is inserted via either the left cephalic (cut-down approach) or subclavian vein (percutaneous approach).
The current ICD system generator houses the sensing and output circuitry in a hermetically sealed titanium shell (can). Electrical signals from the rate-sensing dipole of the defibrillator lead are filtered and amplified for an accurate determination of the ventricular rate. Once the ventricular rate exceeds the programmed detection rate, device therapy is initiated (Fig. 4). The shocking energy is stored within capacitors, which are arranged in series allowing the total output voltage to exceed battery voltage. ICD generators are generally implanted in the left pectoral region because the generator serves as an "active" or "hot" can. The "active" can serve as one of the electrodes in the shocking pathway.
The defibrillator lead system consists of either a single- or double-coil silicone insulated lead with the tip positioned in the trabeculated right ventricular apex. The lead typically contains two smaller electrodes (dipole) for ventricular rate sensing, ATP, and bradycardia pacing. It also contains either one (distal only) or two (proximal and distal) shocking coils. In a single coil defibrillator system, the distal coil and generator serve as the sole shocking vector. In a dual-coil lead system, the shocking pathway is triad or bidirectional: from the distal coil to the generator and proximal coil.
Important ICD options which are critical in selected patients include: 1) an additional atrial lead to provide dual-chamber pacing and improved discrimination of SVT from VT and 2) rate-responsive pacing. Table 1 presents the 1998 American College of Cardiology/American Heart Association (ACC/AHA) Task Force Guidelines for ICD implantation (6).
This form of therapy refers to combining device therapy with substrate modification techniques to improve survival and decrease the arrhythmic burden. ICD implantation is effective in terminating recurrent VT and VF, and modifying the substrate can be effective in preventing recurrent episodes of VT. Patients with multiple defibrillator shocks caused by ventricular tachyarrhythmias can be treated with various antiarrhythmic medications. The risk of pro-arrhythmia is lessened because these patients are "protected" by their ICD. When combining antiarrhythmic drug therapy with the ICD, one must anticipate and test for drug effects on tachycardia rate and energy requirement for arrhythmia termination to optimize patient management. Patients with an ICD who have frequent VT can also be safely and successfully treated with catheter mapping and ablative techniques.
The two most common cardiac disorders associated with sustained monomorphic VT are CAD with prior MI (infarct-related VT) and nonischemic dilated cardiomyopathy. Evidence suggests that the underlying mechanism for sustained VT is reentry involving a fixed substrate consisting of normal myocardium interspersed with islands of poorly conducting fibrotic scar (7). The relatively constant revolution time around the circuit coupled with a fixed exit site results in a uniform tachycardia with a relatively stable rate. Predicting which survivors of MI will develop ventricular tachyarrhythmias is difficult, and risk stratification relies upon the identification of variables associated with increased risk. These variables include:
1) left ventricular dysfunction;
2) nonsustained VT (NSVT);
3) inducibility with nonsuppressibility at electrophysiology study (EPS);
4) abnormal signal-averaged electrocardiograms (SAECG);
ACC/AHA Guidelines on Implantation of Implantable Cardioverter-Defibrillators (ICDs)
1. Cardiac arrest caused by VF or VT not resulting from a transient or reversible cause
3. Syncope of undetermined origin with clinically relevant, hemodynamically significant VT or VF induced at EPS when drug therapy is ineffective, not tolerated, or not preferred
4. Nonsustained VT with coronary disease, prior MI, left ventricular dysfunction, and inducible VF or sustained VT at EPS that is not suppressible by a Class I antiarrhythmic drug
Class IIa None
1. Cardiac arrest presumed to be caused by VF when electrophysiological testing is precluded by other medical conditions
2. Severe symptoms attributable to sustained ventricular tachyarrhythmias while awaiting cardiac transplantation
3. Familial or inherited conditions with a high risk for life-threatening ventricular tachyarrhythmias such as long QT syndrome or hypertrophic cardiomyopathy
4. Non-sustained VT with CAD, prior MI, and left ventricular dysfunction, and inducible sustained VT or VF at EPS
5. Recurrent syncope of undetermined etiology in the presence of ventricular dysfunction and inducible ventricular arrhythmia at EPS study when other cause of syncope have been excluded
1. Syncope of undetermined cause in a patient without inducible ventricular tachy-arrhythmias
3. VF or VT resulting from arrhythmias amenable to surgical or catheter ablation; for example, atrial arrhythmias associated with the WPW, RVOT tachycardia, idiopathic left ventricular tachycardia
4. Ventricular tachyarrhythmias caused by a transient or reversible disorder (e.g., AMI, electrolyte balance, drugs, trauma)
Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful, and effective Class II: Conditions for which there is conflicting evidence and/or divergence of opinion about the usefulness/efficacy of a procedure or treatment Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy Class IIb: Usefulness/efficacy is less well established by evidence/opinion Class III: Conditions for which there is evidence and/or general agreement that a procedure/treatment is not useful/effective and in some cases may be harmful
From: Gregoratos G, Cheitlin MD, Conill A, et al. ACC/AHA guidelines for implantation of cardiac pacemakers and antiarrhythmia devices. J Am Coll Cardiol 1998;31:1175-1209.
