**4. Secondary SCD prevention**

The actual guidelines tell:

ICD in secondary prevention is indicated for survivors of cardiac arrest due to ventricular VF or VT and syncope and VF/VT inducible at electrophysiological study.

The first trial to investigate the use of ICD as first choice treatment in survivors of cardiac arrest compared with antiarrhythmic drugs was the Dutch study [40]. In a relatively small population of 60 patients, a strategy of ICD implantation as first-line treatment was shown to be preferable to medical therapy, conferring a significant reduction of a combined end‐ point of main outcome events, included death, recurrent cardiac arrest, and cardiac trans‐ plantation. Three subsequent randomized clinical trials have evaluated the effect of ICD on overall mortality [41-43]. The AVID (Antiarrhythmics Versus Implantable Defibrillators) tri‐ al is the only trial to demonstrate statistically significant mortality reduction from ICD thera‐ py in secondary prevention. After an interim analysis, the study was prematurely discontinued due to a 9% absolute increase in death in the antiarrhythmic group (mainly amiodarone) at 18 months (24.0% vs. 15.8%, p=0.02).

What the guidelines don't tell is that, although statistical adjustments were attempted, it is difficult to overlook the >3-fold utilization of beta-blockers in the ICD group (38.1% vs. 11.0% at 1 year) and the 5% higher incidence of atrial fibrillation and NYHA functional class III heart failure in the antiarrhythmic group, and lower incidence of congestive heart failure in the ICD group as additive confounding variables that amplified net clinical benefit in fa‐ vor of ICD therapy. Moreover, clinical benefit was not observed in patients with an EF >35% and <20% [44]. While the number needed to treat in this trial was 11 ICD implants to save 1 life, the unadjusted improvement in mean survival was only 0.21 year, or 2.6 months (31 vs. 29 months). This small difference was reduced by 15% when adjustments were made for heart failure and EF. This modest prolongation of life was valued at \$85,522 [45], which in‐ cluded the untoward costs of the 4% absolute increase in rehospitalizations in the ICD group (60% vs. 56%, p=0.04).

**5.1. Limiations of studies**

The Multicenter Automatic Defibrillator Implantation Trial (MADIT) and the Multicenter Unsustained Tachycardia Trial (MUSTT) have demonstrated that prophylactic ICD therapy may improve survival in patients with increased risk of arrhythmic death [47,48]. The re‐ sults of this trials may not be directly applicable to current medical practice, as the overall low rate of medication administration is not in compliance with current postmyocardial in‐ fraction treatment guidelines. For instance, in the MADIT only 8% of patients in the control group and 26% of patients in the ICD group were receiving β-blockers at 1 month of followup. Similarly in the MUSTT only 29% of the electrophysiologically guided therapy group was on β-blockers. Moreover the highly selected MADIT population is difficult to categorize as a primary prevention group. Induction of sustained ventricular arrhythmias and procai‐ namide suppression is rarely, if ever, performed in current practice, and this feature may have been important for identifying patients more likely to experience adverse events (mor‐ tality rate 39%). The event rate in the control arm was higher than those seen in secondary prevention trials (25,3% in AVID vs 32% in MADIT, at 2 years). The larger MADIT II study demonstrated a 5,6% absolute mortality benefit (19,8% vs 14,2%) at 20 months of follow-up in ICD arm compared with patients in conventional medical therapy [49]. This difference, the smallest difference seen in any ICD trial demonstrating statistically significant benefit, was likely attenuated by a lower risk population enrolled without spontaneous ventricular arrhythmias or induced by the electrophysiological study. In addition, the equivalent high rate of β-blockers in both arms (70%) and low rate of amiodarone therapy (13% ICD vs 10% control) were likely factors that drove the event rates lower. Several insights often over‐ looked in MADIT II deserve mention. When examining the subgroup analysis, patients with QRS less than 150 msec, and EF greater than 25% did not derive benefit, suggesting that a sicker subpopulation within may be most optimal for selection. These data was confirmed in a MADIT II subanalysis that showed a U-shaped curve for ICD efficacy, demonstrating that patients with the lowest and highest risk scores had attenuated benefit from ICD therapy [50]. Another item of note are an unexpected 5% absolute increase in hospitalization for new or worsened congestive heart failure seen in the ICD group (19,9% vs 14,9%). Of note, this 5% trend in increased heart failure is the exact reverse of the mortality rates and absolute overall benefit. This observation confirmed some of the initial suspicion that right ventricu‐ lar pacing and ICD discharges may have deleterious effects on myocardial function [51]. Furthermore, depriving a patient of sudden death may shift the mode of death to pump fail‐ ure, which has the potential to be more costly and morbid [52]. Similar phenomena were ob‐ served in the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) in which the prevention of arrhythmic death with ICD was counterbalanced by excess death from nonar‐ rhythmic causes [53]. The potential for causal harm from ICD shocks was again suggested by a substudy that showed the increased risk from nonarrhythmic death to be confined only to those that received ICD discharges. Due to the lack of mortality benefit seen immediately after myocardial infarction, the guidelines specify a 40-day blanking period during which ICD implantation is contraindicated. The findings of DINAMIT contradict the inferences from the VALIANT study (VALsartan in Acute myocardial iNfarcTion) [54], which showed that patients with reduced systolic function were at highest risk for sudden cardiac death in

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Two smaller randomized trials, the CIDS (Canadian Implantable Defibrillator Study) and CASH (Cardiac Arrest Study Hamburg) trials, failed to demonstrate statistically significant reductions in mortality with ICD therapy for secondary prevention. These findings occurred despite similar inequities of beta-blockade therapy in ICD patients in the CIDS trial, with significantly higher event rates (44.4% in the CASH trial, 29.6% in the CIDS trial, and 24.0% in the AVID trial in control arms) and longer follow-up (57 months in the CASH trial, 36 months in the CIDS trial, and 18 months in the AVID trial). By current clinical trial stand‐ ards, these trials, which did not meet conventional statistical significance, may not pass muster with the Food and Drug Administration. These nonsignificant trends in favor of ICD therapy prompted a meta-analysis that showed a significant difference in mortality in favor of ICD [46]. With a combined follow-up period of 6 years, patients with defibrillators lived only 4.4 months longer than those treated with antiarrhythmic therapy, and all statistically significant differences were nonsustained, narrowing at 4 years toward negligible after 6 years. As seen in the AVID trial, patients with an EF >35% did not experience survival bene‐ fit from ICD therapy. The skeptic, therefore, might interpret these results as suggesting that ICD confers a relatively small and rather transient survival benefit for secondary prevention in patients with EF of 35-40%, and this might be lost when β-blockers is implemented [31].
