Do madit results apply only to “MADIT patients”?

Do.WDlT Reeulk Apply “MADIT Putiemk”? Seah

Nisam,

Only to

BSEE

r

e field of arrhythmology seems to have been taken by surprise by’the dramatic results recently reported from the Multicenter Automatic Defibrillator Implantation Trial (MADIT).’ This was a prospective, randomized, multicenter study, with allcause mortality as its primary endpoint, based on intention-to-treat analy$is. Full details of the study design. were previou$ published by the study leader, Arthur Moss et al.2 At the time the study was stopped on March 24, 1996, by its Data and Safety Monitoring Committee ,with the concurrence of the investigators, MADIT had randomized 196 high-risk coronary patients from 32 institutions to the implantable cardioverter defibrillator (ICD) versus “best conventional treatment.! ’ The results, as reported by Moss et al,’ were better survival and 54% fewer deaths overall for the ICD cohort (p = 0.009). The l-year reduction in all-cause mortality for ICD patients compared with the control limb was 87%, and this superiority remained >60% at 2 and 3 years of follow-up (Table I). Importantly, three-quarters of the conventional limb patients had been treated with amiodarone, generally acknowledged to be the most effective currently avail/able antiarrhythmic drug. In response to the criticism that the ICD superiority might be due to proarrhythmia from class I ant&rhythmic drugs,3 it should be noted that only 6 of the 39 deaths in the copventional limb occurred in patients on such drugs tand 3 of these were nonarrhythmic.4 In fact, there were slightly more conventional limb deaths among the patients on amiodarone (36%) than not (26%).’ Following publication of the MADIT results, some critics suggested that “the typical MADIT patient is rare indeed.“5 Their implication was that MADIT’s results for high-risk, but asymptomatic, patients have little or no relevance for patients presenting with syncopal yentricular tachycardia (VT) or sudden arrhythmic death. It is this assertion-that MADIT’s results are limited to patients precisely fulfilling the MADIT protocol-that I wish to address in this article.

that is not the question here. The real issue is one of finding any efficacious treatment for such high-risk patients. During the 16 years since Michel Mirowski and his coworkers introduced the ICD into clinical practice,” this therapy has consistently demonstrated its ability to virtually eradicate sudden arrhythmic death, reducing it to zz1% annually in the cohort of implanted recipients.11-14In contrast, antiarrhythmic drugs (and specifically amiodarone) have been associated with sudden death rates of about 10% at 1 year and >20% by 5 years.15-‘8These results were borne out in MADIT, where, at an average followup of 27 months, there were 13 deaths (13%) classified as “primary arrhytbmic” in patients randomized to drugs, versus only 3 deaths (3%) for the ICD patients. The results of the STAT-CHF study’* in asymptomatic patients with congestive heart failure showed amiodarone to be no better than placebo in terms of protection against sudden death and total mortality: patients randomized to amiodarone treatment had 15% sudden deaths and 30.6% overall mortality at 2 years. Moreover, the patients enrolled in STAT-CHF had profiles virtually identical to those in MADIT (Table II). Looking specifically at the ischemic cohort (72% of the patients) in STAT-CHF, they appear to closely resemble the MADIT patients (age 65,99% male, left ventricular ejection fraction 0.25, nonsustained VT), It is not surprising, therefore, that survival for amiodarone-treated ischemic patients in STAT-CHF was equivalent to that for the MADIT control-limb patients, primarily treated with amiodarone (Figure 1). Indeed, the conventional treatment results in MADIT were, if anything, even slightly better than those reported historically.‘5-‘8 Thus, the results with the ICD in the asymptomatic patients in MADIT are virtually identical to its historical performance in patients with a history of VT and ventricular fibrillation (VF). Seen in this light, the MADIT results are not surprising at all, but merely strong-confirmation of data that has been known for many years: the ICD’s protection against sudden death exceeds that provided WERE THE MADIT RESULTS TRULY by amiodarone. What was perhaps somewhat less SURPRISING? clear was the extent to which’the ICD’s superior proThe fact that patients presenting late after post- tection against sudden death would carry over to tomyoctidial infarction yvith compromised left vental survival. tricular function and nonsustained VT are at high risk of arrhythmia has been established by many investigators. 6-9 Such patients are not rare; however, CAN THE MADIT RESULTS BE EXTRAPOLATED? The important challenge remains whether the From CPI/Guidant-Europe, Brussels, Belgium MADIT results canbe applied to patients other than Address for reprints: Seah Nisam, BSEE, CPI/Guidant-Europe, those explicitly meeting the inclusion criteria for the Excelsiorlaan 37, 1930 Zaventem, Belgium. 0 1997 by Excerpta All rights reserved.

