- Email: [email protected]
Update on MADIT: The multkenter automatic defibrillator implantation trial
Update
on MADIT: Tb Multicenter Automatic Defibrillator Implantation Trial Arthur J. MOSS, MD
n 1990, we developed the Multicenter Automatic Iesis,Defibrillator Implantation Trial (MADIT) hypoththat an implanted cardioverter-defibrillator (ICD) would improve survival in high-risk coronary patients when compared with conventional medical management. In the subsequent trial we did not prespecify a comparison drug; management in the conventional arm was left to the discretion of the attending cardiologist, provided the drug was FDA approved. There were 32 participating centers, 30 in the United States and 2 in EuroDe. We enrolled the first patient into MADIT on Didember 27, 1990. The safety monitoring committee recommended termination of the trial on March 2 1, 1996, and the investigators and executive committee met on March 24, 1996, and agreed to terminate the trial. By that time we had randomized 196 patients. The average duration of follow-up was 27 months. The endpoint of this study was total mortality; there were 54 deaths at the time the trial was stopped. Patient enrollment Gteria were nonsustained ventricular tachycardia, prior Q-wave infarction, ejection fraction <35%, and electrophysiologic induction of ventricular tachycardia nonsuppressible with intravenous, procainamide. Thus, all subjects were at high risk. Average ejection fraction turned out to be 26% and the average age was 67 years. Randomization into defibrillator versus best conventional treatment arms tias well balanced. The major dmg used in the nondevice arm (74% of patients) was amiodarone. There were very few patients on type IA agents and none on type IC (Table I). The Kaplan-Meier camulative survival curve for the 196 patients after randomization showed imFrom the Department of Medicine, University of Rochester School of Medicine, Rochester, New York. The MADIT study was supported by a grant from CPI/Guidant to the University of Rochester in accordance with NIH guidelines. Address for reprints: ArthurJ. Moss, MD, Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
16
0 1997 by Excerpta All rights reserved.
Medica,
Inc.
proved survival in the defibrillator arm, with a separation that began very early after implantation; this difference continued to the end of the trial. A logrank statistic p value indicates that the likelihood of this benefit from the defibrillator by chance alone is co.009. We did several statistical analyses. To highlight one aspect of this, we first determined which variables made the most significant contribution to overall mortality, total mortality being the endpoint. There were 2 clinical variables that contributed to the Cox model: left bundle branch block and blood urea nitrogen (BUN). Ejection fraction did not enter into the Cox model because the enrolled patients already had to have an ejection fraction ~35% to enter the study. ICD versus conventional treatment was added to the model, and we found a hazard ratio of 0.46. That is, there was a 54% reduction in total, allcause mortality in the defibrillator group relative to the best conventional treatment. As mentioned, the p value was 0.009.
CONCLUSIONS One of the cmcial questions in any such randomized “mortality” trial is whether there are significant differences in the modes of death, especially cardiac death, between those who received the ICD versus those who received conventional treatment. Table I shows that arrhythmic death was considerably less frequent in the ICD group than in the conventionally treated patients. Thus, this randomized trial demonstrates that an implanted defibrillator is associated with a very significant 54% reduction in total mortality in high-risk coronary patients when compared with conventional medical therapy. Most of this mortality reduction is due to a decrease in arrhythmic death. To our knowledge, this is the first large-scale randomized trial with the automatic ICD. It is most appropriate to honor Dr. Mirowski’s memory with this first public presentation of the positive results of the MADIT trial at the Eighth Annual Mirowski Symposium.
0002-9149/97/$17.00 PII SOOO2-9149(97)00116-l
TAME
I Clinical
Treatment/Pt.
information
No.
on Patients
Months
in Study
1.
0.2
2. 3. A. 5. 6. 7. 8. 9.
1 .o
10. 11.
12. 13. 14. 15.
‘2.4 ,2.9 2.9 3.9 4.9 5.3 5.9 7.4 8.1 9.5 10.7 11.2 11.7
16. 17.
14.1
ia.
