Arrhythmias Focused Review. Sustained Ventricular Tachycardia in Ischemic Cardiomyopathy: Current Management

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1 Sustained Ventricular Tachycardia in Ischemic Cardiomyopathy: Current Management Matthew R. Reynolds, MD, MSc, and Mark E. Josephson, MD, Beth Israel Deaconess Medical Center, and Veterans Affairs Health Care System, Boston, Massachusetts Ventricular tachyarrhythmias are a major cause of morbidity and mortality among patients with left ventricular (LV) dysfunction following myocardial infarction (MI). Fortunately, several effective modalities of therapy are now available to manage this problem. This review examines currently available management options for sustained ventricular tachycardia (VT) in patients with previous MI. Terminology Arrhythmias Focused Review Although widely invoked, we believe the term ischemic cardiomyopathy is imprecise and often inappropriately applied, and that its use should be discouraged. This is not only because the term is both without uniform definition and semantically contradictory as cardiomyopathy refers to a primary disease of cardiac muscle, not arterial supply but also because the term often leads to improper assumptions regarding the mechanisms and management of ventricular arrhythmias. In our experience, many patients with coronary artery disease and LV dysfunction are labeled as having ischemic cardiomyopathy despite having no evidence of previous MI or only a small, discrete infarction. In these cases, severe LV dysfunction likely results from some other disease process, often chronic hypertension, which may have implications for the risk, nature, and management of arrhythmias. Indiscriminate use of the term ischemic cardiomyopathy also leads to an overemphasis on the role that acute ischemia plays in triggering certain ventricular arrhythmias, most notably sustained monomorphic ventricular tachycardia (MMVT). For example, we believe coronary angiography, often performed reflexively, is overutilized in the assessment of patients who present with stable MMVT particularly in cases when the patient s coronary anatomy has been previously defined. Furthermore, though ischemia certainly plays a crucial role in the genesis of malignant arrhythmias and sudden death, the ability of revascularization to prevent subsequent ventricular arrhythmias in patients with preexisting, fixed LV dysfunction is limited, as shown in multiple series including the AVID (Antiarrhythmics Versus Implantable Defibrillators) registry. For all these reasons, we believe the term ischemic cardiomyopathy should be reserved for patients whose LV dysfunction can be clearly attributed to prior infarction or abandoned altogether. A clearer approach would be to categorize patients as having LV dysfunction due to previous infarction(s), to nonischemic heart disease, or to both in practice we refer to the latter group has having mixed myopathy. Pathophysiology of VT in Ischemic Heart Disease The pathophysiology of VT in association with prior MI has been explored in numerous mapping and necropsy studies in animals and humans, and it has been reviewed elsewhere previously. These studies have established reentry as the predominant electrophysiological mechanism responsible for this type of VT. Viable, electrically active bundles of myocytes embedded in or adjacent to areas of dense scar have been shown to create complex regions of slow conduction, with either fixed or functional areas of block, creating the propensity for reentry to occur (Figure 1). Anatomical conduction barriers, such as dense scar or the mitral annulus, also influence the geometry of VT circuits. Sustained MMVT in patients with healed MIs therefore typically results from a relatively fixed arrhythmic substrate, although aspects of the initiation and perpetuation of the rhythm may be functional. When such a substrate is present, acute ischemia is not necessary for the induction of MMVT, nor is treatment of ischemia sufficient therapy for management. Polymorphic VT (PMVT) and Ventricular fibrillation (VF), owing to their unstable nature, are less amenable to mapping in humans; thus, mechanistic studies have been performed primarily in animals and in isolated preparations of myocytes, myocardial wedges, or whole hearts. Acute ischemia is believed to be the primary trigger for PMVT and VF that take place in the absence of congenital or acquired long-qt syndrome or other less common genetic conditions. Ischemia induces regional changes in tissue ph and extracellular