- Email: [email protected]
Who Are the MADIT Patients?
Who Are the MADIT Patients? Steven L. Higgins,
MD,
James L. Daubert,
ways the most important part of a sympoIwithnsiummany comes at the end, during a discussion session, the presentation and discussions among the panel and the audience of real patient cases and physician decisions on patients —in this case, those patients, seen in any cardiology practice, who resemble the “Multicenter Automatic Defibrillator Implantation Trial (MADIT) profile.” It is clear that it will be a challenge for the medical community to bring these patients in to provide the needed benefit, and hopefully the following discussions will highlight and clarify for everybody the challenges and problems presented by this important subset.
CASE 1 A 77-year-old automobile dealership manager had an inferior myocardial infarction (MI) in 1983. One year later, flecainide was initiated for asymptomatic ventricular ectopy. In 1991, the flecainide was discontinued due to unexplained dizzy spells and because of results reported in the recent Cardiac Arrhythmia Suppression Trial (CAST) study.1 He was hospitalized in August 1996 with chest pain, although an acute infarction was excluded. Telemetry monitoring revealed 5 beats of nonsustained ventricular tachycardia (NSVT). The patient was referred to another hospital for angiography, the results of which revealed a left ventricular ejection fraction (LVEF) of 0.25 and complete occlusions of both the right and left anterior descending coronary arteries. An adenosine cardiolite study revealed no evidence for active ischemia. The cardiologist referred the patient for a screening electrophysiologic (EP) study based on the MADIT criteria (Table I). Medications included aspirin, nifedipine, atenolol, and topical nitrates. The EP study results revealed normal conduction characteristics, but reproducibly inducible sustained ventricular tachycardia (VT) (cycle length, 290 msec) with double premature stimuli (S1S2S3). It was terminated with burst pacing. With triple stimuli, ventricular fibrillation (VF) was induced that required defibrillation. The VT was still inducible, although minimally slowed (cycle length, 315 msec) after 1,000 mg of intravenous procainamide. Again, it was pace terminated. The patient was referred for an implantable defibrillator, having met all of the MADIT inclusion criteria without exclusions. A CPI Ventak Mini II (CPI/ Guidant, St. Paul, MN) was inserted the same day. The patient was discharged ,24 hours after an uneventful postoperative course. At 3 months after imFrom the 1996 American Heart Association Meeting, New Orleans, Louisiana. Address for reprints: Masood Akhtar, MD, Milwaukee Heart Institute, 960 North Twelfth Street, Milwaukee, Wisconsin 53201-6342.
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©1997 by Excerpta Medica, Inc. All rights reserved.
MD,
Masood Akhtar,
MD
plant, the patient had an asymptomatic presentation of sustained VT, successfully terminated on the first attempt with antitachycardia pacing. Interrogation of the device confirmed a monomorphic VT (cycle length, 300 msec, 200 beats/min). Brief discussion of case 1: This presentation is relatively straightforward, as the patient meets all MADIT criteria. This case supports the MADIT study finding that the index MI is quite often remote from the presenting arrhythmia. Although the referring hospital transferred the patient for angiography, not EP evaluation, the accepting cardiologist had knowledge of the findings of the MADIT studies and initiated the referral for screening. As there was little need for delay, the device was inserted and the patient discharged with a minimum of excess cost. The presentation of device therapy early after implant also underscores another interesting MADIT finding—20% of patients enrolled in the study had a clinical shock by 3 months, and 60% had a shock by the second year. This is comparable to the frequency of therapy observed in patients undergoing an implanted cardioverter defibrillator (ICD) procedure for cardiac arrest and other symptomatic presentations.2 Dr. Masood Akhtar: This case points up an important question: in the MADIT study, drug testing was done as part of the protocol. Now, in actual clinical practice, realizing the limited value of drug treatment for such a patient, is there a value in doing serial drug testing? Dr. Steven L. Higgins: I cannot tell you when I last did serial drug trials in anybody long term; adding an intravenous drug at the time of the initial study is kind of an independent process. I frequently do it in patients with inducible VF, as Mark Josephson showed years ago, which will bring out the monomorphic VT and may well turn out later to be the patient’s clinical arrhythmia. So, procainamide does have value in that regard. At the present time, I am still following the MADIT criteria and doing the drug evaluation because it is relatively easy and inexpensive to do, but I have not been faced with the situation where a patient who was given intravenous procainamide was no longer inducible. I too would be uncomfortable in sending that patient home. I think such patients are still in the high-risk group. Dr. Akhtar: May I ask, how many in the audience would go through conventional therapy in the event the VT was induced, but suppressed with intravenous procainamide? (Many hands up...) So, it seems that a lot of people are still not certain what to do in this situation. Suppression of inducible VT with procainamide does not necessarily mean the patient is at low risk, and we know that drug therapy has not been particularly helpful overall in high-risk populations. 0002-9149/97/$17.00 PII S0002-9149(97)00624-3
TABLE I MADIT Trial Entry Criteria MADIT inclusion criteria Y $3 weeks after most recent MI Y LVEF #0.35 Y nonsustained VT ($3 beats) Y NYHA class I–III Y Inducible into sustained VT with up to triple stimuli or sustained VF with double stimuli Y VT/VF not suppressible with intravenous procainamide MADIT exclusion criteria Y Clinical sustained VT or VF Y Syncope Y Recent MI (#3 weeks) Y CABG within 2 months Y PTCA within 3 months Y Active ischemia Y Significant comorbidity CABG 5 coronary artery bypass graft; LVEF 5 left ventricular ejection fraction; MADIT 5 Multicenter Automatic Defibrillator Implantation Trial; MI 5 myocardial infarction; NYHA 5 New York Heart Association; PTCA 5 percutaneous transluminal coronary angioplasty; VF 5 ventricular fibrillation; VT 5 ventricular tachycardia.
