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  • Major outcomes from MADIT II

    2019-06-11

    Major outcomes from MADIT-II trial suggested that, once again, the risk of death in defibrillator group was significantly less than conventional-therapy group with hazard ratio of 0.69. In this trial, the major drawback was corrected. The medication use remained balanced between ICD patients, and conventional therapy patients. The size of study population was greater in the latter study. However, hazard ratio of rate of death in the latter trial was higher than the former one. This was mentioned to be due to the lower cutoff of ejection fraction, more vigorous medication [28]. Interestingly, the rate of THZ531 failure hospitalization was unexpectedly high in ICD patients (20% versus 15%). The explanation was uncertain, but was thought to be due to (1) multiple shocks leading to myocardial injury; (2) higher incidence of heart failure progression in ICD patients with longer life span; (3) right ventricular pacing adversely impacting ventricular synchrony. MADIT-II trial was designed without risk stratification, targeting broad range of population. Several subgroup analyses from MADIT-II have been published after the main trial. The advantage of ICD in lowering mortality risk depends on time since the most recent myocardial infarction [29]. The longer after myocardial infarction is associated with the greater mortality reduction. ICD was equally beneficial in diabetic and non-diabetic patients [30]. In addition, age seems not to impact on the mortality benefit from ICD, even though elderly patients, older than 75 years old, were marginally benefitted from ICD [31]. Dhar et al. also showed the QRS duration associated with SCD in non-ICD patients; however, it was not related with SCD and ventricular tachyarrhythmia in ICD patients [32]. However, patients with advanced renal dysfunction do not received the protective effect from ICD [33].
    MADIT-CRT The heart failure event in the MADIT-II trial led to the MADIT-CRT. The similar outcomes were found in SCD-HeFT and DEFINITE trials [34]. From prior study, Bristow et al. demonstrated the mortality reduction from CRT-D and CRT-P as compared to medical therapy alone. However the patients included in this trial were in NYHA class III and IV [35]. This trial was designed in 2005 aiming at patients with NYHA class I and II for preventive purposes [36]. One thousand eight hundred patients were included (consisting of ischemic or non-ischemic cardiomyopathy, a QRS duration more than or equal to 130ms, NYHA class I, II, ejection fraction less than or equal to 30%). These patients were randomized to ICD plus CRT, or ICD alone. Due to the adverse effect of right ventricular pacing, a lower rate limit was set at 40 beats per minute both groups. Primary outcome was assessed for composite of death or non-fatal heart failure. The primary outcome occurred 17.2% in ICD plus CRT patients as compared to 25.3% in ICD only patients, with hazard ratio of 0.66. This risk reduction was attributed by 41% reduction in the risk of heart failure. The hazard ratios for primary end points in ischemic and non-ischemic cardiomyopathy patients were similar. In subgroup analyses, it suggested that CRT-D had equal mortality benefit in each subgroup (regardless of ejection fraction, age, LVESV, LVEDV, NYHA class). Nevertheless, women had greater mortality reduction than men, and this CRT-D will reduce mortality only in patients with QRS width more than or equal to 150ms. This major outcome seemed to be confirmed with REVERSE trial [37].
    MADIT-RIT Growing number of ICD trials lead to the popularity of ICD implantation. Inappropriate therapy from ICD has become THZ531 a problem in clinical practice. Supraventricular tachyarrhythmia remained the most common rhythm causing inappropriate therapy despite the proper ICD programming. Major adverse consequences\' following inappropriate therapy includes pain, anxiety, a poor quality of life, proarrhythmia [38,39]. In addition, this could trigger fatal arrhythmia. Even though, dual-chamber ICD\'s are implanted twice as frequently as single chamber ICD\'s due to proper rhythm detection and differentiation, no randomized controlled trial has shown that proper ICD programming for reducing inappropriate therapy would affect the clinical outcomes. This trial was initiated in 2012 to determine appropriate ICD programing [40].