths in patients with severe heart disease are often due to ventricular arrhythmia. The evidence for this comes from several sources, including recordings made by paramedics, Holter monitor studies, and postmortem classification based on suddenness of hemody- namic collapse. 1 Although not all sudden deaths are due to ventricular tachycardia or fibrillation, there is substantial evidence from paramedic monitoring and Holter reports that most are. 2 Although different schemes have been used to classify death according to presumed mechanisms, there is considerable evidence that between one quarter and half of cardiac deaths are sudden and due to arrhythmia. Thus prevention of the sudden death is an important clinical goal. Over the past two decades methods of risk stratification have been developed and evaluated, in order to target therapy to the subpopulation at greatest risk of sudden death. Techniques have been used in clinical trials of antiarrhythmic agents to select a population at high risk of arrhythmic death. These include some clinical characteristics (decreased left ventricular ejection fraction (LVEF), recent myocardial infarction, New York Heart Association (NYHA) functional class of heart failure), and the use of investigations such as measurement of ventricular ectopy on the 24-hour Holter, programmed ventricular stimulation, signal averaged ECG and heart rate variability. Although all of these techniques identify patients at increased risk of arrhythmic death, and total death as well, there is no evidence that any technique selectively detects increased risk of arrhythmic death. 3 Thus powerful markers of total death, such as poor LVEF, are now used in trials to identify patients at risk of arrhythmic death. To summarize, risk stratification is necessary to select patients at high enough risk of events to justify intervention; however, left ventricular damage, a powerful risk factor for overall cardiac death risk, may be the most efficient means of selecting patients who are at high risk of arrhythmic death. Pharmacologic interventions and sudden cardiac death Classification of antiarrhythmic drugs There have been a number of attempts to classify antiarrhythmic drugs. The most widely used classification is based on the influence of drugs on different phases of the action potential of myocytes (Table 41.1). This system is relatively simple compared to other classifications, but is limited because of the mixed abilities of most antiarrhythmic drugs. 577 41 Prevention and treatment of life-threatening ventricular arrhythmia and sudden death Eugene Crystal, Stuart J Connolly, Paul Dorian Table 41.1 Classification of antiarrhythmic drugs* Action Drugs Class IA Depression of action Quinidine, potential upstroke, procainamide, slow conduction, disopyramide prolong repolarization Class IB Little effect on Lidocaine, mexiletine upstroke in normal tissue, depression of upstroke in abnormal tissue, shortening of repolarization Class IC Marked depression Flecainide, of upstroke, marked propafenone, slow conduction, encainade, ajmaline, slight effect on moricizine repolarization Class II ␤ Blockers Class III Prolong Amiodarone, sotalol, repolarization dofetilide, azimilide, ibutilide Class IV Calcium-channel Verapamil, diltiazem blockers *Many drugs have properties of more than one class, but are classified according to their major effects. Trials of antiarrhythmic therapy in patients with sustained ventricular arrhythmia There have been only a few randomized trials of antiarrhythmic therapy in patients with prior sustained ventricular arrhythmia. These have used active controls and the primary outcome has been arrhythmia recurrence or death. Steinbeck et al 4 conducted a prospective randomized trial in 170 patients to investigate whether electrophysiologic study (EPS)-guided antiarrhythmic therapy improves the long-term outcome of patients with spontaneous and inducible sustained ventricular arrhythmia compared with metoprolol therapy not guided by EPS. EPS-guided therapy consisted of serial EPS testing of inducibility under different antiarrhythmic agents (in sequence: propafenone l disopyramide l sotalol l amiodarone) to identify one that would suppress an initially inducible sustained arrhythmia. There were 55 patients whose arrhythmia was never inducible during the baseline EPS, thereby precluding further serial drug testing, and these patients were treated with metoprolol. The 2 year incidence of the composite outcome of symptomatic arrhythmia recurrence or sudden death was the same for EPS-guided therapy as for metoprolol (46% v 48%). In the Electrophysiological Study Versus Electrocar- diographic Monitoring (ESVEM) study 5,6 patients with inducible VT and any (i) history of cardiac arrest, (ii) sustained VT or (iii) syncope, were randomly assigned to undergo serial testing of the efficacy of the antiarrhythmic drugs either by EPS or by 24 hour Holter monitoring. Patients (n ϭ486) received long-term treatment with the first antiarrhythmic drug that was predicted to be effective on the basis of either repeat EPS or 24 hour Holter. The primary conclu- sion of ESVEM was that therapy guided by EPS and that guided by Holter monitoring are equally effective. 