So I am wondering, what are the options in such patients? Dr. Robert Myerburg: The question is, how many in the audience would go through serial drug testing, let’s say perhaps with oral sotalol, if the VT was inducible? (A few hands up...) Would you go through .1 testing? Anyone? The audience response indicates that few would go on to serial drug testing after failure of the first testing.
CASE 2 This 53-year-old male had had a prior inferior Q-wave MI. A 3-beat run of VT was noted on a 24-hour Holter monitor in 1994. He reported some episodes of very brief dizziness (but denied syncope) and had not had a prior cardiac arrest or episode of sustained VT. His LVEF was determined to be 0.30 by echocardiogram. A thallium-201 stress test revealed an inferior–posterior defect, which was fixed, and no significant ischemic, reversible defect. Coronary angiography on August 22, 1994, showed a 70% stenosis of the right coronary artery, 70% stenosis of the circumflex artery, 100% occlusion of the OM2 branch of the circumflex, and mild irregularities of the left anterior descending coronary artery. Ventriculography showed 11 mitral regurgitation and an LVEF of 0.35. On September 15, 1994, diagnostic EP testing was performed because of NSVT and ischemic cardiomyopathy. The results showed inducible sustained monomorphic VT (cycle length, 270 msec) after an intravenous infusion of procainamide, and sustained monomorphic VT remained inducible (cycle length, 270 msec). The patient met MADIT criteria, signed informed consent, and was randomized to the conventional treatment arm, after which amiodarone loading was begun at a dose of 1,200 mg/day for 5 days. He was discharged on a dose of 600 mg/day for 2 weeks. However, .2 weeks after discharge, the dose of amiodarone had to be reduced to 300 mg/day due to
tremor and fatigue. In March 1995 (6 months later), the patient had a sudden syncopal episode (while still taking amiodarone, 300 mg daily). He was observed to have a pause of 2–3 seconds duration with carotid sinus massage in his cardiologist’s office. He was referred for repeat EP testing, which showed inducible sustained monomorphic VT (cycle length, 220 msec) with double ventricular extrastimuli; the HV interval was normal and no other etiology for his syncope (other than VT) was found. Therefore, he was crossedover to ICD treatment (although for survival analysis, he remained in the conventional treatment arm of MADIT). While awaiting ICD implantation, the patient had recurrent, crescendo transient ischemic attacks, was found to have ipsilateral carotid stenosis, and underwent carotid endarterectomy. After the endarterectomy, he had a brief episode of apparent asystole, while on telemetry, with near syncope. A probable pulmonary embolus was diagnosed after ICD implantation, by severe hypoxemia, and a high-probability perfusion lung scan. Finally, after his ICD implantation, he has done well and has had an appropriate detection of spontaneous VT (at 200 beats/min). Peripheral vascular disease has since been noted, with symptoms of claudication. Brief discussion of case 2: This patient illustrates application of the eligibility criteria for the MADIT study, which included NSVT, an LVEF ,0.36, prior MI, and inducible sustained monomorphic VT, the inducibility of which is not suppressible with intravenous procainamide. He was treated with amiodarone (in the conventional arm of MADIT) and experienced side-effects, which were manageable. However, he had a syncopal episode, underwent repeat EP testing, and was crossed-over to ICD therapy. (However, the MADIT study was analyzed on the basis of intentionto-treat, and thus for survival analysis this patient remained in the conventional arm.) The possible comorbidities of patients with ischemic cardiomyopathy and severe arrhythmias are illustrated well by this patient, who manifested MI, mild congestive heart failure, syncope, inducible and spontaneous VT, possible bradyarrhythmias, carotid stenosis and transient ischemic attacks, pulmonary embolus, and claudication. He is representative of the conventional treatment arm in that most patients were treated with amiodarone; this agent did have to be stopped in some patients whose side-effects were, perhaps, even more significant than those noted in this patient. He is unusual in being one of several who crossed-over to ICD therapy. Dr. Masood Akhtar: Is it true that the MADIT study recruitment process starts 3 weeks post MI? Dr. James L. Daubert: Yes. Dr. Akhtar: Do you think that a patient who has an event—let’s say 2 weeks after MI—is comparable, or would you ignore that? We know that this is not part of the MADIT data, but I would think such a case presents even higher risk. Dr. Daubert: Yes, I think that in generalizing the MADIT results cautiously, those are appropriate comments. Dr. Higgins and I, and others, have all strugA SYMPOSIUM: MADIT
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gled with patients just as you mentioned, who were less than the time cutoff after a percutaneous transluminal coronary angioplasty (PTCA), bypass surgery, or MI. Those exclusions were in the MADIT protocol due largely to the fact that initially such patients would have received a transthoracic ICD, and we were concerned about having them undergo such procedures after transthoracic implantation. These exclusions apply somewhat less now with transvenous devices. So, I think that it would probably be a judicious generalization of the results to consider evaluating patients not in the acute phase, but say 1–2 weeks out. Dr. Akhtar: For years we have been telling referring physicians that we have no specific therapy for NSVT. Years ago, they used to refer such patients, but now, nobody does. Now we have to rethink that philosophy, and it is going to be a real challenge. But how would you recognize these patients? Do you need to do a Holter? Or an exercise test sometime post MI to identify NSVT? If this is not routinely done, I’m not sure we are going to find these patients. If you were to recommend Holters, when should they be done? Dr. Daubert: Doing it electively, one could argue for waiting some months after an event. There may be other patients picked up after an evaluation to rule out MI, or other situations for which they may be on telemetry. But, you are right, this was an issue we faced in recruiting patients for MADIT. In the postCAST era, very few Holters were being done electively, which is certainly one of the things that slowed enrollment in the MADIT study. Dr. Akhtar: Dr. Myerburg, do you have an opinion on the timing of the Holter—this is an important issue? Dr. Robert Myerburg: I think it is a very important issue, because if anything (based on data from years ago), the earlier recognition implies a greater mortality benefit from an earlier intervention. Data from the late 1970s and 1980s on the appearance of NSVT during convalescent or postconvalescent phase of MI showed that there is about a 6-week hiatus during which it appears, some of it disappearing, some only appearing at the end of that. At one point, a recommendation had been made to do a Holter during the index hospitalization, then another Holter at 6 weeks, and if either were positive, the patient was considered high risk. I don’t know if this still holds today, with all the interventions we are doing, but I do think the greatest benefit is going to come from finding these patients as early as possible, as the mortality curve begins kicking in right after the infarct. Now the interesting thing about MADIT is that the average time to enrollment (15 months) is much longer, so we might be missing some of those early patients— hence there might be a substantially larger group available to benefit. Dr. Akhtar: In a sense, do you mean that the MADIT patients are at relatively low risk? Dr. Myerburg: Relatively lower risk—and the converse of that is that you are missing a lot of good candidates because the higher risk starts up earlier. 44F