Medica,

Inc.

0002-9149/97/$17.00 PII 50002.9149(97)001185

27

TAME

I Freedom

from

AibCaute

Mortality

(y

ICD 1 2 3 4

0

97 87 83 71

year years years years

0.04 . .

Conventional

.

.

1

77 68 56 51

. 2’

3

4

5

Years

FK3URE1.ActuaridfmadomFmmalk0use~,comparing outcomes from MADIT with survival for the amiodarundfwd ischemii cohort of the STATCHF~ study. The uppwumt curve showshatswvivalforthelCPtkptdpahtsinMADtTwas

54%ll&ter(p=0.009).seedforfwl(lrw~. (Adaptdfrom

VTNF, and such was also the case for the MADIT cohort. In all other important demographic and clinical characteristics as well-age, sex, previous revascularization, NYHA ,class, etc.-most coronary patients with a history of VTNF are similar to the MADIT patient (Table II). In fact, as may be seen in Table II, if anything the MADIT patients have much poorer left ventricular function and so appear to represent a higher risk cohort than the listed ICD series. Since tie have already cited the significant and compelling data from multiple large series, demonstrating the ability of the ICD to provide secondary prevention against fatal VTNF, the real implication of this extrapolation challenge is whether antiarrhythmic drugs-in particular, amiodarone-might not perform just as well in these other groups. But this appears to be a significant leap of faith that lacks substantiation by the available data.15-‘* Why would these drugs protect patients with a history of VTNF better than they did in the previously asymptomatic ones enrolled in MADIT or in STAT-CHF? As seen in the recently completed European Myocardial Infarction Amiodarone Trial (EMIAT),19 amiodarone failed to impact overall survival in recent postinfarct patients; therefore, why should it do so in even higher-risk patients with similar substrates who have presented with sustained VTNF?

NEng/Ihled’~‘~)

COMPETING. study-i.e., to groups with a previous history of sustained malignant ventricular tachyarrhythmias. First, it should be no&d that’ a previous history of sustained VTNF was an exclusion factor for MADIT patients. Yet nevertheless, as seen in Table II, the MADIT patient profiles closely match those of patients with sustained, symptomatic VT/ VF currently receiving ‘ICDs-i.e., the MADIT patient can be extrapolated as typical of major ICD cohorts.*1-14 Second, it is well established that 275% of patients with sudden death and/or VT have coronary artery disease; most of t/hem have had a previous myocardial infarction. These patients have the same underlying disease and the same myocardial scar known to be the substrate at the origin of many reentrant VTs, as did the MADIT patients. Moreover, patients presenting with ventricular tachyarrhythmias generally have a high degree of impairment of left ventricular function, the strongest predictor of

TABLE II batient

Clinical/Demographic Fogoros’2 (n = 119)

Winkle” (n = 270)

Block’s (n = 183)

Schlepper14 (n = 175)

0.26

0.38.

0.34

0.41

0.32

62 82

lg63

LVEF = left ventricular

28

Characteristics

MADIT’ (n = 196) LVEF Age % Males CAD (%)

RISKS

From the above it is evident that .we can expect the ICD to perform better-in terms of sudden death protection-than the best currently available antiarrhythmic drugs, whether for primary prevention, as in MADIT, or for secondary prevention. Therefore, the only remaining outcomes question concerns whether the competing risk(s) of death due to severe heart failure could in effect nullify the ICD’s superiority in protecting patients against sudden death.*’ The MADIT results also answer this question: both arrhythmic deaths as well as those classified as nonarrhythmic or uncertain were significantly lower in the ICD-treated patients than in those randomized to drug therapy (3 vs 13 and 12 vs 26, respectively).’ A closer look at MADIT and EMIAT-both prospective, randomized trials-shows a dramatic difference in impact of ICD therapy compared with amiodarone therapy (Table III; Figure 2): for the primary endpoint of both studies, all cause mortality, amiodarone had no impact, whereas the ICD reduced

58 80 78

76 ajection

fraction.

THE AMERICAN JOURNAL OF CARDIOLOGY@’

CAD

= coronary

56 78 63

ortety disease.