6 The secondary outcome, related to the efficacy of individual study drug, was very interesting. 5 Sotalol, a ␤ blocking drug with class III activity, was more effective than the class I drugs tested (imipramine, mexiletine, pirmenol, procainamide, propafenone, quinidine). The actuarial probability of a recurrence of arrhythmia after a prediction of drug efficacy by either strategy was significantly lower for patients treated with sotalol than for patients treated with the other drugs (risk ratio (RR) 0·43; 95% CI 0·29, 0·62). With sotalol there were lower risks of death from any cause (RR 0·50; 95% CI 0·30, 0·80), death from cardiac causes (0·50; P ϭ 0· 02) and death from arrhythmia (0·50; P ϭ 0· 04). The cumula- tive percentage of patients in whom a drug was predicted to be effective and in whom it remained effective and tolerated was also higher for sotalol than for the other drugs (P Ͻ0 ·001). Sotalol was more effective than the other six antiarrhythmic drugs in preventing death and recurrences of arrhythmia. In the Cardiac Arrest in Seattle: Conventional versus Amiodarone Drug Evaluation (CASCADE) study, antiarrhythmic drug therapy was evaluated in survivors of out of hospital VF. 7 Amiodarone without EPS or Holter guidance was compared to class I antiarrhythmic agents (quinidine, procainamide, their combination, or flecainide), selected by serial EPS or Holter monitoring. Most of the 228 randomized patients had coronary artery disease with a prior myocardial infarction, and the mean left ventricular ejection fraction was 35Ϯ10%. During a mean follow up of 6 years, amiodarone improved survival compared to the class I agents (53% v 40%, P ϭ0·007). These trials provide evidence that, in survivors of sustained ventricular arrhythmia, amiodarone and sotalol are superior to class I agents. Recommendation Where antiarrhythmic drugs are to be used to prevent the recurrence of ventricular tachyarrhythmia, amiodarone and sotalol are superior to class I antiarrhythmic agents. Trials of antiarrhythmic therapy in patients with asymptomatic non-sustained ventricular arrhythmia, at risk of sudden death Asymptomatic non-sustained ventricular arrhythmia on Holter monitor was determined in the 1980s to be a predic- tor of death in patients surviving myocardial infarction, and these patients were targeted in several trials of antiarrhythmic therapy on the assumption that decreasing asymptomatic ventricular arrhythmia would decrease the occurrence of sudden cardiac death This hypothesis was first tested in the International Mexiletine and Placebo Antiarrhythmic Coronary Trial (IMPACT) 8 and then in the pivotal Cardiac Arrhythmia Suppression Trial (CAST). 9 In IMPACT, 630 patients with recent myocardial infarction were randomly assigned to treatment with mexiletine or placebo. 8 Despite a decrease in the frequency of complex ventricular arrhythmia, after an average follow up of 9 months, the mortality on mexiletine was 7·6% and on placebo was 4·8% (P ϭNS). In the Cardiac Arrhythmic Suppression Trial (CAST) 9 1727 patients with recent onset of myocardial infarction and with asymptomatic, or mildly symptomatic, ventricular arrhythmia (Ն 6 ventricular extrasystoles per hour), sup- pressible by a class I antiarrhythmic drug (encainade, flecainide or moricizine), were randomized to the active antiarrhythmic drug or placebo and followed for arrhythmic death. The trial was halted early because of an increased incidence of arrhythmic cardiac death and non-fatal cardiac arrests in patients treated with encainade and flecainide (4·5% v 1·2%, RR 3·6, 95% CI 1·7, 8·5). These results led to reappraisal of class I drug therapy for sudden death prophylaxis. In a meta-analysis of the results Grade A Evidence-based Cardiology 578 been tested in a randomized trial of 1510 patients with severe left ventricular dysfunction (LVEFՅ 35%) after recent myocardial infarction (DIAMOND MI trial). The primary end point was all-cause mortality. No significant difference was found between the dofetilide and placebo groups in overall mortality (31% v 32%). The cardiac mortality (26% v 28%) and arrhythmic mortality (17% v 18%) were also similar. There were seven cases of torsades de pointes ventricular tachycardia, all in the dofetilide group. 