5) reduced heart-rate variability (HRV); and
Left ventricular function is the most important determinant of post-infarct survival, and most primary prevention studies have included patients with poor left ventricular function (8-11). Infarct survivors with NSVT are at higher risk than patients without ventricular ectopy. NSVT suggests the presence of a functional reentrant circuit capable of initiation, but without manifest sustained propagation of VT. Similarly, electrophysi-ology testing exposes a functional reentrant circuit that may or may not be responsible for the clinical arrhythmia. The ability to induce VT or VF (inducibility) despite procainamide therapy (nonsuppressibility) identifies a subset of patients with NSVT after MI who are at high risk (16). The SAECG identifies areas of slow conduction— a criteria for reentry. Therefore, identification of late potentials is felt to be a risk factor for VT. However, it does not evaluate tissue refractoriness, which is also important for reentry; and therefore does not identify the presence of a viable reentrant circuit. This may partially explain the excellent negative predictive value (absence of slow conduction precludes the presence of a reentrant circuit) but poor positive predictive value (presence of slow conduction is not equivalent to a viable reentrant circuit) in identifying infarct survivors who will develop VT or VF. Reduced HRV and TWA are still under investigation and are widespread clinically. Inclusion criteria of primary prevention studies have used a combination of these risk-stratifying variables, and left ventricular dysfunction is the most important. Several studies have evaluated the effectiveness of ICD therapy in reducing the mortality of infarct survivors.
Primary Prevention for Patients With Prior MI The Role of Antiarrhythmic Drug Therapy in Primary Prevention
The evidence supporting beta-blocker and angiotensin-converting enzyme (ACE)-inhibitor therapy in reducing sudden death after MI is derived from the post-infarct drug trials.
Beta-Blockers. The beneficial effects of beta-blocker therapy in improving survival is partially related to the reduction of sudden cardiac death. The BHAT (Beta-Blocker Heart Attack Trial) Trial was a National Heart, Lung, and Blood Institute-sponsored trial published in 1982, which addressed the efficacy of daily propranolol therapy in reducing all-cause mortality in post-infarct patients (17). Enrolled patients with a documented MI were randomized either to propranolol HCl or placebo. After a mean follow-up of 25 mo in 3,837 patients, total mortality was significantly reduced in the propranolol group compared to placebo (7.2% v. 9.8%, p < 0.005). Subset analysis demonstrated that sudden death was significantly lower in the propranolol group (3.3% vs 4.6%, p < 0.05).
The Norwegian Multicenter Study Group published a trial hypothesizing that timolol therapy reduces mortality in post-infarct patients (18). Enrolled patients with acute MI were randomized to either timolol therapy or placebo. After a mean follow-up of 17 mo in 1884 patients, total deaths, all cardiac deaths, and sudden cardiac deaths were significantly reduced in the timolol group compared to the placebo group (all p < 0.001).
ACE inhibitors. The data on the role of ACE inhibition in the prevention of sudden death in infarct survivors is somewhat disparate. In 1987, the CONSENSUS I (first Cooperative North Scandinavian Enalapril Survival Study) was published, evaluating the effect on mortality of ACE inhibition with enalapril on patients with severe CHF (19). Enrolled patients were randomized to either placebo or enalapril. After a mean follow-up of 188 d in 253 patients, mortality was reduced by 40% (p = 0.002) in the enalapril group compared to placebo. The entire reduction in mortality was attributable to a reduction in deaths caused by progressive heart failure and not sudden cardiac death. Similarly, the SOLVD investigators demonstrated that enalapril reduced mortality compared to placebo in patients with CHF and EF <35%, with the largest reduction occurring in deaths caused by progressive heart failure (20). Enalapril did not significantly affect deaths caused by arrhythmia without pump failure.