18.3 18.3 22.9 ad.7 30.7 33.6 33.7 34.5 41.6 57.9
19.
20. 21. 22. 23. 24. 25. 26. 27
1.
2. 3. 4. 5. 6. 7.
16.0
6.9 7.4 7.9 13.5 1!5.4 17.9
i a.5
a.
18.7
9.
27.3 29.1 42.0
10. 11.
Who
Died
Age/Sex
r
Cause,
CHF
61/M 69/M 76/M 59/M 70/M 68/M 70/M 67/M 68/M 79/M 62/M
According
EF
5
3 14 3 5 3 7 3 30 5 5 16 5 6 27 7 12 3 5 6 9
15 15
SA/M 74/M 59/M 65/M
32 30 25 20 17 20 20 12 24 25 31 20 25 32 30 12
70/M 63/M 60/M 72/M
25 32 23 29
73/M 69/F 66/M 58/M 49/M 49/M 69/M
18
60/M 69/M 62/M 62/M 59/M 50/M 68/M 61/M
72/M
No. Be& in NS-Vl
18
26
67/M 59/M
to Treatment
26 15 25 25 22 3:
60/M
CHF = congestive heart failure; EF = ejection fraction; NS-Vl * Medications at death: amio = qmiodorone; dig = digitalis; t Categorization of the &use of cardiac death as determined
The ibng
of Cardiac
28 29 18’ 20 31 30
10
3 20 3 7 6
20 A 7 29 5 13 8 24 11
3 3
1
Group
Antiarrhythmic Medication(s) at Death”
none omio, mexil omio, dig amio, dig dig amio, mexil amio, dig dig, tocainide amio, dig none dig, quinidine “O”l3 amio omio, procoin none amio amio unknown amio, dig dig, mexil, sotalol none none dig dig, sotalol none none amio, dig
nonarrhythmia nonorrhythmio nonarrhythmia arrhythmia nonarrhythmia nonarrhythmio arrhythmia nonarrhythmia nonarrhythmia nonarrhythmia orrhythmio arrhythmia arrhythmia arrhythmia nonarrhythmia arrhythmia orrhythmio uncertain nonarrhythmia orrhythmio nonarrhythmia arrhythmia nonarrhythmia arrhythmia nonarrhythmia orrhythmio arrhythmia
none
nonarrhythmia arrhythmia uncertain nonarrhythmia nonarrhythmia arrhythmia nonarrhythmia nonarrhythmia nonarrhythmia arrhythmia nonarrhythmia
IlOlli?
dig, mexil beta blocker, none unknown dig dig amio, dig dig, disopyr mexil
dig
= nonsustained ventricular trochycardia. disopyr = disopyramide; mexil = mexiletine; procoin = procoinomide. by the Endpoint Review Committee using the Hinkla-Thaler Classification
QT Interval
e long QT syndrome is an infrequent disorder but more common than once thought. It is largely familial, maybe 85-90%, with about 10% of cases being sporadic and without a familial pattern. The hallmark, of the disorder is delayed repolarization, although some affected family members have near-normal QT intervals. Arrhythmogenic syncopq and, of course, the propensity to sudden death are clear cut. Figure 1 is a typical electrocardiogram (ECG) showing one form of the disorder. The unusual
Cause of Cardiac Death’
rcheme.‘3
Syndrome
pattern should be noted: not only the profound bradycardia, but also the rather long ST segment before the T wave at its very end. This pattern is characteristic of a specific genetic etiology, as discussed below. Figure 2 is an ECG showing the onset of torsade de pointes. The torsade rhythm ended spontaneously, with a very long pause, and then reverted to sinus rhythm with long delayed repolarization T waves. This is the hallmark of syncope as we understand it, and it would not have taken very
THE MIROWSKI SYMPOSIUM
17
FIGURE 1. Twelve-lead ebctrocardiigram from a patient with chromosome 34inked long QT syndrome (LQT3).