19 In the Azimilide Postinfarct Survival Evaluation (ALIVE) trial the effect of azimilide, another pure class III agent, was evaluated in 3717 patients with recent myocardial infarction, with LVEFϽ 35% and with low heart rate variability. Azimilide had no effect on mortality (HR ϭ1·0). 20 ␤ Blockers in patients at risk of sudden death ␤ Blockers are the single type of agent most frequently studied in postmyocardial infarction patients for the prevention of death, with more than 12 large trials reported. A meta- analysis of the ␤ blocker trials, reported in 1985, showed a significant reduction in mortality during treatment after myocardial infarction. 21 The data from this meta-analysis also indicated a highly significant 30% reduction in sudden cardiac death with ␤ blockers. The risk of non-sudden death was also decreased by 12%, but this difference was not significant. Recent ␤ blocker trials in CHF patients also show a reduction in both overall and sudden cardiac death. 22–24 In summary, antiarrhythmic drugs have been extensively evaluated in randomized trials as prophylactic agents against death, but little tested against recurrence of arrhythmia. ␤ Blockers are effective against arrhythmic death (about 20–30% reduction) and non-arrhythmic deaths, and reduce overall mortality significantly. Amiodarone has a moderate effect against sudden death and a neutral effect on other deaths, therefore its overall effect on total mortality is modest. Class I antiarrhythmic drugs are harmful, probably owing to proarrhythmic effects. Pure class III agents are at best neutral, and in the case of one agent, d-sotalol, actually harmful. ␤ Blocker therapy is indicated in all patients at high risk for sudden death, and amiodarone is the treatment of choice for control of specific arrhythmias where concern about possible proarrhythmic effects is an issue (especially in patients with ischemic heart disease and/or left ventricular dysfunction). Pure class III antiarrhythmic agents clearly do not reduce mortality when used prophylactically in high-risk patients. The different results of D-sotalol, dofetilide and azimilide trials are probably due to differences in the design of the studies and differences in risk of torsades de pointes between the agents. Prevention and treatment of life-threatening ventricular arrhythmia and sudden death 579 of 138 trials of antiarrhythmic prophylactic therapy in patients after myocardial infarction, 10 there were 660 deaths among 11 712 patients allocated to receive class I agents and 571 deaths among 11 517 corresponding control patients (51 trials: odds ratio (OR) 1·14; 95% CI 1·01, 1·28; P ϭ0 ·03). There is therefore considerable evidence that class I antiarrhythmic drugs are harmful when used as prophylactic agents in high-risk patients. Amiodarone is a class III antiarrhythmic agent which has been extensively studied in patients at risk of sudden arrhythmic death. Amiodarone has several properities other than class III effect, including an antiadrenergic effect. The two largest trials (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial, CAMIAT 11 and European Myocardial Infarction Amiodarone Trial, EMIAT 12 ) both showed a reduction in arrhythmic death but no significant reduction in overall death. Meta-analysis of data from all 13 randomized controlled trials of amiodarone (89% of patients, after myocardial infarction) showed a significant reduction in total mortality (OR 0·87, 95% CI 0·78–0·99) and a significant reduction in arrhythmic death (OR 0·71, 95% CI 0·59, 0·85). 13,14 Analysis of the interaction between the treatment and baseline factors suggested an important positive relation- ship between ␤ blocker use and amiodarone effect, 15 such that patients on ␤ blockers received a significantly greater benefit from amiodarone than those not on ␤ blockers. D-Sotalol, a pure class III agent, was evaluated for prevention of sudden death in a placebo controlled trial of 3121 patients with recent myocardial infarction and left ventricular ejection fraction Ͻ40%, or symptomatic heart failure with a remote myocardial infarction (Survival with Oral d-sotalol, or SWORD trial). 16 Among 1549 patients assigned to d-sotalol there were 78 deaths (5·0%) compared to 48 (3·1%) among the 1572 patients assigned to placebo (RR 1·65, 95% CI 1·15, 2·36). Presumed arrhythmic deaths (RR 1·77, 95% CI 1·15, 2·74) accounted for the excess mortality in the d-sotalol group. This proarrhythmic fatal effect of d-sotalol was greater in patients with a left ventricular ejection fraction of 31–40% than in those with lower ejection fractions (RR 4·0 v 1·2, P ϭ0 ·007). Another pure class III compound, dofetilide, was tested in patients with symptomatic heart failure. In the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) 1518 patients were randomized to dofetilide or placebo. 