potassium concentration. These perturbations have been shown to create areas of conduction slowing and block as well as heterogeneity in repolarization with the creation of transmural electrical gradients. Loss of the I to -mediated action potential dome in the epicardium has recently been shown to predispose to Phase 2 reentry, which appears to be one major mechanism underlying PMVT and VF in acute ischemia. Recent studies also support the hypothesis that VF can be induced without ischemia owing to the emergence of functional arcs of block located near scars leading to spiral-wave reentry. Other mechanisms of PMVT have also been reported. One group has focused on the importance of ectopic beats arsing from Purkinje fibers at the border zone of chronic infarctions as a trigger for PMVT. 63

2 Figure 1. Anatomic specimen demonstrating the typical pathologic substrate for ventricular tachycardia with prior myocardial infarction. Muscle bundles embedded in or at the edges of dense scar create the propensity for reentry. Mapping and anatomic pathology data suggest that most of these circuits are subendocardial (layers a d), but, as shown, are complex and may involve mid-myocadial or even epicardial layers as well. Emergency Management of Sustained VT Unstable VT Emergency management of sustained VT should generally follow the Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care published by the American Heart Association, most recently updated in The first and most crucial step in the initial management of sustained VT is the assessment of patient stability. In general, the stability of a rhythm is a function of the patient s underlying cardiac status and the rate of the rhythm. Ventricular tachycardia at rates below 150 beats/ min is frequently well tolerated, whereas VT at rates above 200 beats/min are usually unstable. Whenever possible, 12-lead electrocardiograms (ECGs) should be obtained and analyzed before beginning therapy. Acutely unstable patients as evidenced by altered consciousness, severe hypotension, chest pain or respiratory compromise, or other signs of significant end-organ hypoperfusion require prompt electrical cardioversion. Organized tachycardias should always be cardioverted with shocks synchronized to the QRS complex; VF must be shocked asynchronously. Historical guidelines with monophasic defibrillation waveforms suggested initial starting energies of 200 J for external cardioversion, with escalating energies on successive shocks up to the usual maximum of 360 J. Recent studies with biphasic external defibrillators suggest similar efficacy with repeated 150 J biphasic shocks compared with escalating monophasic shocks. We tend to favor higher, rather than lower, initial energies; there is no compelling evidence that higher initial energies lead to adverse patient outcomes, whereas lower energies can delay termination of the rhythm or even destabilize organized rhythms (Figure 2). Most hospitals continue to stock manual external defibrillators; that is, interpretation of rhythms and decisions about therapy are controlled by the operator. However, automated external defibrillators (AEDs) are being used with increasing frequency in a variety of public settings. The accuracy of AED rhythm interpretation and the success of AED defibrillation have been shown to be excellent, and AEDs have the advantage of simple and efficient operation that can be safely performed with minimal training by nonmedical personnel, including police, fire, and layperson first-responders. Many ambulance and fire crews and some hospitals are therefore replacing their older defibrillators with AEDs, some of which can also be operated in a manual mode. Patients who are refractory to multiple attempts at external cardioversion, or who have incessant/recurrent VT, should be treated with intravenous (IV) amiodarone, based on the results of the ARREST and ALIVE trials, which proved this agent to be superior to placebo and lidocaine, respectively. Nonrandomized data collected on patients with VT storm also support the use of IV beta-blockers for this situation. Although IV epinephrine has long been part of resuscitation guidelines, in part because of its property of lowering the defibrillation threshold, IV vasopressin was added to the published algorithms in 2000 as an alternative vasoconstrictor. Data published after the 2000 guidelines suggest that vasopressin may be a safer choice in patients with recurrent, unstable VT/VF. Stable VT Patients presenting with stable MMVT offer a few treatment options. External cardioversion of stable VT is safe and effective. In addition to the issues raised above, particular attention should be paid to adequate sedation in a stable patient. Occasionally, patients with implantable cardioverter-defibrillators (ICDs) present with well-tolerated VT that may be slower than the programmed detection limit of the device, and therefore not automatically treated. In these cases, manual antitachycardia pacing is an effective intervention that can avoid the risks and limitations of other therapies. Surprisingly, few well-conducted studies have been performed to evaluate the efficacy of antiarrhythmic drugs in 64

