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Special Lecture
Recent Advances in the Treatment of Arrhythmias
Augustus Grant
Duke University Medical Center, Durham, NC
 
  • Atrial Fibrillation and Atrial Flutter
  • Contemporary Management of AF and Atrial Flutter
  • Non-Pharmacologic Strategies for AF
  • Ventricular Arrhythmias
  • Role of Antiarrhythmic Drugs for Ventricular Arrhythmias
  • Radiofrequency Catheter Ablation for Ventricular Arrhythmias
  • Transthoracic Epicardial Catheter Ablation of VT



  • Atrial Fibrillation and Atrial Flutter


    The prevalence of atrial fibrillation (AF) sharply increases after 65 years of age, and by 80 years, roughly 10% of the population will have AF, regardless of gender. Currently, about 2 million people in the US have AF and this is projected to double by the year 2025.

    Major management strategies for AF are 1) relief of symptoms, by effective rate control or restoration and maintenance of normal sinus rhythm (NSR), 2) prevention of thromboembolic complications, and 3) prevention of tachycardia-induced cardiac myopathy.

    The safety of the drugs used to control rate (calcium channel blockers, beta-adrenergic blockers, digitalis) and the non-pharmacologic strategies to control rate are advantages for this strategy. However, disadvantages include possible poor rate control throughout the 24-hour period and the substantial effort required by the patient and physician to control rate effectively.

    Rhythm control has a number of putative advantages (few supporting data): better relief of symptoms, reduction of stroke risk, hemodynamically better in certain forms of structural heart disease (left ventricular inflowing obstruction such as in mitral stenosis; outflow obstruction such as hypertrophic cardiomyopathy and aortic stenosis); and preventing tachycardia-induced cardiomyopathy. The disadvantages of rhythm control are low efficacy, possible hospitalization for initiating antiarrhythmic drug therapy, and limited availability of non-pharmacologic strategies.

    The clinical dilemma has been whether to use rate control or rhythm control.  The usual clinical practice has been to first try rhythm control, and use rate control when rhythm control is unsuccessful. Data from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) and the Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) trial, addresses this dilemma.

    Rate control showed a small, but not statistically significant, survival benefit over rhythm control in the AFFIRM trial, conducted in the US and Canada; the 2 strategies were shown to be at least equivalent. No significant difference between rate control and rhythm control was seen in the RACE trial, conducted in Europe, at 2.3 years of follow-up, with 17% and 22% of each group, respectively, experiencing the cumulative primary endpoint of death from cardiovascular disease, thromboembolic complications, bleeding, the need for pacemaker implantation, or adverse drug reaction. At the end of the study, 10% of the rate control group and 23% of the rhythm control group had NSR.

    AFFIRM and RACE show that rate control is just as good as rhythm control for managing AF.  Therefore, the rate control strategy should be used earlier in the course of treating patients. Importantly, anticoagulation should not be stopped despite the presence of NSR.

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    Contemporary Management of AF and Atrial Flutter


    For paroxysmal atrial flutter or AF, with minimal or no symptoms, treatment comprises anticoagulation and rate control as needed. Drugs are not needed to prevent recurrence of AF.  For AF with significant or disabling symptoms, treatment is anticoagulation and rate control. A trial period of antiarrhythmic drug to try to maintain NSR may be needed for disabling symptoms.

    For lone AF (in the absence of structural heart disease), the recommended sequence of drugs is flecainide (relatively well tolerated, few non-cardiac side effects), propafenone and sotalol. When these drugs fail, proceed to dofetilide and amiodarone; treatment is more complicated with these 2 drugs in general. When dofetilide or amiodarone fail, resort to disopyramide, procainamide, or quinidine. In a special subgroup of patients with vaguely mediated AF, disopyramide may be particularly useful.

    For underlying structural heart disease, drug selection to maintain NSR must be done very carefully, to avoid the increase in mortality seen in a number of studies in this setting.  For congestive heart failure, use amiodarone and dofetilide. Prospective data from the Diamond Congestive Heart Failure Study and the CHF Stat Study show that amiodarone and dofetilide do not increase mortality in patients with AF. For coronary artery disease (CAD), the initial drug of choice is sotalol and the second choice is amiodarone and dofetilide.

    For hypertension, drug selection is based on the extent of left ventricular hypertrophy (LVH) by echocardiography. For an LV wall greater than 1.4 cm, select amiodarone, because of the significant risk of torsade de pointes with many antiarrhythmic drugs. For an LV wall thickness less than 1.4 cm, the initial drug choice is flecainide with amiodarone, and secondary choice is dofetilide and sotalol.