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Dr. David Cannom: A comment, and a plea: As a MADIT investigator, I’ve been doing Holters on all of my patients with coronary disease in the post-MADIT era and have found 3 patients, up to now, who were inducible and nonsuppressed, and these have received ICDs. I think that from all we know of the MADIT results, this is a very reasonable clinical practice. What I don’t think is reasonable—and I noted a similar caution from you, Dr. Akhtar, following Dr. Moss’ paper at NASPE—is to deviate from the MADIT protocol in terms of implanting patients who are inducible, but nonsuppressed. That is simply going beyond the MADIT data. The MADIT data say that patients have to be non-suppressible, and until any of us are smart enough to get the next protocol together and publish, we can’t go beyond these MADIT criteria. At this point, I would put nonsuppressible patients on drugs and follow them. I don’t know of any data that suggest that I am doing the wrong thing by not putting devices in these patients. Dr. Akhtar: As far as the data are concerned, it was pointed out that patients in the MADIT study who were suppressed nevertheless had significantly higher mortality than those who were noninducible. Dr. Cannom: As you know, these data are anecdotal; there was no registry of the patients who were not brought into the main MADIT trial, so there are no systematic data to suggest that those patients are at high risk. Dr. Akhtar: I agree, and I think we need to do a systematic, randomized study on such a population, perhaps as a follow up to MADIT-I.
CASE 3 A 66-year-old hospital food services worker was noted to have asymptomatic ventricular ectopy at the time of noncardiac surgery. A Holter monitor revealed frequent preventricular contractions and NSVT up to 8 beats. An echocardiogram revealed a mild cardiomyopathy with an LVEF of 0.50. No treatment or EP evaluation was recommended. Eight years later, she presented with symptomatic congestive heart failure. An echocardiogram revealed a cardiomyopathy with the LVEF now 0.25. Treatment with diuretics, digoxin, and an angiotensin-converting enzyme (ACE) inhibitor was initiated. A Holter monitor again revealed asymptomatic NSVT, 3–15 beats in duration. She was referred for angiography, which revealed normal coronary anatomy, but a dilated cardiomyopathy, with an LVEF of 0.20. She was referred for EP study. EP evaluation revealed mild sinus and atrioventricular node conduction disease. There was easily inducible, sustained, polymorphic VT and VF, with single stimuli (S1S2). After 1,000 mg of intravenous procainamide, monomorphic VT (cycle length, 300 msec) was induced with double stimuli. A transvenous ICD was inserted the same day, and the patient discharged the next day without incident. During 6 months of follow- up, there have been 2 events: (1) presyncope associated with NSVT, which terminated before therapy delivery; and (2) asymptomatic monomorphic
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VT, successfully terminated with antitachycardia pacing. Brief discussion of case 3: This case presents a common dilemma in clinical practice; there are no randomized studies to precisely guide management. Whereas this patient meets 5 of 6 MADIT inclusion criteria (Table I), the associated cardiac pathology is not coronary disease, but rather an idiopathic dilated cardiomyopathy (DCM). Review of available research reveals several pertinent points regarding arrhythmia management in DCM: (1) NSVT is common (40 –50% in several studies; (2) mortality is high in DCM (25– 45%/year)—1 of 3 deaths being sudden3; (3) NSVT may predict increased sudden death risk (up to 3-fold increase)4; (4) EP inducibility may predict increased sudden death risk (.3-fold risk)5; and (5) there is no controlled clinical trial of ICD therapy in asymptomatic DCM patients. The electrophysiologist involved (S.L. Higgins) recognized that the primary treatment options were an ICD or no treatment at all. As no further data were available, a clinical decision was made to implant the ICD. Hopefully, when trials such as the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) are completed, reliable guidelines will be available for treatment of this patient subgroup. The electrophysiologist states that his therapeutic decision was not influenced by the fact that the patient was his motherin-law. Dr. Masood Akhtar: Although we are discussing the MADIT results at great length, all of us continue to practice regardless of the MADIT results; many of these patients are coming to our care, year after year, and we have to make decisions. Many of these patients have ended up with devices. Do you think you would have considered amiodarone in this case at all? Dr. Akhtar: I’m not really aware of data that amiodarone is any better in dilated cardiomyopathy than for coronary disease, and in this case you just have to go with what you think is the best case therapy. Dr. David Cannom: I frankly think you can make a good case for putting a device in this patient because of what we know about the risk of dilated cardiomyopathy, which I think is a higher risk than a coronary cardiomyopathy group. This is almost a “bridge-totransplant” subset, which has shown a very high ICD firing rate. I agree entirely with what Dr. Higgins did, and in a comparable patient I would have done the same. But this is an area where there is no clinical trial to guide you. It is a clinical judgment, which is what it all gets back to. Dr. Akhtar: When post-MI patients with coronary artery disease who fit the MADIT criteria are involved, that is one thing. However, when the patients fall out of that, you still have to make clinical decisions. We know at this time that one cannot depend heavily on drug therapy for the prevention of sudden death. So whenever you feel that there is a high-risk population, if you are really going to intervene, it has to be an ICD. I don’t see it any other way. So you can say that it is not part of the protocol, but it is a clinical judgment that you have to make.