Chromosome
Chmmosomo
3
11
FKXJRE 3. Ebctrocardiographic phenotypes in patients with QT syndromelinkedtogeneticma 3 arson chromosome 3 (LQT3), chrumosome 7 (LQTZ), and chromosome 11. (Reprinted with permission from Circub tioll.7
II NF
VS
much more for this to have resulted in sudden death. Three mutant genes have been identified and linked to gene markers on chromosomes 3, 7, and 11: SCNSA, the sodium channel gene (chromosome 3), the HERG potassium channel gene (chromosome 7), and the KVLQTl gene (chromosome 11). Genotypes with these mutants are associated with specific ECG phenotypes; that is, the genes for the long QT syndrome manifest themselves in very specific repolarization disorders. Figure 3 shows ECG patterns of patients with ionic channel mutations involving chromosome 3 (sodium channel gene), chromosome 7 (potassium channel gene), and chromosome 11 (a novel potassium channel gene). There is some overlap, but for the most part, it is very minimal. From the T-wave pattern of the ECG, we can be certain if the case involves a chromosome 3 mutation and almost certain if it involves a chromosome 11 mutation; the remainder fall into the third group, chromosome 7.’ There probably, exist several more genes affecting the expression of repolarization. 18
THE AMERICAN
JOURNAL
OF CARDIOLOGY@
VOL.
Thus, there are specific phenotypes (in terms of the morphology of the electrocardiogram) for the various specific genotypes. Mutation of the sodium channel gene SCNSA is the cause of chromosome 3-linked long QT syndrome (LQT3). There is a deletion in exon nine of the gene, and this results in an altered sodium channel structure; there is slow leakage of sodium into the myocyte at a time when the sodium channel is ordinarily closed completely. This is associated with disordered cardiac function. In addition, this defect is associated with shortening of the refractory period, which is what gives rise to repetitive firing. Incidentally, it is interesting that there is a very similar skeletal muscle sodium channel gene located on chromosome 17 that is responsible for myotonic dystrophy (congenital myotonia), where repetitive firing causes the condition. Indeed, congenital myotonia may be considered a first cousin to the LQT3 disorder. Figure 4 is a schema of the sodium channel. There are 4 domains (Dl-4), and the long QT syndrome mutation for LQT3 is in the linker between domains
79 (6A)
MARCH
20,
1997
Once the nature of the disordered function was identified, there arose the possibility of developing gene-specific therapy. We transfected the mutant gene into an embryonic kidney cell, expressed the alpha subunits of the sodium channel, and were able to detect the leakage currents (see article by Myerburg). It had been known for a long time that the socalled class IB antiarrhythmic agents (lidocaine, tocainide, mexiletine) actually tighten the sodium channel gates. When we added lidocaine to the bath, the leakage currents were eliminated and, at the same time, me refractory period was prolonged. We have administered intravenous lidocaine to 2 long QT syndrome patients with the SCNSA disorder. On the baseline ECG the corrected QT (QT,) was 520 msec. With lidocaine, there was QT shortening and a normal configuration to the T-wave. Three hours after lidocaine, the ECG returned to baseline. We were then able to reproduce this normalization of the QT interval with oral to&ride. Thus, we were able to develop gene-specific therapy related to the molecular disorder. In summary, I have highlighted the clinical and ECG phenotypes of long QT syndrome, focusing on one specific gene mutation (SCNSA), and presented preliminary findings about molecular therapeutics for LQT3.
pemlissiatl
flwl
a//.‘)
3 and 4. The deletion there of a 3-amino acid sequence (KPQ) gives rise to altered sodium channel structure and activity.*
1. Wang Q, Shen .I, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA. Kcating M. SCNSA mutations associated with an inherited cardiac arrhythmia. Cell 1995;80:805-811. 2. Moss AJ, Zareba W, Benhorin J, Lccati EH, Hall WJ, Robinson JL, Schwartz PJ, Towbin JA, Vincent GM, Lebmann MH, Keating MT, MacCluer JW, Timothy KW. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995;92:2929-2934.