In 1991 the V-HEFT II (second Vasodilator-Heart Failure Trial) was published, comparing the effect on mortality of hydralazine/isosorbide dinitrate combination vs enalapril in patients with congestive heart failure (CHF) (21). Enrolled patients with chronic heart failure were randomized to either hydralazine/isosorbide dinitrate or enalapril therapy. After 2 yr of follow-up in 804 patients, mortality was lower in the enalapril arm (p = 0.016), attributable mostly to a reduction in sudden death.
The results of the SAVE (Survival and Ventricular Enlargement) trial suggests that the beneficial effects of ACE inhibitors on infarct survivors may be a reduction in recurrent MI (22). Both the TRACE study (22a) and a recent meta-analysis (22b) suggested that these agents reduce the incidence of sudden death in infarct survivors.
Type 1 antiarrhythmic agents. Complex ventricular ectopy carries an independent risk for infarct survivors. An important question is whether or not suppression of ventricular ectopy reduces mortality and improves survival in these patients. The original CAST (Cardiac Arrhythmia Suppression Trial) trial, published in 1989, was developed to answer this so-called premature ventricular contraction (PVC) hypothesis (23). Inclusion criteria were ventricular ectopy (>6 PVC/h) with reduced left ventricular function post-MI (EF < 40% with remote (>90 d-2 yr) MI or EF < 55% with recent (<90 d) MI). Enrolled patients underwent an initial titration phase to establish an effective antiarrhythmic agent (encainide, flecainide, or moricizine) with documented arrhythmia suppression. Patients then underwent the main phase and were randomized to either the effective antiarrhythmic agent or corresponding placebo. After a mean follow-up of 10 mo in 1498 patients, the use of encainide and flecainide was discontinued because of an increased risk of death or cardiac arrest resulting from arrhythmia associated with the active drugs (RR: 2.64, p = 0.0001). The CAST trial demonstrated that Type 1C antiarrhythmic agents can be harmful to the post-infarct patient—especially those with reduced left ventricular function—and that arrhythmia suppression does not improve survival. Subsequently, a meta-analysis suggested that all Type 1 agents (Na-channel blockers) are detrimental in the primary prevention of post-infarct patients (24).
Type 3 antiarrhythmic agents. The effectiveness of Type 3 antiarrhythmic agents (K-channel blockers) has been studied, and amiodarone has been the drug best evaluated (see Table 2). Besides its direct antiarrhythmic properties, amiodarone also has anti-ischemic and beta-blocking effects. In chronic oral doses, it is not significantly negatively inotropic, and in fact, may improve left ventricular systolic function. Despite its extracar-diac side effects, it is generally well-tolerated in patients with CHF.
In 1990, the BASIS (Basel Antiarrhythmic Study of Infarct Survival) study was published (25). This was a three-arm trial, which hypothesized that amiodarone or another antiarrhythmic agent improved survival over placebo in post-infarct patients with high-grade (Lown 3 or 4B) ventricular ectopy. Enrolled patients were randomized to low-dose amiodarone (200mg/d), individualized antiarrhythmic therapy (initial treatment with quinidine or mexiletine), or placebo. During the 1-yr follow-up in 312 patients, amiodarone was associated with a 61% mortality reduction compared to placebo (p = 0.05). Patients randomized to the antiarrhythmic arm did not demonstrate improved survival compared to placebo.
In 1995, the CHF STAT (Survival Trial of Antiarrhythmic Treatment-Congestive
Heart Failure) trial was published (26). The CHF-STAT trial hypothesized that amiodarone reduces mortality in patients with CHF, EF <40%, and > 10 PVC/h. Enrolled patients were randomized to either amiodarone (300 mg/d) or placebo. Most patients (55%) were New York Heart Association class II. Seventy percent of the patients had ischemic heart disease. After a median follow-up of 45 mo in 674 patients, no difference in mortality was observed between the two treatment groups (p = 0.6). Further analysis demonstrated that amiodarone was effective in suppressing ventricular ectopy (arrhythmia suppression), and that there was a trend toward a reduction in overall mortality in patients with nonischemic cardiomyopathy (p = 0.07).