    Azimilide, a new drug for treating AF, blocks the rapid and slow component of the delayed rectified potassium channel. No difference in overall mortality was seen between the azimilide-treated and control patients in the ALIVE trial (Azimilide Post-Infarct Survival Evaluation). A 57% reduction in the incidence of AF and atrial flutter was seen in the azimilide-treated group, compared to control, in the approximately 3,000 post-MI patients (FF 15% to 25%, low heart rate variability) followed for 1 year. Torsade de pointes and neutropenia were observed in less than 1% of patients.  More trials of azimilide are underway to obtain regulatory approval.

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    Non-Pharmacologic Strategies for AF


    One strategy is A-V junction ablation and pacemaker implantation, which has a 95% success rate and a 2-3% incidence of sudden death. The risk of sudden death persists, even when the pacing rate is increased to about 85 bpm in the 3 months following pacemaker implantation. Other risks include persisting thromboembolic risk and lifelong pacemaker-dependency. Focal catheter ablation of AF is another strategy. The current approach is segmental pulmonary vein isolation and linear atrial ablation. The efficacy is 75%. The risks include pulmonary vein stenosis and pulmonary thromboembolism. Surgical ablation during concomitant mitral and coronary artery surgery is a third approach.

    Two significant studies, by Saksena and by Mirza, have used multi-site pacing to prevent AF, in patients with spontaneous or drug-induced bradyarrhythmia who already require a pacemaker for their slow rhythms. Dual-site pacing and biatrial pacing are the two strategies used. In dual-site pacing, sites in the high and low right atrium are selected. Biatrial pacing involves the right atrium and the coronary sinus. Dual-site pacing decreased the frequency of AF in both studies. The studies suggest it is reasonable to consider dual-site pacing in patients with AF who require a pacemaker.

    The current strategy for pulmonary vein isolation, refined since its introduction by Haissaguerre, uses segmental pulmonary vein isolation; the area from which the focus is arising is identified and then ablated. Usually, only about 20% of the pulmonary vein circumference must be ablated. An ablation within the atrial floor is usually performed in this strategy. Although this approach can cure about 75% of patients, significant recurrence of AF remains.

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    Ventricular Arrhythmias


    Prophylactic therapy to prevent sudden death is one approach. The MADIT II trial compared conventional therapy and ICD implantation for prophylactic therapy in patients with documented MI and an EF of 30% or less within three months of entry. The study was stopped at 20 months, as recommended by the Data and Safety Monitoring Board. A 25% mortality reduction with an ICD in patients with a LVEF less than 30% or no associated ventricular arrhythmia was found in MADIT II.

    It was first estimated that roughly 300,000 patients in the US would meet implantation criteria based on the MADIT II study, for about a 10% increase in the total national health care expenditure. Thus, a substantial downward revision to10,000 patients was made. The actualnumber of patients meeting the MADIT criteria likely liessomewhere between these extremes. Zypes stated in an editorial that the current challenge is the need for a simpler device for primary and secondary prevention in patients who do not have an arrhythmia as their initial presenting symptom.  In the MADIT population, less than 5% of patients who received an ICD had a device discharge. However, the current trend is actually for more complex ICD devices, rather than the simpler device that would be useful for primary prevention.

    The current devices are 1) dual-chamber ventricular ICD, for coexisting atrial and ventricular arrhythmias, 2) dual-chamber atrioventricular ICD, for drug-refractory AF, for both atrial and ventricular fibrillation, and 3) multi-site pacing ICD, for class II or III heart failure and QRS prolongation of no greater than 140 ms.

    Presently, data supports an ICD for primary prevention in: 1) non-sustained VT with coronary artery disease and LV dysfunction, 2) CAD with LV dysfunction and LVEF less than 31%, 3) familial syndromes with a high risk of sudden death (LQT syndrome, Brugada syndrome, hypertrophic cardiomyopathy, RV dysplasia), and 4) refractory heart failure necessitating cardiac transplantation.

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    Role of Antiarrhythmic Drugs for Ventricular Arrhythmias


    The MADIT and AVID studies have fairly conclusively settled the role of ventricular arrhythmias. The MADIT trial showed that survival was clearly superior in patients receiving an ICD, compared with patients receiving conventional therapy (antiarrhythmic drugs). Even when the MADIT trial data is corrected for the higher use of beta blockers in the ICD patients, in response to criticism, this trial, and at least two others, firmly show ICD therapy to be superior to antiarrhythmic drugs for ventricular arrhythmias.