3 Figure 2. A patient with sustained monomorphic ventricular tachycardia is externally cardioverted with a synchronized, low-energy (50 J) monophasic shock. This low-energy shock results in ventricular fibrillation. terminating stable MMVT. Current guidelines are therefore influenced by studies of antiarrhythmic drugs in unstable VT/VF. Though historically favored and typically well tolerated in the acute setting, IV lidocaine appears to be ineffective at terminating sustained MMVT, converting the rhythm in only 10 20% of patients in nonrandomized series. Two small randomized studies showed that both IV sotalol (not available in the U.S.) and IV procainamide were 3 4 times more effective than lidocaine in terminating stable VT. Current guidelines recommend IV procainamide as an option for sustained wide-complex tachycardias if LV function is preserved. We are not aware of any large studies documenting the efficacy of IV amiodarone at terminating stable, sustained MMVT. One series reported a 40% success rate with IV amiodarone, at doses of 1050 or 2100 mg infused over 24 h, in unstable patients with incessant VT/VF who had failed lidocaine, procainamide, and bretylium. Based on the potential for pro-arrhythmia, vasodilation, and negative inotropy associated with class I antiarrhythmic drugs, current guidelines suggest using only IV lidocaine which is ineffective but probably safe or amiodarone for stable, sustained VT in the setting of significant LV dysfunction (EF [ejection fraction] 40% or clinical heart failure). In our experience, IV procainamide can be used safely in the presence of LV dysfunction, but this requires judgment and careful supervision. Intravenous amiodarone also causes vasodilation, which can exacerbate underlying sinus node dysfunction or conduction system disease. Secondary Prevention of Sustained VT Implantable Cardioverter-Defibrillators In the past decade, ICDs have become firmly established as the first-line therapy for survivors of unstable ventricular arrhythmias; the use of ICDs for primary prevention in high-risk patients continues to expand as well. The ICDs offer an opportunity for antitachycardia pacing, which can terminate as many as 70 80% of VT episodes, and for automatic defibrillation, which can now be completed in a few seconds. The therapeutic efficacy of ICDs in terminating VT/VF therefore exceeds 95%. The evidence in favor of using ICDs for secondary prevention of VT comes from three randomized clinical trials summarized in Table 1, all of which enrolled a substantial proportion of patients with ischemic heart disease and prior infarctions. These studies randomized both survivors of VF or poorly tolerated VT, and also patients with unexplained syncope and structural heart disease, to ICD implantation or drug therapy, primarily with amiodarone. Each showed a 20 30% reduction in all-cause mortality with ICD implantation, although only in AVID was the difference statistically significant. The three trials, taken together, support the use of ICDs for secondary prevention. Posthoc analyses of the AVID and CIDS trials have shown that patients with reduced LV function and symptomatic heart failure derive a larger clinical benefit than do patients with normal LV function and/or no heart failure. Patients with prior MI and well-tolerated VT were not enrolled in any of the secondary-prevention ICD trials; therefore, ICD implantation in this circumstance has never 65