In 1997, both the EMIAT (European Myocardial Infarction Amiodarone Trial) and CAMIAT (Canadian Myocardial Infarction Amiodarone Trial) trials were published (27,28). The EMIAT trial tested the ability of amiodarone to improve survival in post-infarct patients with EF <40%. Enrolled patients were randomized to either amiodarone (200mg/d) or placebo. After a median follow-up of 21 mo in 1486 patients, no difference in total mortality was observed between the two groups. The CAMIAT trial hypothesized that amiodarone improves survival in post-infarct patients with ventricular ectopy (>10 PVC/h or 1 run of VT). The primary end point was an outcome cluster of arrhythmic death and resuscitated VF. Enrolled patients were randomized to either amiodarone (200 mg/d) or placebo. After a mean follow-up of 1.79 yr in 1202 patients, the amiodarone group was associated with a lower outcome cluster than placebo (0.6% vs 3.3%, (p = 0.16). Concomitant beta-blocker therapy with amiodarone further lowered the outcome cluster. In a meta-analysis of this and other trials evaluating amiodarone in patients with prior MI or CHF showed a survival benefit for amiodarone (28a).
In 1998, the SWORD (Survival With Oral D-Sotalol) trial was published (29). The hypothesis of the trial was that prophylactic administration of oral d-sotalol reduced total mortality in survivors of MI (either recent (6-42 d) MI with EF <40% or remote (>42 d) MI with symptoms of CHF). Enrolled patients were randomized to either sotalol (up to 200 mg twice daily) or placebo. After enrolling 3,121 patients of the planned 6400, the trial was prematurely terminated because of the increased mortality associated with sotalol (5.0% vs 3.1% p = 0.006).
The first primary prevention trial demonstrating improved survival with ICD therapy in patients with CAD was MADIT (Multicenter Automatic Defibrillator Implantation Trial) (16) (see Table 3). Published in 1996, the MADIT trial hypothesized that ICD therapy improves survival over conventional medical therapy in high-risk (EF <35%, asymptomatic NSVT, and inducible, nonsuppressible ventricular tachyarrhythmias). Enrolled patients were randomized to either ICD implantation or conventional medical therapy. After a mean follow-up of 27 mo in 196 patients, 15 deaths were observed in the ICD group compared to 39 deaths in the conventional group (p = 0.009). One criticism of the MADIT trial, however, is that patients randomized to the ICD group were more often on beta-blocker therapy than the conventional group. It has been suggested that the beta-blocker therapy, and not the ICD, conferred the improved survival.
In 1997, the CABG Patch trial was published (30). The CABG Patch trial tested the hypothesis that ICD therapy would improve survival in high-risk (EF<35%, abnormal SAECG) patients undergoing elective coronary-artery bypass grafts (CABG). Enrolled patients were randomized to either ICD implantation or control. After a mean follow-up of 32 mo in 900 patients, no difference was observed in survival between the two groups (p = 0.64). The lack of benefit of ICD therapy may be partly attributable to the poor positive predictive value of the SAECG in identifying patients with CAD who will develop VT or VF, or the improvement in outcome related to coronary revascularization. In fact, in the CABG Patch trial, the ICD did significantly reduce the risk of arrhythmic death, but the proportion of arrhythmic deaths in the trial was too small to cause a difference in overall mortality (30a).
In 1999, the MUSTT (Multicenter UnSustained Tachycardia Trial) trial was published. This trial tested the ability of electrophysiology-guided antiarrhythmic therapy to improve survival in high-risk (EF <40%, asymptomatic NSVT) post-infarct patients (31,32). Enrolled patients underwent a baseline EPS and SAECG. Based upon the results of electrophysiology testing alone, patients were divided into a "low-risk" (noninducible) group and "high-risk" (inducible) group. The low-risk group was observed. The high-risk group was further randomized to either electrophysiology-guided antiarrhythmic therapy or standard (no antiarrhythmic) therapy. The group receiving electrophysiology-guided therapy underwent drug evaluation. Drug respond-ers were observed on drug therapy. Drug nonresponders were eligible for ICD implantation. Data from 704 patients demonstrated a significant reduction in overall mortality for the group randomized to electrophysiology-guided antiarrhythmic therapy as compared to the group receiving no antiarrhythmic therapy. Post-hoc analysis revealed that essentially all the benefit was a result of ICD implantation. Overall 5-yr mortality was 24% for patients receiving defibrillators and 55% for those who did not receive an ICD. The results of the MUSTT trial suggest that ICD implantation is warranted in post-infarct patients who have an EF <40%, asymptomatic NSVT, and inducible ventricular tachyarrhythmias at EPS. Patients who otherwise qualified for MUSTT but were nonin-ducible at EPS were followed in a registry. Although these patients fared better than the inducible patients who received standard therapy, the risk of sudden death was 12% after 2 yr (32a). Thus, the MUSTT registry suggests that although EPS are useful in risk-stratifying these patients, a single negative EPS does not necessary imply very low risk.