THE MIROWSKI SYMPOSIUM
19
on MADIT: Tb Multicenter Automatic Defibrillator Implantation Trial Arthur J. MOSS, MD
n 1990, we developed the Multicenter Automatic Iesis,Defibrillator Implantation Trial (MADIT) hypoththat an implanted cardioverter-defibrillator (ICD) would improve survival in high-risk coronary patients when compared with conventional medical management. In the subsequent trial we did not prespecify a comparison drug; management in the conventional arm was left to the discretion of the attending cardiologist, provided the drug was FDA approved. There were 32 participating centers, 30 in the United States and 2 in EuroDe. We enrolled the first patient into MADIT on Didember 27, 1990. The safety monitoring committee recommended termination of the trial on March 2 1, 1996, and the investigators and executive committee met on March 24, 1996, and agreed to terminate the trial. By that time we had randomized 196 patients. The average duration of follow-up was 27 months. The endpoint of this study was total mortality; there were 54 deaths at the time the trial was stopped. Patient enrollment Gteria were nonsustained ventricular tachycardia, prior Q-wave infarction, ejection fraction <35%, and electrophysiologic induction of ventricular tachycardia nonsuppressible with intravenous, procainamide. Thus, all subjects were at high risk. Average ejection fraction turned out to be 26% and the average age was 67 years. Randomization into defibrillator versus best conventional treatment arms tias well balanced. The major dmg used in the nondevice arm (74% of patients) was amiodarone. There were very few patients on type IA agents and none on type IC (Table I). The Kaplan-Meier camulative survival curve for the 196 patients after randomization showed imFrom the Department of Medicine, University of Rochester School of Medicine, Rochester, New York. The MADIT study was supported by a grant from CPI/Guidant to the University of Rochester in accordance with NIH guidelines. Address for reprints: ArthurJ. Moss, MD, Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642.
16
0 1997 by Excerpta All rights reserved.
Medica,
Inc.
proved survival in the defibrillator arm, with a separation that began very early after implantation; this difference continued to the end of the trial. A logrank statistic p value indicates that the likelihood of this benefit from the defibrillator by chance alone is co.009. We did several statistical analyses. To highlight one aspect of this, we first determined which variables made the most significant contribution to overall mortality, total mortality being the endpoint. There were 2 clinical variables that contributed to the Cox model: left bundle branch block and blood urea nitrogen (BUN). Ejection fraction did not enter into the Cox model because the enrolled patients already had to have an ejection fraction ~35% to enter the study. ICD versus conventional treatment was added to the model, and we found a hazard ratio of 0.46. That is, there was a 54% reduction in total, allcause mortality in the defibrillator group relative to the best conventional treatment. As mentioned, the p value was 0.009.
CONCLUSIONS One of the cmcial questions in any such randomized “mortality” trial is whether there are significant differences in the modes of death, especially cardiac death, between those who received the ICD versus those who received conventional treatment. Table I shows that arrhythmic death was considerably less frequent in the ICD group than in the conventionally treated patients. Thus, this randomized trial demonstrates that an implanted defibrillator is associated with a very significant 54% reduction in total mortality in high-risk coronary patients when compared with conventional medical therapy. Most of this mortality reduction is due to a decrease in arrhythmic death. To our knowledge, this is the first large-scale randomized trial with the automatic ICD. It is most appropriate to honor Dr. Mirowski’s memory with this first public presentation of the positive results of the MADIT trial at the Eighth Annual Mirowski Symposium.
0002-9149/97/$17.00 PII SOOO2-9149(97)00116-l
TAME
I Clinical
Treatment/Pt.
information
No.
on Patients
Months
in Study
1.
0.2
2. 3. A. 5. 6. 7. 8. 9.
1 .o
10. 11.
12. 13. 14. 15.
‘2.4 ,2.9 2.9 3.9 4.9 5.3 5.9 7.4 8.1 9.5 10.7 11.2 11.7
16. 17.
14.1
ia.