4 Table 1. Major Randomized Trials of ICDs for Secondary Prevention of Ventricular Arrhythmias Trial N Population Follow-up (Months) Therapy Total Mortality Comment AVID (1997) 1016 Near fatal VF, poorly tolerated VT, or unexplained syncope with EF 40% CIDS (2000) 659 Prior cardiac arrest or hemodynamically unstable VT CASH (2000) 407 Prior cardiac arrest and documented ventricular arrhythmias 36 ICD vs. antiarrhythmic drugs 25% mortality (ICD) vs. 36% (medical), RR 31% (p 0.02) 60 ICD vs. amiodarone 8% (ICD) vs. 10% mortality (medical), RR 20% (p NS) 57 ICD vs. amiodarone vs. metoprolol vs. propafenone 36% (ICD) vs. 44% (amiodarone/metoprolol), RR 23% (p 0.081) Mortality benefit was seen particularly in those with EF 20 34% 50% risk reduction in those with LVEF 35%; age 70; and NYHA class III or IV (p ) Interim analysis showed a 61% higher all-cause mortality rate in propafenone arm, which was discontinued AVID Antiarrhythmics Versus Implantable Defibrillators trial; CIDS Canadian Implantable Defibrillator Study; CASH Cardiac Arrest Study, Hamburg; VF ventricular fibrillation; VT ventricular tachycardia; ICD implantable cardioverter-defibrillator; RR relative risk; EF (left ventricular) ejection fraction; NYHA New York Heart Association class. been shown to improve survival and cannot be expected to prevent VT recurrence. Alternative therapies, such as antiarrhythmic drugs or VT ablation, could yield similar or even better clinical results. Further study is required. Because the mode of action of ICDs is therapeutic rather than preventative, patients with frequent recurrences of VT and VF often require additional therapies to avoid adverse events such as syncope or painful shocks. One important modality that may be underutilized particularly as more ICDs are implanted by nonelectrophysiologists is antitachycardia pacing (ATP). The efficacy of ATP can be assessed in the electrophysiology (EP) laboratory before, during, or after ICD implantation through programmed stimulation during a standard EP study, or through noninvasive programmed stimulation (NIPS) using a previously implanted device. Recent data have also shown that empirically programmed ATP is highly effective even for relatively fast VT in patients with no prior history of sustained VT. Antiarrhythmic Drugs With the current ease of implantation and wider availability of ICDs, antiarrhythmic drugs have moved from the principal means of preventing and controlling VT to an ancillary role in preventing frequent device therapies. This is in part due to the poor performance of antiarrhythmic drug therapy in numerous clinical trials. In both primary- and secondary-prevention studies, multiple class I antiarrhythmic drugs (particularly the class IC drugs) and d-sotalol were shown to increase mortality compared with placebo. Oral amiodarone did reduce arrhythmic mortality in several large, randomized, and primary-prevention trials, but its effects on total mortality have been neutral in most cases. Amiodarone (and a mixture of class I drugs) was associated with higher all-cause mortality than ICD therapy in the CASH, CIDS, AVID, MUSTT, and MADIT studies, although the differences did not reach statistical significance in all cases, and beta-blocker use was imbalanced in several of these trials. Most recently, amiodarone was equivalent with placebo, and inferior to ICDs, on the endpoint of total mortality in a mixed population of ischemic and nonischemic cardiomyopathy patients with EFs 35% studied in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Despite their inferiority with respect to total mortality when compared with ICDs, antiarrhythmic drugs are moderately effective at suppressing both inducible and spontaneous VT. Oral amiodarone appears to be the most effective drug, with historical studies suggesting 50 60% efficacy in preventing VT recurrences. Chronic amiodarone therapy is associated with a well-known incidence of noncardiac toxicities, for which careful screening and follow-up are required. Class III antiarrhythmic drugs also have some efficacy in suppressing VT. In a recent randomized study, both oral d,l-sotalol (160 mg bid) and dofetilide (500 g bid) suppressed the inducibility of VT in about 35% of patients. Either of these drugs is a reasonable option in patients intolerant of amiodarone, or in whom the desire to avoid amiodarone toxicity is strong. Both drugs are renally cleared and can cause pro-arrhythmia through QT prolongation. Dofetilide also has a number of important drug drug interactions, but has a larger body of safety data for use in patients with prior MI and/or symptomatic heart failure than does sotalol. Class IA antiarrhythmic drugs have largely fallen out of favor because of side effects, the risk of pro-arrhythmia, and the availability of better options for many patients. There is reason to believe, based on the ESVEM trial, that d,l-sotalol may be more effective than class I agents at suppressing recurrent VT, although this may be due in part to its beta-blocking properties. Nonetheless, class IA agents such as procainamide and quinidine are also associated with a roughly 30% success rate in suppressing inducible VT, and 66