    The role of anti-arrhythmic drugs in patients with an ICD is: 1) to reduce the number of VT episodes and shocks required from the ICD, 2) to lengthen the tachycardia cycle length to allow conversion of VT by anti-tachycardia pacing, and 3) to prevent supraventricular arrhythmias, for example, AF.

    The use of anti-arrhythmic drugs to reduce the number of episodes of VT and VF is supported by a few studies. In a study of inducible VT by Kuhlkamp and colleagues, patients who remained inducible on sotalol were randomized to ICD plus sotalol or ICD only. The VT free interval was higher in the sotalol-treated group compared to ICD alone. Sotalol appears effective in reducing the frequency of ICD discharges in patients with VT.

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    Radiofrequency Catheter Ablation for Ventricular Arrhythmias


    The role of radiofrequency (RF) catheter ablation has been established for a subset of patients with VT, and in some it is curative. One groups is patients with idiopathic VT from the right ventricular outflow tract and a similar tachycardia arising in the intraventricular septum. The success rate is 90-95%. The other group is bundle branch re-entrant VT, most frequently observed in cardiomyopathy. For this VT, ablation is in the region of the right bundle branch distal to the His potential.

    Structural heart disease, particularly CAD, presents the greatest challenge for VT ablation, because of 1) the large size of the re-entrant circuit, 2) the multiple morphologies of VT, with an average of 3 different morphologies in each patient, 3) hemodynamic instability during VT, limiting the extent of catheter mapping, 4) mid-myocardial and sub-epicardial location of some arrhythmia circuits, and 5) the presence of  endocardial clots, particularly LV aneurysms, requiring warfarin for a substantial period of time to show that the clot is organized, before proceeding with catheter ablation.

    Saline-cooled RF catheters are used for large reentrant circuits and for reentrant circuits located in the mid-myocardium, or sub-epicardium. These catheters can produce larger and deeper burns from the endocardium. Epicardial mapping and ablation is useful in some patients in whom the reentrant circuit location is mid-myocardial or sub-epicardial.

    RF energy can be delivered for longer periods of time, from 60 to 180 seconds, because of the saline-cooled catheter. For impedance greater than 250 ohms, automatic shutdown occurs. RF catheter ablation can be applied with electrode temperatures ranging from 40 to 50 degrees centigrade.

    A multicenter study of catheter ablation for refractory VT by Calkins and colleagues showed that at about 1 year, about 50% of patients had recurrent VT. Patient survival was about 50%. Major procedure-related complications of saline-cooled catheter ablation in this study were stroke or TIAs, AV block, cardiac tamponade, injury to the aortic valve, myocardial infarction, and damage to the femoral artery access site. In total, 8% of patients had complications. Four procedural deaths occurred in the 146 study patients.

    In a study by Delacretaz using a conventional RF catheter, 33% of patients were non-inducible, VT was modified in 45% patients, and there was no impact on VT in 22% of patients. At 12 to 18 months, about 66% of patients were free of VT and 33% had VT recurrence. Heart failure was found to be a more important cause of death in these patients.

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    Transthoracic Epicardial Catheter Ablation of VT


    The rationale for transthoracic epicardial catheter ablation of VT in studies by Sosa and colleagues was the epicardial location of the reentrant circuit in 15% of VT patients. The routes to the epicardium include surgery, direct visualization through the cardiac veins, and pericardial puncture as introduced by Sosa and colleagues. Pericardial access cannot be used in patients with prior cardiovascular surgery.
     
    The approach used by Sosa and colleagues involved the sub-xiphoid insertion of an epidural needle. The needle position is verified by injecting 1-2 ml of contrast, and also is aided by positioning a catheter in the coronary sinus and prior coronary angiography. In 10% of patients, ventricular perforation occurred. High-quality stable electrograms were obtained in the patients in whom the procedure was successful. Thermal mapping was used; RF pulses of 60 degrees Fahrenheit for 10 seconds, or 30 seconds if VT was interrupted. The major concern was the risk of damage to coronary arteries. Preceding animal studies showed that this risk was significant only when there was less than 12 mm between the site of RF ablation and the coronary artery.  A success rate of 60% was reported, in patients primarily with Chagat’s disease.

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