VOL. 79 (6A]

MARCH 20, 1997

i: 74

total mortality (comp&d primarily to amiodarone) ‘TAB&E 111 Causes of Death in EMIAT19 and MADIT’ by >50%. Examining the mod&s of death in these 2 studies All Causes Arrhythmic Nonarrhythmic” gives further insight into this significant difference in outcomes: In EMIAT, amiodarone reduced arEMIAT placebo 102 50 52 (rl = 743) rhythmic deaths by 34% compared with placebo, but EMIAT amiodarone 103 33 70 this benefit was negated by its 35% excess mortality (n = 743) for nonarrhythmic deatW9; in MADIT, the ICD lowMADIT conventional 39 13 26 ered arrhythmic deaths by >75% compared with pa- - therapy (n = 101) tients receiving convendional therapy (i.e., more than MADIT ICD (n = 95) 15 3 12 double the reduction ac!ieved by amiodarone in EM*Includes deaths from unknown WJUIBS. IAT) and even the rate Qf nonurrhythmic deaths was markedly lower in MAlPIT for those patients receiving ICDs-the opposite of what happened with amiodarone-treated pat@ts ‘in EMIAT. rhythmic mortality would have to be that much Before learning of the EMIAT and MADIT re- greater in order to compensate. sults, we addressed posqible explanations for the obIn a recent review of this question of competing served higher nonarrhythmic mortali;? among pa- risks, Fogoros2j noted that such results depend only tients receiving ant&rhythmic drugs. Of course it on the population being treated and the duration of is very difficult to identify the precise cause of death. observation; the results are quite independent of However, we can detetine that the reasons for these whether the particular ant&rhythmic agent is amiodiverging outcomes in MADIT and EMIAT (ICD vs darone (or another drug) or the ICD. Thus, if the medical therapy) cannot be better patient follow-up, competing risks dominate, for a given patient or a inasmuch as patients in both randomized limbs of given population, then obviously neither agent can MADIT were seen within similar follow-up times. grossly improve survival. By the same token, given Following the results from MADIT, one suggestion to patients whose risk is largely arrhythmic (of .was that the ICD-by promptly reverting ventricular course, there will be unavoidable overlap), the agent tachyarrhythmiasmidht be playing a significant that better protects against sudden death must contribute to enhanced overall survival. This is precisely role in preventing secondary myocardial dysfunction and deaths. what occurred in MADIT, with the reduction in nonHowever, whatever the mechanism, one fact is arrhythmic mortality coming as an unexpected “boexclear: the ICD produces no excess mortality. Thus, nus.” (Concerning competing risks, MADIT whereas in EMIAT, deaths from reinfarction, respi- cluded patients in NYHA class IV, those with rator$ problems (pulmonary fibrosis), and other evidence of active ischemia, and in general those judged to have a life expectancy 50% being treated for ceiving ICDs. To the extent that any agent might NYHA class II/III heart failure) can have excellent actually contribute to nonarrhythmic mortality (as survival from all-cause mortality through at least 3 seen with arniodarone in EMIAT), its impact on ar- years, if adequately protected against sudden death. Amiodarone

vs. ICD (EM/AT/MAD/T)

J 20.0%; P E P death: all-cause, arrhythmic, nonorrhythmic, as repod

qnd from ttm

0.0% -All ClUss

Non-An+ythmic

-20.0%

;9 e 2

-40.0%

5

-60.0%

2studiis. ’

I

I

n EMIAT Amiodarone vs placebo 1 q MADIT ICD ve Conventiinal Therapy

2s

1 I

(

-80.0%

THE MIROWSKI SYMPOSIUM

29

CONCLUSION Thus, limiting our remarlb to patients with coronary artery disease whose cli&cal status is at least no worse than those entered into MADIT, it seemsquite evident that the ICD therapy results are not restricted to exclusively “MADIT protocol” patients, and certainly appear to hold true for patients with previous history of sustained VT/VF. Whether they also hold true for other prophylactic populations depends on the outcomes of ongoing studies.23s”