CASE 4 A 65-year-old previously healthy patient experienced an inferior MI while vacationing in the Caribbean. Subsequently, sustained VT occurred, with symptoms of palpitations, but without syncope or cardiac arrest. The episode of VT was terminated (in an emergency room) with lidocaine. Subsequently, EP testing showed inducible VT (cycle length, 400 msec), identical to the clinical VT. This morphology of VT was successfully eliminated with a radiofrequency catheter ablation procedure, with the successful ablation site being in the inferior basal left ventricle. Single-vessel coronary artery disease was present, with occlusion of the right coronary artery, and no significant stenoses of the other major epicardial coronary vessels. His LVEF was 0.35– 0.40. The recordings from his ablation session showed the induction of the clinical wide-complex tachycardia. Surface leads 1, AVF, and V1 had a right bundle branch type morphology. Recording from the first intracardiac signal, the ablation catheter in the inferior basal left ventricle, showed a possibly promising electrogram with some fractionation and some activity before the start of the QRS. Ablation at that site terminated the VT and rendered that VT noninducible. After his ablation, he had inducible rapid VT with double extrastimuli and underwent ICD implantation. He subsequently experienced several shocks (while dancing at a Christmas party) due to probable sinus tachycardia. Evaluation after this event did not show inducibility of the “clinical VT.” He has not yet had any detections of VT or VF during several months of follow up. Brief discussion of case 4: Patient 4 contrasts with the patient in Case 2, who was enrolled in the MADIT study. Patient 4 was similar in having had a prior MI, a reduced LVEF (just slightly exceeding the MADIT cutoff of 0.36), and having ventricular arrhythmia. He would have been excluded from MADIT, however, because of his sustained episode of VT (and because his LVEF was slightly too high). After apparent cure of his “clinical” slow-to-moderate sustained VT, he somewhat more closely fit the MADIT criteria in having inducible sustained VT; he received an ICD in somewhat of a prophylactic indication given the inducible rapid VT, and has yet to have an episode. However, he has benefited in not requiring antiarrhythmic drug therapy, although he did have an episode of several ICD shocks for sinus tachycardia, requiring reprogramming of the ICD. This case raises several important and controversial issues about the role of catheter ablation in ventricular arrhythmia patients: (1) the role of catheter ablation in possibly eliminating all morphologies of VT, or only the slow, incessant or clinically apparent ones; and (2) the need for treatment of so-called nonclinical VTs (many electrophysiologists feel that such arrhythmias may occur in follow up despite the fact that they have not been previously observed). Dr. Masood Akhtar: As you pointed out, the LVEF of the patient in this case borders on the MADIT LVEF criterion. The question here is, how many peoA SYMPOSIUM: MADIT
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ple are comfortable with ablation as the initial therapy for VT in association with MI; we all do ablations in patients resistant to drugs, who are having many ICD shocks. The monomorphic VT that you see in patients with coronary disease is not the last VT you are going to see. I think that maybe if they live long enough, there will be others. These patients with chronic coronary artery disease have a substrate that could change, so I therefore think a more broad-spectrum therapy such as the ICD is safer in the long run.
CONCLUSION
Dr. Albert L. Waldo: It is my privilege to close the session. Thank you, Dr. Akhtar. I think it finished the way it started—very strongly, with a lot of questions still to be answered and a lot of perspective provided.
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I really think the presentations were superb. Thanks very much also, to all of you who have stayed so long.
1. Echt DS, Liebson PR, Mitchell LB, et al, and the CAST Investigators.
Mortality and morbidity in patients randomized to receive encainide, flecainide, or placebo in the Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781-788. 2. Bocker D, Block M, Isbruch F, et al. Comparison of frequency of aggravation of ventricular tachyarrhythmias after implantation of automatic defibrillators using epicardial versus nonthoracotomy lead systems. Am J Cardiol 1993;71: 1064 –1068. 3. Tamburro P, Wilber D. Sudden death in idiopathic dilated cardiomyopathy. Am Heart J 1992;124:1035–1045. 4. Kinder C, Tamburro P, Kopp et al. The clinical significance of nonsustained ventricular tachycardia: current perspectives. PACE 1994;17:637– 664. 5. Gradman A, Deedwania P, Cody R, et al. Predictors of sudden death in mild-to-moderate heart failure. J Am Coll Cardiol 1989;14:564 –570.