Both MADIT and MUSTT demonstrate that ICD therapy can improve survival in selected post-infarct patients with NSVT. Two studies in progress are investigating the role of the ICD in selected post-infarct patients with no documented ventricular arrhythmias (33). MADIT II (Multicenter Automatic Defibrillator Implantation Trial II) attempts to respond to the criticism that the first MADIT was applicable only to a small subset of patients with CAD. In order to broaden the potential applicability of primary prevention, MADIT II is enrolling infarct survivors with EF <30%. Enrolled patients are randomized to either ICD therapy or to a control group. Patients randomized to the ICD group undergo baseline device-based electrophysiology testing at the time of implant to assess the predictive value of the EPS in these patients. All patients also undergo postrandomization noninvasive risk assessment using SAECG, HRV, and TWA. SCD-HeFT (Sudden Cardiac Death-Heart Failure Trial) is a randomized, prospective, three-arm trial comparing ICD therapy, amiodarone, and placebo in patients with either ischemic or nonischemic cardiomyopathy (EF <35%, Class II, or III CHF). The results of this trial will hopefully define the role of both ICD and amiodarone therapy in high-risk patients with no "visible" arrhythmic risk and various etiologies of heart failure. Finally, the studies will suggest whether or not the ICD may serve as a bridge to cardiac transplantation in high-risk patients with ischemic cardiomyopathy and advanced CHF who can await heart transplantation from home.
Summary of Primary Prevention for Patients With Prior Myocardial Infarction
ICD therapy has been shown to be beneficial in the primary prevention of selected high-risk post-infarct patients (Table 2) (34-36). All such patients have significantly reduced left ventricular function and documented ventricular ectopy. It remains to be determined whether or not the ICD will be beneficial for patients with left ventricular dysfunction and no documented arrhythmia. Evidence suggests that suppression of PVC's with type 1 antiarrhythmic therapy does not improve survival. Post-infarction beta-blocker therapy reduces sudden death and improves mortality. ACE inhibitors improve survival and possibly sudden death in post-infarct patients with left ventricular dysfunction and CHF. The beneficial effects of prophylactic amiodarone in the post-infarct patient have not been firmly established (Table 3). It may have a more beneficial role in the primary prevention of arrhythmias in patients with nonischemic dilated cardiomyopathy.
Primary Prevention for Patients With Nonischemic Dilated Cardiomyopathy The Role of Antiarrhythmic Drug Therapy in Primary Prevention
In 1994, the GESICA (Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina) trial was published (37). The GESICA trial hypothesized that low-dose amiodarone (300 mg/d) would improve survival in patients with severe CHF (Class II-IV CHF, EF <35%). Enrolled patients were randomized to either amiodarone or placebo. Approximately 38% had a prior MI, and 10% had Chagas disease. After a mean follow-up of 2 yr in 516 patients, amiodarone was associated with a 28% mortality reduction compared to placebo (33.5% deaths vs 41.6% deaths (p = 0.024). However, mortality in both groups remained high. The results of the GESICA and CHF-STAT trial suggest that amiodarone may be effective in reducing mortality in patients with nonischemic cardiomyopathy (26,37).
Data evaluating the effectiveness of ICD therapy on the primary prevention of patients with nonischemic dilated cardiomyopathy is scarce. Several trials are currently under investigation to answer this issue. The SCD-HEFT trial has been previously mentioned (33). The ongoing DEFINITE trial hypothesizes the ICD therapy will improve survival in patients with nonischemic cardiomyopathy (EF <35%, symptomatic CHF) and NSVT or >10 PVC/h). Enrolled patients are randomized to either ICD therapy with conventional heart-failure treatment or conventional heart-failure treatment alone. The primary end point is overall mortality (37a).
Summary of Primary Prevention for Patients With Nonischemic Dilated Cardiomyopathy
The role of ICD therapy is unclear, but is under investigation. Amiodarone therapy may be more effective in reducing overall mortality compared to patients with ischemic heart disease.
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