1. MOSS AJ. Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, and Heo M, for the MADIT hivestieators. Imoroved survival with an implanted defibrillator in uadents with corona& disease’ at high risk of vtnttickar arrhythmias, N .&gl J Med 1996:335:1933-1940. 2. MADlT Executive Committee. Multicenter automatic defibrillator implantation trial (MADIT): design and clinical protocol. FACE Pacing Clin Electmphysiol 1991;14(11):920-927. 3. Friedman P, Stevenson W. Unsustained ventricular tachycardia-to treat or not to treat. (Editorial.) N Engl JMed 1996:335:1984-1985. 4. Moss A. Update on MADIT. The multicenter automatic defibrillator implantation trial. Am J Cardiol 1997;79(6q): 16- 17. 5. AVID Executive Committee. MADIT results: implications for AVID? AVID newslener vol. 4. Seattle, Washington, April 24, 1996:2. 6. Anderson K, De CaMilla J, Mos$ A. Clinical significance of ventricular tachycardia (3 beats or longer) in the posthospital phase of myocardial infarction. Circulation 1978;57:890-897. 7. Kadish A, Schmaltz S, Calkins H, Morady F. Management of nonsustained ventricular tachycatdia guided by electrophysiological testing. PACE Pacing Clin Elecrrophysiol 1993;16:1037-1050. 8. Wilber D, Olshansky B, Moran J, Scanlon P. Electmphysiologic testing and nonsustained ventricular tachycardia: use and limitation in patients with coron3z artery disease and impaired ventricular function. Circulation 1990;82:350-

9. Buxton A, Matchlinski F, Waxman H, Flares BT, Cassidy DM, Josephson MB. Prognostic factors in nonsustained ventricular tachycardia. Am J Cardiol 1984,53:1275-1279.

30

THE AMERICAN JOURNAL OF CARDIOLOGY”

10. Mirowski M, Reid P, Mower M, Watkins L, Gott VL, Schauble JF, Langer A, Heilman MS, Kolenik SA, Fischell RE, Weisfeldt ML, Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med 1980;303:322-324. 11. Winkle R, Mead H, Ruder M, Gaudiani VA, Smith NA, Buch WS, Schmidt P, Shipman T. Long-term outcome with me automatic implantable cardioverter defibrillator. JAti CON Cardiol 1989;13:1353-1361. 12. Fogoros R, Elson J, Bonnet C. Survival of patients who have received ;p~l.u;priate shocks from their implantable defibrillators. PACE 1991;14:184213. Block M, Breithardt G. Long-term follow-up and clinical results of implantable cardioverter-defibrillators. In: Zipes D, Jalife J, eds. Cardiac Elecrrophysiology: From Cell IO EedEide. Philadelphia: Saunders, 19951412-1425. 14. Schlepper M, Neuzner J, Pits&tier H. Implamable cardioverter defibrillator: effect on survival. PACE Pacing Clin Electrophysiol 1995;18:569-578. 15. DiCarlo L, Momdy F, Sauve J, Malone P, Davis J, Evans-Bell T, Winston S, Scheinman M. Cardiac arrest and sudden death in patients treated with amiodarone for sustained VT or VF: risk stratification based on clinical variables. Am J Cardiol 1985;55:372-314. 16. Herre J, Sauve M, Scheimnan M. Long-term results of amiodarone therapy with recurrent sustained ventricular tachycardia or ventricular fibrillation. JAm Co11 Cardiol 1989;13:442-449. 17. Weinberg B, Miles W, Klein S, Bolander JB, Dusman RE, Stanton MS, Heger JJ, Langefeld C, Zipes DP. Five-year follow-up of 589 patients treated with amiodarone. Am Heart J 1993;125:109-120. 18. Singh S, Pletcher R, Fisher SG, Singh B, Lewis HD, Deedwania PC, Massie BM, Collmg C, Laxzeti D. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl JMed 1995;333:77-82. 19. Camm J. European myocardial infarct amiodarone trial (EMIAT). oral presentation at North American Society for Pacing and Electrophysiology (NASPE), Seattle, May 16,1996. 20. Sweeney M, Ruskin J. Mortality benefits and the implantable cardioverter defibrillator. Circulation 1994;89:1851-1858. 21. Josephson M, Nisam S. Prospective trials of implantable cardioverter defibrillators versus drugs: are they addressing the right question? Am J Cardiol 1996;77:859-863. 22 Fogoros R. Impact of the implantable cardioverter defibrillator on mortality: the axiom of overall implantable cardioverter defibrillator survival. Am J Cardiol 1996,78:57-61. 23. Nisam S, Thomas A, Mower M, Hauser R, et al. Identifying patients for prophylactic automatic implantable cardioverter defibrillator therapy: status of prospective studies. Am Heart J 1991;122:607-612. 24. Bigger JT. Prediction and prevention of sudden cardiac death. In: Estes M, Manolis A, Wang P, eds. Implantable Cardiovener-De$brillators. New York: M. Decker, 1994557-583.

VOL. 79 (6A)

MARCH 20, 1997