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SEPTEMBER 11, 1997
MD,
James L. Daubert,
ways the most important part of a sympoIwithnsiummany comes at the end, during a discussion session, the presentation and discussions among the panel and the audience of real patient cases and physician decisions on patients —in this case, those patients, seen in any cardiology practice, who resemble the “Multicenter Automatic Defibrillator Implantation Trial (MADIT) profile.” It is clear that it will be a challenge for the medical community to bring these patients in to provide the needed benefit, and hopefully the following discussions will highlight and clarify for everybody the challenges and problems presented by this important subset.
CASE 1 A 77-year-old automobile dealership manager had an inferior myocardial infarction (MI) in 1983. One year later, flecainide was initiated for asymptomatic ventricular ectopy. In 1991, the flecainide was discontinued due to unexplained dizzy spells and because of results reported in the recent Cardiac Arrhythmia Suppression Trial (CAST) study.1 He was hospitalized in August 1996 with chest pain, although an acute infarction was excluded. Telemetry monitoring revealed 5 beats of nonsustained ventricular tachycardia (NSVT). The patient was referred to another hospital for angiography, the results of which revealed a left ventricular ejection fraction (LVEF) of 0.25 and complete occlusions of both the right and left anterior descending coronary arteries. An adenosine cardiolite study revealed no evidence for active ischemia. The cardiologist referred the patient for a screening electrophysiologic (EP) study based on the MADIT criteria (Table I). Medications included aspirin, nifedipine, atenolol, and topical nitrates. The EP study results revealed normal conduction characteristics, but reproducibly inducible sustained ventricular tachycardia (VT) (cycle length, 290 msec) with double premature stimuli (S1S2S3). It was terminated with burst pacing. With triple stimuli, ventricular fibrillation (VF) was induced that required defibrillation. The VT was still inducible, although minimally slowed (cycle length, 315 msec) after 1,000 mg of intravenous procainamide. Again, it was pace terminated. The patient was referred for an implantable defibrillator, having met all of the MADIT inclusion criteria without exclusions. A CPI Ventak Mini II (CPI/ Guidant, St. Paul, MN) was inserted the same day. The patient was discharged ,24 hours after an uneventful postoperative course. At 3 months after imFrom the 1996 American Heart Association Meeting, New Orleans, Louisiana. Address for reprints: Masood Akhtar, MD, Milwaukee Heart Institute, 960 North Twelfth Street, Milwaukee, Wisconsin 53201-6342.
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©1997 by Excerpta Medica, Inc. All rights reserved.
MD,
Masood Akhtar,
MD
plant, the patient had an asymptomatic presentation of sustained VT, successfully terminated on the first attempt with antitachycardia pacing. Interrogation of the device confirmed a monomorphic VT (cycle length, 300 msec, 200 beats/min). Brief discussion of case 1: This presentation is relatively straightforward, as the patient meets all MADIT criteria. This case supports the MADIT study finding that the index MI is quite often remote from the presenting arrhythmia. Although the referring hospital transferred the patient for angiography, not EP evaluation, the accepting cardiologist had knowledge of the findings of the MADIT studies and initiated the referral for screening. As there was little need for delay, the device was inserted and the patient discharged with a minimum of excess cost. The presentation of device therapy early after implant also underscores another interesting MADIT finding—20% of patients enrolled in the study had a clinical shock by 3 months, and 60% had a shock by the second year. This is comparable to the frequency of therapy observed in patients undergoing an implanted cardioverter defibrillator (ICD) procedure for cardiac arrest and other symptomatic presentations.2 Dr. Masood Akhtar: This case points up an important question: in the MADIT study, drug testing was done as part of the protocol. Now, in actual clinical practice, realizing the limited value of drug treatment for such a patient, is there a value in doing serial drug testing? Dr. Steven L. Higgins: I cannot tell you when I last did serial drug trials in anybody long term; adding an intravenous drug at the time of the initial study is kind of an independent process. I frequently do it in patients with inducible VF, as Mark Josephson showed years ago, which will bring out the monomorphic VT and may well turn out later to be the patient’s clinical arrhythmia. So, procainamide does have value in that regard. At the present time, I am still following the MADIT criteria and doing the drug evaluation because it is relatively easy and inexpensive to do, but I have not been faced with the situation where a patient who was given intravenous procainamide was no longer inducible. I too would be uncomfortable in sending that patient home. I think such patients are still in the high-risk group. Dr. Akhtar: May I ask, how many in the audience would go through conventional therapy in the event the VT was induced, but suppressed with intravenous procainamide? (Many hands up...) So, it seems that a lot of people are still not certain what to do in this situation. Suppression of inducible VT with procainamide does not necessarily mean the patient is at low risk, and we know that drug therapy has not been particularly helpful overall in high-risk populations. 0002-9149/97/$17.00 PII S0002-9149(97)00624-3
TABLE I MADIT Trial Entry Criteria MADIT inclusion criteria Y $3 weeks after most recent MI Y LVEF #0.35 Y nonsustained VT ($3 beats) Y NYHA class I–III Y Inducible into sustained VT with up to triple stimuli or sustained VF with double stimuli Y VT/VF not suppressible with intravenous procainamide MADIT exclusion criteria Y Clinical sustained VT or VF Y Syncope Y Recent MI (#3 weeks) Y CABG within 2 months Y PTCA within 3 months Y Active ischemia Y Significant comorbidity CABG 5 coronary artery bypass graft; LVEF 5 left ventricular ejection fraction; MADIT 5 Multicenter Automatic Defibrillator Implantation Trial; MI 5 myocardial infarction; NYHA 5 New York Heart Association; PTCA 5 percutaneous transluminal coronary angioplasty; VF 5 ventricular fibrillation; VT 5 ventricular tachycardia.