18.3 18.3 22.9 ad.7 30.7 33.6 33.7 34.5 41.6 57.9
19.
20. 21. 22. 23. 24. 25. 26. 27
1.
2. 3. 4. 5. 6. 7.
16.0
6.9 7.4 7.9 13.5 1!5.4 17.9
i a.5
a.
18.7
9.
27.3 29.1 42.0
10. 11.
Who
Died
Age/Sex
r
Cause,
CHF
61/M 69/M 76/M 59/M 70/M 68/M 70/M 67/M 68/M 79/M 62/M
According
EF
5
3 14 3 5 3 7 3 30 5 5 16 5 6 27 7 12 3 5 6 9
15 15
SA/M 74/M 59/M 65/M
32 30 25 20 17 20 20 12 24 25 31 20 25 32 30 12
70/M 63/M 60/M 72/M
25 32 23 29
73/M 69/F 66/M 58/M 49/M 49/M 69/M
18
60/M 69/M 62/M 62/M 59/M 50/M 68/M 61/M
72/M
No. Be& in NS-Vl
18
26
67/M 59/M
to Treatment
26 15 25 25 22 3:
60/M
CHF = congestive heart failure; EF = ejection fraction; NS-Vl * Medications at death: amio = qmiodorone; dig = digitalis; t Categorization of the &use of cardiac death as determined
The ibng
of Cardiac
28 29 18’ 20 31 30
10
3 20 3 7 6
20 A 7 29 5 13 8 24 11
3 3
1
Group
Antiarrhythmic Medication(s) at Death”
none omio, mexil omio, dig amio, dig dig amio, mexil amio, dig dig, tocainide amio, dig none dig, quinidine “O”l3 amio omio, procoin none amio amio unknown amio, dig dig, mexil, sotalol none none dig dig, sotalol none none amio, dig
nonarrhythmia nonorrhythmio nonarrhythmia arrhythmia nonarrhythmia nonarrhythmio arrhythmia nonarrhythmia nonarrhythmia nonarrhythmia orrhythmio arrhythmia arrhythmia arrhythmia nonarrhythmia arrhythmia orrhythmio uncertain nonarrhythmia orrhythmio nonarrhythmia arrhythmia nonarrhythmia arrhythmia nonarrhythmia orrhythmio arrhythmia
none
nonarrhythmia arrhythmia uncertain nonarrhythmia nonarrhythmia arrhythmia nonarrhythmia nonarrhythmia nonarrhythmia arrhythmia nonarrhythmia
IlOlli?
dig, mexil beta blocker, none unknown dig dig amio, dig dig, disopyr mexil
dig
= nonsustained ventricular trochycardia. disopyr = disopyramide; mexil = mexiletine; procoin = procoinomide. by the Endpoint Review Committee using the Hinkla-Thaler Classification
QT Interval
e long QT syndrome is an infrequent disorder but more common than once thought. It is largely familial, maybe 85-90%, with about 10% of cases being sporadic and without a familial pattern. The hallmark, of the disorder is delayed repolarization, although some affected family members have near-normal QT intervals. Arrhythmogenic syncopq and, of course, the propensity to sudden death are clear cut. Figure 1 is a typical electrocardiogram (ECG) showing one form of the disorder. The unusual
Cause of Cardiac Death’
rcheme.‘3
Syndrome
pattern should be noted: not only the profound bradycardia, but also the rather long ST segment before the T wave at its very end. This pattern is characteristic of a specific genetic etiology, as discussed below. Figure 2 is an ECG showing the onset of torsade de pointes. The torsade rhythm ended spontaneously, with a very long pause, and then reverted to sinus rhythm with long delayed repolarization T waves. This is the hallmark of syncope as we understand it, and it would not have taken very
THE MIROWSKI SYMPOSIUM
17
FIGURE 1. Twelve-lead ebctrocardiigram from a patient with chromosome 34inked long QT syndrome (LQT3).