17,18 The study treatment was initiated in hospital and included 3 days of cardiac monitoring and dose adjustment. During a median follow up of 18 months, 311 patients in the dofetilide group (41%) and 317 patients in the placebo group (42%) died (OR, 0·95; 95% CI 0·81, 1·11). Treatment with dofetilide significantly reduced the risk of hospitalization for worsening CHF, rate of conversion and risk of recurrence of atrial fibrillation. There were 25 cases of torsades de pointes in the dofetilide group (3·3%), compared to none in the placebo group. Dofetilide has also [...]... Prog Cardiovasc Dis 1985; 27: 33 5 7 1 22.Carson P Beta-blocker therapy in heart failure Cardiol Clin 2001;19:26 7 7 8, vi 23.The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial Lancet 1999;353: 9–1 3 24.Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet 1999;353:200 1 7 25.Cohn JN, Johnson G,... 1999;4:8 3–9 1 49.Bardy GH, Lee KL, Mark DB The Sudden Cardiac Death in Heart Failure Trial: pilot study [Abstract] PACE 19 97; 20:1148 50.Hohnloser SH, Connolly SJ, Kuck KH et al The defibrillator in acute myocardial infarction trial (DINAMIT): study protocol Am Heart J 2000;140 :73 5–9 585 Evidence-based Cardiology 51.Dorian P Combination ICD and drug treatments – best options Resuscitation 2000;45:S 3–6 52.Pacifico... Amiodarone Myocardial Infarction Arrhythmia Trial Investigators Lancet 19 97; 349: 67 5–8 2 12.Julian DG, Camm AJ, Frangin G et al Randomised trial of effect of amiodarone on mortality in patients with leftventricular dysfunction after recent myocardial infarction: EMIAT European Myocardial Infarct Amiodarone Trial Investigators Lancet 19 97; 349:66 7 7 4 13.Amiodarone Trials Meta-Analysis Investigators Effect of prophylactic... infarction has been demonstrated in randomized trials.2 5–2 7 A recent meta-analysis28 incorporated data from 15 trials that included 15 104 patients having 900 SCDs ACE inhibitor therapy resulted in a significant reduction in total mortality (OR 0·83; 95% CI 0 71 , 0· 97) , cardiovascular death (OR 0·82, 95% CI 0·69, 0· 97) and SCD (OR 0·80; 95% CI 0 70 , 0·92) Also, the meta-analysis suggested that a reduction... cardiac arrhythmias N Engl J Med 2001;345:1 47 3–8 2 2.Bayes de Luna A, Coumel P, Leclercq JF Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 1 57 cases Am Heart J 1989;1 17: 15 1–9 3.Albert CM, Ruskin JN Risk stratifiers for sudden cardiac death (SCD) in the community: primary prevention of SCD Cardiovasc Res 2001;50:18 6–9 6 4.Steinbeck G, Andresen D, Bach P... ventricular arrhythmias N Engl J Med 19 97; 3 37: 1 57 6–8 3 41.Connolly SJ, Hallstrom AP, Cappato R et al Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials AVID, CASH and CIDS studies Antiarrhythmics vs Implantable Defibrillator study Cardiac Arrest Study Hamburg Canadian Implantable Defibrillator Study Eur Heart J 2000; 21:2 07 1–8 42.Moss AJ, Hall WJ, Cannom DS et al Improved... Multicenter Unsustained Tachycardia Trial Investigators N Engl J Med 2000;342:193 7 4 5 45.Bigger JT Jr Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery Coronary Artery Bypass Graft (CABG) Patch Trial Investigators N Engl J Med 19 97; 3 37: 156 9 7 5 46.Moss AJ, Zareba W, Hall WJ et al Prophylactic implantation of a defibrillator... Investigators N Engl J Med 1993;329:44 5–5 1 7. Greene HL The CASCADE Study: randomized antiarrhythmic drug therapy in survivors of cardiac arrest in Seattle CASCADE Investigators Am J Cardiol 1993 ;72 :70 F–4F 8.International mexiletine and placebo antiarrhythmic coronary trial: I Report on arrhythmia and other findings Impact Research Group J Am Coll Cardiol 1984;4:114 8–6 3 9.The Cardiac Arrhythmia Suppression... Engl J Med 1999;341:85 7 6 5 18.Torp-Pedersen C, Moller M, Bloch-Thomsen PE et al Dofetilide in patients with congestive heart failure and left ventricular dysfunction N Engl J Med 1999;341:85 7 6 5 19.Kober L, Bloch Thomsen PE, Moller M et al Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial Lancet 2000; 356:205 2–8 20.Camm AJ Azimilide... death.50 The study aims to enroll 675 patients shortly after their infarction (day 6 to day 40) who have reduced left ventricular function (LVEF Յ 0·35) and impairment of cardiac autonomic function, shown by depressed heart rate variability (standard deviation of normal to normal R–R intervals 70 ms) or elevated average 24 hour heart rate (mean 24 hour R–R interval 75 0 ms, assessed by Holter monitoring) . Clin Elecrophysiol 1998;21:252 7 3 2. 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