So I am wondering, what are the options in such patients? Dr. Robert Myerburg: The question is, how many in the audience would go through serial drug testing, let’s say perhaps with oral sotalol, if the VT was inducible? (A few hands up...) Would you go through .1 testing? Anyone? The audience response indicates that few would go on to serial drug testing after failure of the first testing.
CASE 2 This 53-year-old male had had a prior inferior Q-wave MI. A 3-beat run of VT was noted on a 24-hour Holter monitor in 1994. He reported some episodes of very brief dizziness (but denied syncope) and had not had a prior cardiac arrest or episode of sustained VT. His LVEF was determined to be 0.30 by echocardiogram. A thallium-201 stress test revealed an inferior–posterior defect, which was fixed, and no significant ischemic, reversible defect. Coronary angiography on August 22, 1994, showed a 70% stenosis of the right coronary artery, 70% stenosis of the circumflex artery, 100% occlusion of the OM2 branch of the circumflex, and mild irregularities of the left anterior descending coronary artery. Ventriculography showed 11 mitral regurgitation and an LVEF of 0.35. On September 15, 1994, diagnostic EP testing was performed because of NSVT and ischemic cardiomyopathy. The results showed inducible sustained monomorphic VT (cycle length, 270 msec) after an intravenous infusion of procainamide, and sustained monomorphic VT remained inducible (cycle length, 270 msec). The patient met MADIT criteria, signed informed consent, and was randomized to the conventional treatment arm, after which amiodarone loading was begun at a dose of 1,200 mg/day for 5 days. He was discharged on a dose of 600 mg/day for 2 weeks. However, .2 weeks after discharge, the dose of amiodarone had to be reduced to 300 mg/day due to
tremor and fatigue. In March 1995 (6 months later), the patient had a sudden syncopal episode (while still taking amiodarone, 300 mg daily). He was observed to have a pause of 2–3 seconds duration with carotid sinus massage in his cardiologist’s office. He was referred for repeat EP testing, which showed inducible sustained monomorphic VT (cycle length, 220 msec) with double ventricular extrastimuli; the HV interval was normal and no other etiology for his syncope (other than VT) was found. Therefore, he was crossedover to ICD treatment (although for survival analysis, he remained in the conventional treatment arm of MADIT). While awaiting ICD implantation, the patient had recurrent, crescendo transient ischemic attacks, was found to have ipsilateral carotid stenosis, and underwent carotid endarterectomy. After the endarterectomy, he had a brief episode of apparent asystole, while on telemetry, with near syncope. A probable pulmonary embolus was diagnosed after ICD implantation, by severe hypoxemia, and a high-probability perfusion lung scan. Finally, after his ICD implantation, he has done well and has had an appropriate detection of spontaneous VT (at 200 beats/min). Peripheral vascular disease has since been noted, with symptoms of claudication. Brief discussion of case 2: This patient illustrates application of the eligibility criteria for the MADIT study, which included NSVT, an LVEF ,0.36, prior MI, and inducible sustained monomorphic VT, the inducibility of which is not suppressible with intravenous procainamide. He was treated with amiodarone (in the conventional arm of MADIT) and experienced side-effects, which were manageable. However, he had a syncopal episode, underwent repeat EP testing, and was crossed-over to ICD therapy. (However, the MADIT study was analyzed on the basis of intentionto-treat, and thus for survival analysis this patient remained in the conventional arm.) The possible comorbidities of patients with ischemic cardiomyopathy and severe arrhythmias are illustrated well by this patient, who manifested MI, mild congestive heart failure, syncope, inducible and spontaneous VT, possible bradyarrhythmias, carotid stenosis and transient ischemic attacks, pulmonary embolus, and claudication. He is representative of the conventional treatment arm in that most patients were treated with amiodarone; this agent did have to be stopped in some patients whose side-effects were, perhaps, even more significant than those noted in this patient. He is unusual in being one of several who crossed-over to ICD therapy. Dr. Masood Akhtar: Is it true that the MADIT study recruitment process starts 3 weeks post MI? Dr. James L. Daubert: Yes. Dr. Akhtar: Do you think that a patient who has an event—let’s say 2 weeks after MI—is comparable, or would you ignore that? We know that this is not part of the MADIT data, but I would think such a case presents even higher risk. Dr. Daubert: Yes, I think that in generalizing the MADIT results cautiously, those are appropriate comments. Dr. Higgins and I, and others, have all strugA SYMPOSIUM: MADIT
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gled with patients just as you mentioned, who were less than the time cutoff after a percutaneous transluminal coronary angioplasty (PTCA), bypass surgery, or MI. Those exclusions were in the MADIT protocol due largely to the fact that initially such patients would have received a transthoracic ICD, and we were concerned about having them undergo such procedures after transthoracic implantation. These exclusions apply somewhat less now with transvenous devices. So, I think that it would probably be a judicious generalization of the results to consider evaluating patients not in the acute phase, but say 1–2 weeks out. Dr. Akhtar: For years we have been telling referring physicians that we have no specific therapy for NSVT. Years ago, they used to refer such patients, but now, nobody does. Now we have to rethink that philosophy, and it is going to be a real challenge. But how would you recognize these patients? Do you need to do a Holter? Or an exercise test sometime post MI to identify NSVT? If this is not routinely done, I’m not sure we are going to find these patients. If you were to recommend Holters, when should they be done? Dr. Daubert: Doing it electively, one could argue for waiting some months after an event. There may be other patients picked up after an evaluation to rule out MI, or other situations for which they may be on telemetry. But, you are right, this was an issue we faced in recruiting patients for MADIT. In the postCAST era, very few Holters were being done electively, which is certainly one of the things that slowed enrollment in the MADIT study. Dr. Akhtar: Dr. Myerburg, do you have an opinion on the timing of the Holter—this is an important issue? Dr. Robert Myerburg: I think it is a very important issue, because if anything (based on data from years ago), the earlier recognition implies a greater mortality benefit from an earlier intervention. Data from the late 1970s and 1980s on the appearance of NSVT during convalescent or postconvalescent phase of MI showed that there is about a 6-week hiatus during which it appears, some of it disappearing, some only appearing at the end of that. At one point, a recommendation had been made to do a Holter during the index hospitalization, then another Holter at 6 weeks, and if either were positive, the patient was considered high risk. I don’t know if this still holds today, with all the interventions we are doing, but I do think the greatest benefit is going to come from finding these patients as early as possible, as the mortality curve begins kicking in right after the infarct. Now the interesting thing about MADIT is that the average time to enrollment (15 months) is much longer, so we might be missing some of those early patients— hence there might be a substantially larger group available to benefit. Dr. Akhtar: In a sense, do you mean that the MADIT patients are at relatively low risk? Dr. Myerburg: Relatively lower risk—and the converse of that is that you are missing a lot of good candidates because the higher risk starts up earlier. 44F
