MADIT-II trial

The MADIT II trial addressed some of the issues raised by the MADIT. The MADIT II trial evaluated patients with ischemic cardiomyopathy (history of myocardial infarction > 1 month before entry). New York Heart Association Functional Class I-III congestive heart failure, and left ventricular ejection fraction < 0.30 (documented within 3 months), with or without ventricular ectopy. The study enrolled 1,232 patients to assess if an ICD improve total mortality compared to optimal therapy alone. No Holter or electrophysiology test criteria were required for enrollment. Optimal medical therapy included angiotensin-converting-enzyme inhibitors, beta-blockers, diuretics, and lipidlowering statin drugs (172). 

Data from the MADIT II trial indicated that the estimated cost/LYS by the ICD is relatively high at 3.5 years ( 235,000) but is projected to be substantially lower over the course of longer time horizons ( 78,600-114,000 in a projection to 12 years) (212). Their reason for these costs was likely due to the average survival gain for the defibrillator arm being only 2 months. 

Because the above trials showed a >50% relative reduction in total mortality with ICD therapy, MADIT II used broader entry criteria for primary prevention of SCD, removing the criteria for NSVT and EPS 1,232 patients with a history of MI > 30 days prior and an EF < 30% were randomized to conventional therapy or ICD implantation [10]. Conventional therapy was comparable in both arms and included a high rate of use of beta blockers, angiotensin-converting enzyme inhibitors, and statins (over two thirds for all medications in both arms). The trial was stopped early at 20 months because the relative reduction in total mortality... 

Survival curves in MADIT II did not separate until 9 months after enrollment, raising the question of when an ICD should be implanted after MI or revascularization. Two notable negative primary prevention trials may answer this question. The Coronary Artery Bypass Graft Patch (CABG-Patch) Trial evaluated whether primary prevention with ICD at the time of surgical revascularization in patients with EF < 35% and a positive SAECG would reduce total mortality [33]. At 32 months follow-up, no difference was found, suggesting that there is no additional benefit to ICD therapy at the time of revascularization. 

The results of MADIT II were met with some skepticism, but later confirmed by the recent Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) [24]. This study evaluated the benefit of ICD therapy versus amiodarone or placebo as primary prevention in over 2,500 patients with stable NYHA class II or III heart failure and EF < 35%, without the requirement for NSVT or EPS. Patients with both ischemic and nonischemic etiologies for cardiomyopathy were included. Over a follow-up of 4 years, there was no benefit of amiodarone over placebo for overall mortality, but ICD therapy resulted in a significant 23% reduction in overall mortality [p = 0.007] (Fig. 3.5). The benefit of ICD therapy was comparable for ischemic and nonischemic cardiomyopathy. 

Bloomfield DM, Steinman RC, Namerow PB, et al. Microvolt T-wave alternans distinguishes between patients likely and patients not likely to benefit from implanted cardiac defibrillator therapy a solution to the multicenter automatic defibrillator implantation trial (MADIT) II conundrum. Circulation. Oct 5 2004 110(14) 1885-1889. 

The MADIT-CRT trial is enrolling patients who have an indication for an ICD, a low ejection fraction (LVEF < 40%), Class I or II heart failure, and a prolonged QRS duration to either an ICD alone or a CRT-D device. The primary endpoint of this study is all-cause mortality. 

A serious deleterious outcome associated to date primarily with myoblasts (and with thawed BM in chemotherapy patients) (50) is the incidence of cardiac electrical instability for a presumed transient period after cell delivery. These early reports of electrical instability in patients after the receipt of autologous skeletal myoblasts have led to doubts about the safety of these cells as a treatment in the injured heart. Patients who received myoblasts in the earliest clinical studies (33,38) were extremely ill patients with an expected high potential for negative electrical events. In fact, many of the patients who were included in the early trials met the Multicenter Automatic Defibrillator Implantation Trial MADIT-II criteria, which were presented after those trials began, and suggested that all patients who met those criteria be treated with AlCDs. As a result, in more recent clinical studies, many investigators have only enrolled patients who receive AlCDs... 

When the primary prevention trials started using LVEF as essentially the sole criterion for ICD implantation (i.e., not requiring inducibility of VT/VF at EPS), the absolute reduction in mortality decreased with a corresponding increase in the number needed to treat to save one life. For instance, in MUSTT the absolute reduction in mortality was 31% and the number needed to treat was three at five years, and in MADIT the absolute reduction in mortality was 19% with a number needed to treat of four at two years. However, in MADIT-II and SCD-HeFT the absolute mortality reduction was 6% and 7% respectively, with a number... 

In the near future, we may find out that CRT also benefits patients with early heart failure by preventing progression of disease. The MIRACLE-ICD11 trial was a pilot study that showed LV reverse remodeling in patients with NYHA functional class II (22). This is undergoing further evaluation in the ongoing REVERSE and MADIT-CRT trials which are prospectively looking at clinical events and mortality in patients with mild heart failure (NYHA I-II) and wide QRS at baseline (23,24). 

Statins may lower mortality in heart failure patients independent of any effects on coronary artery disease. This has been shown through SCD-HeFT data. Statins can also reduce appropriate ICD discharge in few studies including MADIT II post hoc subanalysis (92,115). To date, no randomized controlled trial has evaluated the influence of statins on malignant ventricular arrhythmias or cardiac death independent of the effect on coronary artery disease. 

Arguably, ICDs for primary prevention has greater benefit for the entire population than ICDs for secondary prevention. Several key primary prevention trials have been completed M IT, MUSTT, CABG-Patch (Coronary Artery Bypass Graft surgery), MADIT II, DINAMIT (Defibrillator in Acute Myocardial Infarction Trial), DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation), SCD-HeFT, CAT (CArdiomyopathy Trial), and AMIOVERT (AMIOdarone VERsus implanv cardioverTer-defibrillator) trials (Table 14.4) (54,119,172-174). 

While practical issues related to medical practice may be a limiting factor for referral for ICDs, there are concerns about small risks of ICD implants in the minds of physicians and patients that overshadow the possible benefits. It may be that many at risk of SCD may die anyway with or without an ICD (based on concomitant conditions and based on age) and these decisions are factored in by treating physicians. It is possible that physician bias or ignorance of the benefits of ICDs plays a role. The prejudices of the physicians caring for patients, in part, may be correct. It is possible that the MADIT II and SCD-HeFT trials do not reflect adequately the risk the average patient with impaired ventricular function has for SCD. Further, the real risk of SCD may be overemphasized. This, and the lack of consistent data in all populations, may affect the enthusiasm for patient referrals for ICDs. 

Zwanziger, J., et al., The cost effectiveness of implantable cardioverter-defibrillators results from the Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II. J Am Coll Cardiol, 2006. 47(11) p. 2310-8. 

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