5 Table 2. Selected Series of VT Ablation in Patients With Prior Myocardial Infarction Investigators N Indication Ablation Technique Acute Success Long-Term Success Complications Morady et al. (1993) Gonska et al. (1994) Strickberger et al. (1997) Rothman et al. (1997) Stevenson et al. (1998) Callans et al. (1998) Calkins et al. (2000) Marchlinski et al. (2000) 15 Hemodynamically stable MMVT 136 Single documented MMVT, failed AAD 21 Frequent ICD Rx for VT despite AAD (mean 34 Rx in 36 days) 35 Recurrent tolerated MMVT Standard RF; mapping of stable VT 80% of VTs in 73% of patients DC 64, RF 72 75% 16% recurrence over 2 years Standard RF; mapping during VT Standard RF of mappable VTs 52 Tolerated VT RF for all inducible & mappable VTs targeted 66 Recurrent sustained VT despite ICD/ AAD 146 Sustained, stable VT, failed AAD 16 Fast, nontolerated VT Standard RF of mappable VTs Saline-irrigated RF ablation (4 mm) Standard RF with linear lesions based on substrate mapping 76% (clinical VT) 78% (induced & targeted VTs) 86% (clinical VT), 31% completely noninducible 71% effective ; 40% completely noninducible 58% clinical VT ablated; 85% of inducible VTs ablated 75% mappable VT; 41% noninducible Frequency of ICD Rx 2 99% over 1 year; 50% had 1 recurrent Rx 9% recurrence in noninducibles; 47% in inducible, nonclinical over months 67% free of VT over 3 years 46% recurrence of any VT in 8 months 75% VT-free over 3 36 months None 12% AV block (n 1) AV block (n 2); femoral access (n 3) Femoral access (n 1) TIA (n 1) MI, death (n 1) Tamponade (n 2) TIA (n 1) 8% major (4 stroke/tia; 4 tamponade; 2 AV block); 4 deaths CVA (n 1) MMVT monomorphic ventricular tachycardia; ICD implantable cardioverter-defibrillator; AAD antiarrhythmic drug; VT ventriculartachycardia; RF radiofrequency; DC direct current; AV atrioventricular; TIA transient ischemic attack; MI myocardial infarction; CVA cerebrovascular accident. may play a role in preventing device therapies in selected patients. Finally, the class IB drugs lidocaine and mexiletine can be safely used in combination with other medications (e.g., class III drugs or amiodarone) for suppression of VT in difficult cases. Intravenous lidocaine should only be used for short durations. Ablative Therapy The concept of ablative therapy for recurrent MMVT was originally explored with the use of VT surgery before the advent of catheter-based ablation. The lack of predictable success in controlling VT with classical aneurysmectomy led to the development of mapping techniques to define VT circuits and guide subendocardial resection. Concepts developed during map-guided VT surgery paved the way for current catheter-based techniques. Over time, catheter-based ablation using percutaneous techniques has become a good option for the treatment of recurrent VT, without the morbidity of open-heart surgery. To date, no major randomized trials of VT ablation have been completed, but a number of single and multicenter series have been reported, as summarized in Table 2. Most of these series have involved either patients with a single predominant, tolerated clinical VT, or patients with incessant VT, often triggering numerous ICD therapies. Results have been fairly consistent, with most series reporting 70 80% success rates in elimination of the presenting clinical rhythms, typically associated with a major reduction in the subsequent burden of device therapies. Complication rates have been generally acceptable, although a small number of major adverse events, including tamponade, stroke, atrioventricular block, and death, have been reported. Ablation is less frequently able to eliminate all inducible VTs; owing to their complex arrhythmic substrates, a substantial proportion of patients have recurrent VT, often of different morphologies, despite acutely successful procedures. Nonetheless, the need to ablate all fast, nonclinical VTs induced in patients who have successful ablation of a slow, tolerated clinical VT has not been established. Thus, ablation of a tolerated clinical VT, and of other inducible VTs that share a common isthmus, may be a reasonable option as sole initial therapy in some patients. Some exciting innovations have recently been applied to overcome some of the limitations of VT ablation and improve its effectiveness. Many patients have fast, poorly tolerated VTs that preclude mapping using traditional methods requiring a stable, sustained rhythm. Substrate 67

