Prophylactic implantable cardioverter defibrillator trials: MUSTT, MADIT, and beyond. Multicenter Unsustained Tachycardia Trial. Multicenter Automatic Defibrillator Implantation Trial.

MUSTT and MADIT have clearly shown the survival benefit of an implantable cardioverter defibrillator (ICD) in patients with previous myocardial infarction, left ventricular ejection fraction < or = 0.40, and nonsustained ventricular tachycardia (VT), and who have had sustained VT induced at electrophysiology study. Progress in primary prevention of sudden cardiac death (SCD) depends on a concerted effort by clinicians to identify and appropriately treat MUSTT/MADIT-type patients; further research to more precisely define patient subgroups at risk for SCD and the willingness of industry to develop a lower priced ICD for prophylactic use are needed.

Primary prevention of sudden cardiac death with implantable cardioverter defibrillators: lessons learned from MADIT and MUSTT.

The MADIT study lead to the first approved prophylactic indication for ICDs in patients with previous myocardial infarction, depressed left ventricular systolic function, nonsustained ventricular tachycardia (VT), and inducible sustained VT. However, criticisms have been raised with respect to the study design and patient selection. The MUSTT yielded similar results (51% lower mortality by ICD vs no antiarrhythmic drugs) in a comparable population. The results of MUSTT address the major criticisms of MADIT: (1) MADIT was a "small" study (n = 196), while MUSTT randomized 704 patients. (2) MADIT had an "imbalance" in its prescription of beta-blockers, whereas the "imbalance" favored the control group in MUSTT: (51% vs 34%). (3) MADIT had no untreated limb, but MUSTT did. (4) MADIT's control group mortality (32% at 2 years) was considered by some as "unrealistically high", yet MUSTT measured a similar rate (28% at 2 years). (5) MADIT presented no information relative to patients without inducible arrhythmias, but MUSTT recorded their outcomes in a registry. In conclusion, the combined results of MADIT and MUSTT confirm the appropriateness of their risk stratification schemes and the survival benefits of ICD therapy as a highly effective primary prevention in this high risk population.

Perspectives: does amiodarone increase non-sudden deaths? If so, why?

Despite the antiarrhythmic efficacy of amiodarone, a definitive correlation between amiodarone treatment and increased non-arrhythmic mortality in patients with heart failure and depressed ventricular function has been reported. Results from research in the field of cardiac resynchronization therapy in heart failure may provide some explanations to this observation. We discussed the hypothetical link between amiodarone and non-arrhythmic mortality, which might have a cause--effect relationship, based on cardiac electromechanical disarrangement provoked by electrophysiological properties of amiodarone.

Safety and efficacy of implantable defibrillator therapy with programmed shock energy at twice the augmented step-down defibrillation threshold: results of the prospective, randomized, multicenter Low-Energy Endotak Trial.

Whether the safety and efficacy of implantable cardioverter defibrillator (ICD) therapy can be assured with lower output devices is an important question. The purpose of this study was to evaluate whether programming the device output at twice the augmented defibrillation threshold was as safe and effective as using the maximum energy. Patients indicated for ICD therapy, but without slow monomorphic ventricular tachycardia (MVT), who achieved an augmented defibrillation threshold (DFT plus) < or = 15 joules (J) with a single endocardial lead system and a biphasic defibrillator were included in the study. Prior to ICD implantation, patients were randomized into 2 groups. The shock energies in test group patient were set as follows: first shock at twice DFT plus, the second to fifth shocks at maximum output (34 J). In control group patients, all shocks were programmed at 34 J. The study population consisted of 166 consecutive patients (mean age 57.4 +/- 12.1 years, mean left ventricular ejection fraction 36.8 +/- 13.8%). Mean DFT plus was 9.6 +/- 3.2 J in test group patients and 10.1 +/- 3.5 J in control group patients (p = 0.36). During a mean follow-up of 24.2 +/- 9.6 months, 736 arrhythmia episodes were analyzed. The first shock efficacy was 98.3% in the test group patients versus 97.4% in the control group (p = 0.45). Total mortality was 6%, equally distributed in both study groups. The results of this study prove that the method of doubling the defibrillation energy at the DFT plus level provides an adequate safety margin in defibrillator therapy.

ICD trials: an extraordinary means of determining patient risk?

Extensive clinical experience with the implantable cardioverter defibrillator (ICD) combined with recently completed prospective, randomized trials like MADIT and AVID, have demonstrated the lifesaving efficacy of this therapy and its superiority compared to conventional medical management in treating patients at high risk of sudden arrhythmic death. This evidence has in turn spurred great interest in further ICD studies. Since the ability of the ICD to save lives is no longer in question, there is a need to reexamine the real objectives of these new studies.

Can implantable defibrillators reduce non-arrhythmic mortality?

Several authors have made the intriguing observation that Implantable Cardioverter Defibrillators (ICD) appear not only to reduce sudden deaths, but also mortality due to non-arrhythmic causes. Studies have shown that this observation can not be attributed to patient selection bias. In trying to explain this apparent anomaly, it should be noted that two treatment strategies are being compared. Thus, it might be that, under certain circumstances, antiarrhythmic drugs contribute to non-arrhythmic deaths, not that ICDs reduce them. There appear to be some plausible explanations for this phenomenon, e.g., the long-term effect on cardiac function of episodes of ventricular tachycardia lasting for several hours for patients treated solely by antiarrhythmic drugs, compared to their quick termination by an ICD. However, further research into this curious mode of death issue is needed, and may provide further insights into patient populations deriving greatest benefit from one therapy or the other.

The AVID trial: evidence based or randomized control trials--is the AVID study too late? Antiarrhythmics Versus Implantable Defibrillators.

A great body of clinical evidence has been accumulated--before and without the AVID trial--showing that implantable defibrillators prolong life better than currently available antiarrhythmic drugs. With this evidence already available, we question the validity of a trial that attempted, in effect, to place a price tag on life and quality of life.

Clinical implications of the "Multicenter Automatic Defibrillator Implantation Trial" (MADIT)

Efficacious therapy for chronic coronary patients, known to be at high risk of sudden arrhythmic death, has been a long-lasting challenge for cardiologists. The "Multicenter Automatic Defibrillator Implantation Trial" (MADIT) has demonstrated in a prospective, randomized trial that such patients achieve 54% better survival (p < or = 0.009) when treated with implantable defibrillators (ICDs) compared to conventional pharmaceutical therapy-primarily amiodarone. The identification of these patients is well-defined, and patients with previous myocardial infarction fitting the appropriate risk profile as defined by MADIT (ejection.fraction < or = 0.35), non-sustained ventricular tachycardia should seriously be considered for prophylactic ICD implantation.

Mortality trials with implantable defibrillators.

The continuing disappointing results from recent major studies with antiarrhythmic drugs combined with the continuing excellent outcomes with implantable cardioverter-defibrillators is making it exceedingly difficult, ethically, to conduct future randomized trials comparing the 2 treatment options. On the other hand, the high quality of stored Holter electrograms and the therapy history retrievable from current implantable cardioverter-defibrillators creates opportunities for needed trials on drug efficacy without this ethical dilemma.