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Dr. David Cannom: A comment, and a plea: As a MADIT investigator, I’ve been doing Holters on all of my patients with coronary disease in the post-MADIT era and have found 3 patients, up to now, who were inducible and nonsuppressed, and these have received ICDs. I think that from all we know of the MADIT results, this is a very reasonable clinical practice. What I don’t think is reasonable—and I noted a similar caution from you, Dr. Akhtar, following Dr. Moss’ paper at NASPE—is to deviate from the MADIT protocol in terms of implanting patients who are inducible, but nonsuppressed. That is simply going beyond the MADIT data. The MADIT data say that patients have to be non-suppressible, and until any of us are smart enough to get the next protocol together and publish, we can’t go beyond these MADIT criteria. At this point, I would put nonsuppressible patients on drugs and follow them. I don’t know of any data that suggest that I am doing the wrong thing by not putting devices in these patients. Dr. Akhtar: As far as the data are concerned, it was pointed out that patients in the MADIT study who were suppressed nevertheless had significantly higher mortality than those who were noninducible. Dr. Cannom: As you know, these data are anecdotal; there was no registry of the patients who were not brought into the main MADIT trial, so there are no systematic data to suggest that those patients are at high risk. Dr. Akhtar: I agree, and I think we need to do a systematic, randomized study on such a population, perhaps as a follow up to MADIT-I.
CASE 3 A 66-year-old hospital food services worker was noted to have asymptomatic ventricular ectopy at the time of noncardiac surgery. A Holter monitor revealed frequent preventricular contractions and NSVT up to 8 beats. An echocardiogram revealed a mild cardiomyopathy with an LVEF of 0.50. No treatment or EP evaluation was recommended. Eight years later, she presented with symptomatic congestive heart failure. An echocardiogram revealed a cardiomyopathy with the LVEF now 0.25. Treatment with diuretics, digoxin, and an angiotensin-converting enzyme (ACE) inhibitor was initiated. A Holter monitor again revealed asymptomatic NSVT, 3–15 beats in duration. She was referred for angiography, which revealed normal coronary anatomy, but a dilated cardiomyopathy, with an LVEF of 0.20. She was referred for EP study. EP evaluation revealed mild sinus and atrioventricular node conduction disease. There was easily inducible, sustained, polymorphic VT and VF, with single stimuli (S1S2). After 1,000 mg of intravenous procainamide, monomorphic VT (cycle length, 300 msec) was induced with double stimuli. A transvenous ICD was inserted the same day, and the patient discharged the next day without incident. During 6 months of follow- up, there have been 2 events: (1) presyncope associated with NSVT, which terminated before therapy delivery; and (2) asymptomatic monomorphic
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VT, successfully terminated with antitachycardia pacing. Brief discussion of case 3: This case presents a common dilemma in clinical practice; there are no randomized studies to precisely guide management. Whereas this patient meets 5 of 6 MADIT inclusion criteria (Table I), the associated cardiac pathology is not coronary disease, but rather an idiopathic dilated cardiomyopathy (DCM). Review of available research reveals several pertinent points regarding arrhythmia management in DCM: (1) NSVT is common (40 –50% in several studies; (2) mortality is high in DCM (25– 45%/year)—1 of 3 deaths being sudden3; (3) NSVT may predict increased sudden death risk (up to 3-fold increase)4; (4) EP inducibility may predict increased sudden death risk (.3-fold risk)5; and (5) there is no controlled clinical trial of ICD therapy in asymptomatic DCM patients. The electrophysiologist involved (S.L. Higgins) recognized that the primary treatment options were an ICD or no treatment at all. As no further data were available, a clinical decision was made to implant the ICD. Hopefully, when trials such as the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) are completed, reliable guidelines will be available for treatment of this patient subgroup. The electrophysiologist states that his therapeutic decision was not influenced by the fact that the patient was his motherin-law. Dr. Masood Akhtar: Although we are discussing the MADIT results at great length, all of us continue to practice regardless of the MADIT results; many of these patients are coming to our care, year after year, and we have to make decisions. Many of these patients have ended up with devices. Do you think you would have considered amiodarone in this case at all? Dr. Akhtar: I’m not really aware of data that amiodarone is any better in dilated cardiomyopathy than for coronary disease, and in this case you just have to go with what you think is the best case therapy. Dr. David Cannom: I frankly think you can make a good case for putting a device in this patient because of what we know about the risk of dilated cardiomyopathy, which I think is a higher risk than a coronary cardiomyopathy group. This is almost a “bridge-totransplant” subset, which has shown a very high ICD firing rate. I agree entirely with what Dr. Higgins did, and in a comparable patient I would have done the same. But this is an area where there is no clinical trial to guide you. It is a clinical judgment, which is what it all gets back to. Dr. Akhtar: When post-MI patients with coronary artery disease who fit the MADIT criteria are involved, that is one thing. However, when the patients fall out of that, you still have to make clinical decisions. We know at this time that one cannot depend heavily on drug therapy for the prevention of sudden death. So whenever you feel that there is a high-risk population, if you are really going to intervene, it has to be an ICD. I don’t see it any other way. So you can say that it is not part of the protocol, but it is a clinical judgment that you have to make.
