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Fig. 4. CABG Patch results: Actuarial survival curves for patients treated with the defibrillator and with conventional therapy. See text. (From: Bigger TJ, for the Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after CABG surgery. N Engl J Med 1997;337:1569-1575. Copyright © 1997 Massachusetts Medical Society.)

inducible ventricular arrhythmia during electrophysiologic studies. The ICD in this trial was simply one of the forms of antiarrhythmic therapy to which patients might be guided when relying on electrophysiologic testing.

In MUSTT, patients with CAD, NSVT, and a LVEF less than 0.4 underwent electrophysiologic testing to see if sustsained VT could be induced. If VT was inducible, patients were then randomized to "conservative treatment" with beta-blockers and angiotensin-converting enzyme (ACE) inhibitors, or to therapy guided by electrophysio-logic testing (including serial drug testing with up to three antiarrhythmic drugs, or an ICD after at least one failed antiarrhythmic drug test).

The results of MUSTT were recently published (17). Of 2202 patients enrolled in the study, 704 who had inducible VT were randomized. Patients randomized to the antiarrhythmic therapy group had a significantly reduced arrhythmic mortality compared to the conservative therapy group at both 24 and 60 mo of follow-up (12% vs 18% at 24 mo, and 25% vs 32% at 60 mo; p = 0.043). There was also a trend toward a reduction in all-cause mortality in the antiarrhythmic therapy group, although a statistical significance was not reached.

Most remarkably, 46% of patients in the antiarrhythmic therapy group who received the ICD had a 92% 60-mo survival. Furthermore, when patients with the defibrillator were removed from the analysis, there was no significant difference in outcome between the antiarrhythmic therapy group and the conservative group. Thus, virtually all of the survival benefit in the antiarrhythmic therapy group appears to have been imparted by the ICD. In fact, patients treated with antiarrhythmic drugs appeared to do worse than the conventionally treated patients. Fig. 5 illustrates the results of MUSTT.

The results of MUSTT are therefore entirely consistent with those of MADIT.

Fig. 5. MUSTT results: Actuarial estimates of event rates (cardiac arrest or death from arrhythmia).

(A) EPG (electrophysiological^ guided therapy) vs conventional therapy. See text.

(B) The EPG group is divided into patients with and without ICDs. Note that all of the benefit is in the ICD group, and that the EPG patients without ICDs did worse than the conventional group. See text. (From: Buxton A, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999;341:1882-1890. Copyright © 1999 Massachusetts Medical Society.)

Fig. 5. MUSTT results: Actuarial estimates of event rates (cardiac arrest or death from arrhythmia).

(A) EPG (electrophysiological^ guided therapy) vs conventional therapy. See text.

(B) The EPG group is divided into patients with and without ICDs. Note that all of the benefit is in the ICD group, and that the EPG patients without ICDs did worse than the conventional group. See text. (From: Buxton A, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999;341:1882-1890. Copyright © 1999 Massachusetts Medical Society.)

MUSTT confirms that, in patients with NSVT, CAD, and depressed LVEFs, the EPS may identify a subset with a substantial risk of sudden arrhythmic death; and the ICD is effective in significantly reducing that risk and prolonging overall survival.

Reconciling MADIT, MUSTT, and CABG Patch

Both MADIT and MUSTT showed a strong benefit in using the ICD as primary prophylactic therapy, whereas CABG Patch showed no benefit at all. How can studies that randomize seemingly similar groups of patients (i.e., patients with ischemic heart disease, the presence of left ventricular dysfunction, and a marker for arrhythmic risk) yield such different results? The answer is that the patients studied in these trials, although superficially similar, were actually quite different, and that given those differences, the Axiom of Overall Survival predicts these results.

Simply put, the patients finally enrolled in the CABG Patch trial had a low arrhythmic event rate, and so were not eligible to have their lives significantly prolonged by the ICD. In contrast, patients in MADIT and MUSTT had a relatively high arrhythmic event rate, so that removing the risk of arrhythmic death with the ICD significantly prolonged overall survival.

Why was the prognosis of patients eligible for CABG Patch so much better than for patients eligible for the other two trials? First, the screening for eligibility to MADIT and MUSTT was far more rigorous than for CABG Patch. Specifically, it appears likely that the EPS has a much higher predictive value at an indicator of arrhythmic risk than does a positive SAECG. And secondly, all patients randomized in the CABG Patch trial had successful revascularization surgery. Indeed, successful revascularization was a criterion for randomization. This systematic elimination of ischemia is very likely to have had at least some antiarrhythmic value.

In any case, the MADIT and MUSTT screening criteria were much more effective in identifying a high-risk subgroup of enrollees than those used in CABG Patch. The first criterion of the Axiom (the risk of sudden death must be sufficiently high) was met in these two trials; it was not in CABG Patch. Thus, the reduction in sudden death provided by the ICD had a measurable effect on overall survival in MADIT and MUSTT, whereas it did not in CABG Patch.

Summary of Primary Prevention Trials

Two well-designed multicenter trials have now shown that the ICD can significantly increase overall survival in carefully selected patients who have not yet experienced a sustained ventricular tachyarrhythmia. Based on the results of both MADIT and MUSTT, electrophysiologic testing should be strongly considered in patients with coronary CAD, depressed left ventricular function, and NSVT. If sustained VT is induced, those patients should receive an ICD.

How important is electrophysiologic testing in selecting patients for primary prophylaxis with the ICD? This question remains open. In the MUSTT trial, the EPS identified patients at high risk of arrhythmic death. Patients who met the clinical criteria for inclusion but were not inducible at EPS also had a significant risk of arrhythmic death (and total mortality) during follow-up (17a). A similar registry had not been published for the MADIT study. Although it is likely that the EPS (or lack thereof) accounts for at least some of the difference in outcomes between MADIT and MUSTT on one hand, and CABG Patch on the other, we cannot yet prove this theory.

Three ongoing trials will give us more insight as to whether electrophysiologic testing is necessary in identifying patients who will benefit from primary prophylaxis with the implantable ICD. The Sudden Cardiac Death in Heart Failure Trial (SCD HeFT) (17b) is enrolling 2400 patients with either CAD or dilated cardiomyopathy and a LVEF of less than 0.35. Patients will simply be randomized to therapy with conventional drugs, amiodarone, or the ICD. The MADIT II trial (17b) is enrolling patients with CAD and a LVEF of less than 0.3. These patients will be randomized to either conventional therapy or the ICD. DEFINITE (17c) randomizes patients with nonischemic cardiomyopathy and NSVT to either an ICD or conventional therapy. If inducibility during electrophysiologic testing really is an important prognostic indicator, then MADIT II may have difficulty demonstrating a significant survival benefit with the ICD. Since electrophysiologic testing is less sensitive and less specific in nonischemic compared with ischemic myopathies, the effect of omitting this "qualifying" test is less clear in DEFINITE and SCH HeFT.

It is interesting to speculate what the Axiom of Overall Survival may predict about the outcome of SCD HeFT, DEFINITE, and MADIT II. Since these trials enroll very broad populations of patients, it seems likely that (unlike MADIT and MUSTT) they will tend to dilute Population 2 patients with patients from Population 3—and even Population 1. Thus, the Axiom seems to suggest that these trials will either be negative, or like AVID, will show a significant but short-lived benefit from the ICD.

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