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  • LY335979 MADIT trial enrolled adult patients with prior myoc

    2019-06-12

    MADIT trial enrolled 196 adult patients with prior myocardial infarction more than 3 weeks (Q wave or elevated cardiac enzyme), with non-sustained ventricular tachycardia (a run of 3–30 of ventricular ectopic beats with a rate more than 120 beats per minute), with left ventricular ejection fraction less than or equal to 0.35, and NYHA class I–III. The trial excluded patients with coronary artery bypass grafting within 2 months or coronary angioplasty within 3 months prior to the study. Wilber et al. had found patients with coronary artery disease with abnormal ventricular function had 50% incidence of sudden death in 2 years if ventricular arrhythmia were inducible, and the inducibility of ventricular arrhythmia was a significant independent predictor for sudden death [21]. From this study, the inducibility of ventricular arrhythmia was included in eligibility criteria. The primary end-point was the all-cause mortality. The study compared the primary outcomes in patients with ICD versus conventional therapy. Termination of trial was initiated when 51 deaths were reported, and the efficacy boundary of sequential design was crossed. Major outcomes from MADIT trial suggested that the risk of death in defibrillator group was significantly less than conventional-therapy group with hazard ratio of 0.46. This over-all mortality LY335979 was contributed from reduction in cardiac death. However, there was no explanation why more patients with a defibrillator in the study died from non-arrhythmia causes than patients without a defibrillator. This was postulated from investigators that it might because of misclassification of the cause of death [20]. From this trial, ICD was approved for indication for primary prevention in high-risk patients. This trial had been criticized in several aspects, since it was published in 1996. Moreover, another similar cohort, The Multicenter Unsustained Tachycardia Trial (MUSTT), was often compared to MADIT [22]. One of the important differences was that beta-blockers were used in 16% in patients in MADIT trial, as compared to 40% in MUSTT trial. The imbalance of beta-blocker use favored ICD-treated patients in MADIT trial (15% control group, 26% ICD group), as compared with MUSTT, which favored the control group (51% control group, 34% ICD group). However, both trials showed the similarity of the outcomes in that the mortality reduction was observed particularly in ICD-treated patients. The absence of untreated group in MADIT trial was also discussed that this could be attributed to harm caused by antiarrhythmic drug in conventional group LY335979 [23]. The “conventional group” was also questioned. This group was suggested to confine with non-antiarrhythmic therapy, and in fact, there was marked variability in management in this group—the choice of treatment was on physician\'s decision. The other important limitation is the reproducibility of ventricular arrhythmia. Senges et al. found that non-sustained ventricular tachycardia on Holter monitor in patients fulfilling MADIT criteria had limited clinical value in patient selection for programmed ventricular stimulation [24].
    MADIT-II Electrophysiological testing has been used to identify who is at risk of sudden cardiac arrest, but its utility in patients with coronary artery disease and left ventricular dysfunction remains uncertain. In addition, electrophysiological testing in MADIT trial could possibly select the high-risk patients who less likely to be respond to antiarrhythmic drug therapy [25]. In addition, two-year mortality rate is in the range of 20% in patients with coronary artery disease with ejection fraction less than or equal to 0.30, with the optimal therapies [26]. From above reasons, MADIT-II did not include electrophysiologic testing for selection criteria. Moss et al. initiated MADIT-II in 1999 [27]. This trial enrolled 1232 patients with prior myocardial infarction more than 4 weeks (Q wave or elevated cardiac enzyme), with left ventricular ejection fraction less than or equal to 0.30, and NYHA class I–III. The trial excluded patients with coronary artery bypass grafting or coronary angioplasty within 3 months prior to the study. Repetitive ventricular ectopy was eliminated from inclusion criteria after the study began because almost all eligible patients had such arrhythmia. Primary outcome was death from any causes.