Chromosome
Chmmosomo
3
11
FKXJRE 3. Ebctrocardiographic phenotypes in patients with QT syndromelinkedtogeneticma 3 arson chromosome 3 (LQT3), chrumosome 7 (LQTZ), and chromosome 11. (Reprinted with permission from Circub tioll.7
II NF
VS
much more for this to have resulted in sudden death. Three mutant genes have been identified and linked to gene markers on chromosomes 3, 7, and 11: SCNSA, the sodium channel gene (chromosome 3), the HERG potassium channel gene (chromosome 7), and the KVLQTl gene (chromosome 11). Genotypes with these mutants are associated with specific ECG phenotypes; that is, the genes for the long QT syndrome manifest themselves in very specific repolarization disorders. Figure 3 shows ECG patterns of patients with ionic channel mutations involving chromosome 3 (sodium channel gene), chromosome 7 (potassium channel gene), and chromosome 11 (a novel potassium channel gene). There is some overlap, but for the most part, it is very minimal. From the T-wave pattern of the ECG, we can be certain if the case involves a chromosome 3 mutation and almost certain if it involves a chromosome 11 mutation; the remainder fall into the third group, chromosome 7.’ There probably, exist several more genes affecting the expression of repolarization. 18
THE AMERICAN
JOURNAL
OF CARDIOLOGY@
VOL.
Thus, there are specific phenotypes (in terms of the morphology of the electrocardiogram) for the various specific genotypes. Mutation of the sodium channel gene SCNSA is the cause of chromosome 3-linked long QT syndrome (LQT3). There is a deletion in exon nine of the gene, and this results in an altered sodium channel structure; there is slow leakage of sodium into the myocyte at a time when the sodium channel is ordinarily closed completely. This is associated with disordered cardiac function. In addition, this defect is associated with shortening of the refractory period, which is what gives rise to repetitive firing. Incidentally, it is interesting that there is a very similar skeletal muscle sodium channel gene located on chromosome 17 that is responsible for myotonic dystrophy (congenital myotonia), where repetitive firing causes the condition. Indeed, congenital myotonia may be considered a first cousin to the LQT3 disorder. Figure 4 is a schema of the sodium channel. There are 4 domains (Dl-4), and the long QT syndrome mutation for LQT3 is in the linker between domains
79 (6A)
MARCH
20,
1997
Once the nature of the disordered function was identified, there arose the possibility of developing gene-specific therapy. We transfected the mutant gene into an embryonic kidney cell, expressed the alpha subunits of the sodium channel, and were able to detect the leakage currents (see article by Myerburg). It had been known for a long time that the socalled class IB antiarrhythmic agents (lidocaine, tocainide, mexiletine) actually tighten the sodium channel gates. When we added lidocaine to the bath, the leakage currents were eliminated and, at the same time, me refractory period was prolonged. We have administered intravenous lidocaine to 2 long QT syndrome patients with the SCNSA disorder. On the baseline ECG the corrected QT (QT,) was 520 msec. With lidocaine, there was QT shortening and a normal configuration to the T-wave. Three hours after lidocaine, the ECG returned to baseline. We were then able to reproduce this normalization of the QT interval with oral to&ride. Thus, we were able to develop gene-specific therapy related to the molecular disorder. In summary, I have highlighted the clinical and ECG phenotypes of long QT syndrome, focusing on one specific gene mutation (SCNSA), and presented preliminary findings about molecular therapeutics for LQT3.
pemlissiatl
flwl
a//.‘)
3 and 4. The deletion there of a 3-amino acid sequence (KPQ) gives rise to altered sodium channel structure and activity.*
1. Wang Q, Shen .I, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA. Kcating M. SCNSA mutations associated with an inherited cardiac arrhythmia. Cell 1995;80:805-811. 2. Moss AJ, Zareba W, Benhorin J, Lccati EH, Hall WJ, Robinson JL, Schwartz PJ, Towbin JA, Vincent GM, Lebmann MH, Keating MT, MacCluer JW, Timothy KW. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995;92:2929-2934.
THE MIROWSKI SYMPOSIUM
19