a Fundación Jiménez Diaz, Madrid, Spain
b Guidant Corporation, Brussels, Belgium
* Corresponding author. Guidant European Headquarters, Park Lane Culliganlaan 2B, Diegem 1831, Belgium (S. Nisam)
We thank Dr. Sharma and his colleagues for their interest in our article and wish to respond to the issues they have raised.1
Regarding ß-blocker use in the MADIT study,2 Moss has shown that the ICD benefit "...remained significant after adjustment for ß-blocker use".3 The Multicenter UnSustained Tachycardia Trial (MUSTT)with patients nearly identical in profile to those in MADIThad a strong ß-blocker imbalance favoring the control limb (51% of controls versus only 34% of the ICD patients,
), so that the global hazard ratio favoring ICD therapy (0.49) was further improved to 0.45, following adjustment for this imbalance.4
Most of the authors' letter concerns MADIT II,5 which our article did not address at all, as it had not been published at the time we submitted our paper. Nevertheless, we do not share the opinion of Sharma et al. that amiodarone should have been the control limb therapy of MADIT II. We do not know of any guidelines suggesting the combined use of amiodarone and ß-blockers in post-myocardial infarction patients with severe left ventricular dysfunction. Conversely, most MADIT II controls received drugs, which have been shown to reduce mortality in this clinical setting, namely beta-blocking agents (70%) and ACE inhibitors (72%). In patients with chronic ischemic heart disease and depressed systolic left ventricular functionprecisely those entered in MADIT IIseveral randomized controlled trials have shown that amiodarone has no impact on all-cause survival, 6,7 which was the primary endpoint of the study. We do not include CAMIAT in the latter comment because the ejection fraction was unreported, but also in this study in post-myocardial infarction patients with complex ventricular arrhythmias, amiodarone failed to show any survival benefit.8 Since MADIT II excluded patients with a history of previous sustained ventricular tachycardia or fibrillation, there was no evidence-based reason to use amiodarone prophylactically in the control group. Concerning the paper by Boutitie et al.,9 which Sharma et al. refer to, the patients receiving ß-blockers represent a far lower risk group than those in MADIT II (>75% in NYHA class I as compared to 39% in the control group of MADIT II). A further difficulty in evaluating the ß-blockers/amiodarone interaction in the Boutitie et al. analysis is that only half the patients were on ß-blockers at randomization, and by 20 months, nearly 50% were no longer taking them, in contrast to MADIT II, where 70% were still on ß-blockers at time of last follow-up.
On the issue of revascularization, the MADIT II investigators were strongly recommended to look for and treat any correctible ischemia, prior to enrolling patients in the study.10 In fact, the CABG-Patch trial referred to in the letter 11 had terminated just prior to the start of MADIT II, and its neutral results were one of the primary reasons for making sure that patients with ischemic problems be attended to well before they could be considered for the MADIT II trial.
The final point of Sharma et al. concerns the results of the ongoing SCD-Heft study, which we agree is an important trial. However, as reported recently by the Principal Investigator of the study,12 approximately half of the patients enrolled were of non-ischemic origin (ironically, due to physicians' growing reluctance to randomize ischemic patients following MADIT and MUSTT), and many of the enrolled patients had ejection fractions above the MADIT II cut-off (30 versus 35% in SCD-Heft), so there may be a power issue in comparing the outcomes of the two studies.
References