CASE 4 A 65-year-old previously healthy patient experienced an inferior MI while vacationing in the Caribbean. Subsequently, sustained VT occurred, with symptoms of palpitations, but without syncope or cardiac arrest. The episode of VT was terminated (in an emergency room) with lidocaine. Subsequently, EP testing showed inducible VT (cycle length, 400 msec), identical to the clinical VT. This morphology of VT was successfully eliminated with a radiofrequency catheter ablation procedure, with the successful ablation site being in the inferior basal left ventricle. Single-vessel coronary artery disease was present, with occlusion of the right coronary artery, and no significant stenoses of the other major epicardial coronary vessels. His LVEF was 0.35– 0.40. The recordings from his ablation session showed the induction of the clinical wide-complex tachycardia. Surface leads 1, AVF, and V1 had a right bundle branch type morphology. Recording from the first intracardiac signal, the ablation catheter in the inferior basal left ventricle, showed a possibly promising electrogram with some fractionation and some activity before the start of the QRS. Ablation at that site terminated the VT and rendered that VT noninducible. After his ablation, he had inducible rapid VT with double extrastimuli and underwent ICD implantation. He subsequently experienced several shocks (while dancing at a Christmas party) due to probable sinus tachycardia. Evaluation after this event did not show inducibility of the “clinical VT.” He has not yet had any detections of VT or VF during several months of follow up. Brief discussion of case 4: Patient 4 contrasts with the patient in Case 2, who was enrolled in the MADIT study. Patient 4 was similar in having had a prior MI, a reduced LVEF (just slightly exceeding the MADIT cutoff of 0.36), and having ventricular arrhythmia. He would have been excluded from MADIT, however, because of his sustained episode of VT (and because his LVEF was slightly too high). After apparent cure of his “clinical” slow-to-moderate sustained VT, he somewhat more closely fit the MADIT criteria in having inducible sustained VT; he received an ICD in somewhat of a prophylactic indication given the inducible rapid VT, and has yet to have an episode. However, he has benefited in not requiring antiarrhythmic drug therapy, although he did have an episode of several ICD shocks for sinus tachycardia, requiring reprogramming of the ICD. This case raises several important and controversial issues about the role of catheter ablation in ventricular arrhythmia patients: (1) the role of catheter ablation in possibly eliminating all morphologies of VT, or only the slow, incessant or clinically apparent ones; and (2) the need for treatment of so-called nonclinical VTs (many electrophysiologists feel that such arrhythmias may occur in follow up despite the fact that they have not been previously observed). Dr. Masood Akhtar: As you pointed out, the LVEF of the patient in this case borders on the MADIT LVEF criterion. The question here is, how many peoA SYMPOSIUM: MADIT
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ple are comfortable with ablation as the initial therapy for VT in association with MI; we all do ablations in patients resistant to drugs, who are having many ICD shocks. The monomorphic VT that you see in patients with coronary disease is not the last VT you are going to see. I think that maybe if they live long enough, there will be others. These patients with chronic coronary artery disease have a substrate that could change, so I therefore think a more broad-spectrum therapy such as the ICD is safer in the long run.
CONCLUSION
Dr. Albert L. Waldo: It is my privilege to close the session. Thank you, Dr. Akhtar. I think it finished the way it started—very strongly, with a lot of questions still to be answered and a lot of perspective provided.
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I really think the presentations were superb. Thanks very much also, to all of you who have stayed so long.
1. Echt DS, Liebson PR, Mitchell LB, et al, and the CAST Investigators.
Mortality and morbidity in patients randomized to receive encainide, flecainide, or placebo in the Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991; 324:781-788. 2. Bocker D, Block M, Isbruch F, et al. Comparison of frequency of aggravation of ventricular tachyarrhythmias after implantation of automatic defibrillators using epicardial versus nonthoracotomy lead systems. Am J Cardiol 1993;71: 1064 –1068. 3. Tamburro P, Wilber D. Sudden death in idiopathic dilated cardiomyopathy. Am Heart J 1992;124:1035–1045. 4. Kinder C, Tamburro P, Kopp et al. The clinical significance of nonsustained ventricular tachycardia: current perspectives. PACE 1994;17:637– 664. 5. Gradman A, Deedwania P, Cody R, et al. Predictors of sudden death in mild-to-moderate heart failure. J Am Coll Cardiol 1989;14:564 –570.
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