6 mapping where areas of dense scar, areas with abnormal (low in amplitude, prolonged in duration, and fractionated ) local electrograms, and late potentials are delineated during sinus rhythm with 3-dimensional mapping systems has been used to direct empiric ablation attempts with some success. Noncontact mapping, which allows for rapid localization of transient rhythms, has also been reported to be of use in particular patients. Several groups have also reported favorable initial results with the use of epicardial mapping and ablation, using a subxyphoid approach, for patients in whom endocardial ablation has failed. Evolving catheter technologies (e.g., saline irrigation) may also improve the success of VT ablation in the future. Conclusions Despite great advances in the prevention and treatment of coronary artery disease, sustained VT in the setting of a previous MI remains a common and serious clinical problem. Provided that patients quickly reach medical attention, available therapies are associated with a high and improving likelihood of success. With an aging population, a growing number of MI survivors, and rising incidence of ICD implantation, understanding of these management options will become increasingly important for all cardiologists. Questions and Answers 1. What is the most common mechanism of sustained ventricular tachycardia in patients with prior myocardial infarction? Reentry in/around scar. 2. What is the recommended starting energy for external cardioversion/defibrillation of ventricular tachycardia or fibrillation? Not less than 200 J monophasic or 150 J biphasic. Higher starting energies are acceptable/encouraged. 3. What is the probability of terminating sustained, welltolerated monomorphic VT with intravenous (IV) lidocaine? Procainamide? Lidocaine terminates monomorphic VT about 10 20% of the time. We are not aware of studies comparing it with placebo in this circumstance. In a series where patients with stable monomorphic VT were randomized to IV lidocaine or procainamide, initial success with lidocaine was only 20% (3 of 15 patients) but was 80% for procainamide (12 of 15 patients). 4. What is the most effective antiarrhythmic drug for preventing recurrent monomorphic VT? This question has never been adequately addressed. In the ESVEM trial (see Klein RC, Eur Heart J 1993;14 Suppl H:78 84) oral d,l-sotalol appeared to be more effective than a variety of class I agents, but the study was not designed with that as a primary hypothesis. Amiodarone is probably the most effective drug for this indication, but has not been studied head-to-head with sotalol or dofetilide. 5. A patient is receiving numerous ICD shocks because of recurrent monomorphic VT, despite antiarrhythmic drug therapy. What is the likelihood of controlling the patient s clinical VT with catheter ablation? First, be sure that the patient s ICD is programmed to deliver antitachycardia pacing, which can painlessly terminate the majority of VT episodes without requiring shocks. As outlined in Table 2, typical series have reported 70 80% acute success rates in treating the predominant clinical VTs. Suggested Reading The Antiarrhythmics Versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997;337: Delacrétaz E, Stevenson WG. Catheter ablation of ventricular tachycardia in patients with coronary heart disease. Part II: Clinical aspects, limitations, and recent developments. Pacing Clin Electrophysiol 2001;24: Dorian P, Cass D, Schwartz B, Cooper R, Gelaznikas R, Barr A. Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation. N Engl J Med 2002;346: Gorgels AP, van den Dool A, Hofs A, et al. Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Am J Cardiol 1996;78:43 6. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Part 6: Advanced cardiovascular life support; section 2: defibrillation. Circulation 2000;102 Suppl I: I Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Part 6: Advanced Cardiovascular Life Support; section 5: pharmacology I: Agents for Arrhythmias. Circulation 2000;102 Suppl I: I Lee DS, Green LD, Liu PP, et al. Effectiveness of implantable defibrillators for preventing arrhythmic events and death. J Am Coll Cardiol 2003;41: Mehta D, Curwin J, Gomes JA, Fuster V. Sudden death in coronary artery disease: acute ischemia versus myocardial substrate. Circulation 1997;96: Address correspondence and reprint requests to Mark E. Josephson, MD, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA