This application responds to NIH Challenge Grant RFA-OD-09-003, under the broad Challenge Area (04) and focuses on Comparative Effectiveness Research in a prior NHLBI sponsored clinical trial (The Sudden Cardiac Death in Heart Failure Trial, SCD-HeFT, UO1s HL55297, HL55496, HL55766). The Specific Challenge Topic is 04-HL-106: Implantable cardioverter defibrillators and cardiac resynchronization therapy in heart failure. No clinical trial that has examined implantable cardioverter defibrillator (ICD) therapy outcome data for longer than a few years. SCD-HeFT, conducted from 1997 to 2003, had the largest number of patients and the longest average follow-up at 45.5 months. This study changed the national reimbursement policy for ICD therapy and remains the reference point for all other ICD evaluations in patients with congestive heart failure from ischemic or non-ischemic systolic dysfunction. More than 26 peer-reviewed publications have resulted from this work, including three NEJM papers, with more being drafted. Despite the duration and quality of SCD-HeFT, the role of ICD therapy in the management of patients with heart failure has been questioned because of four principal concerns: numbers needed to treat to save a life, lead integrity over time, the negative consequences of shock therapy, and the cost of the therapy. At the time of the public presentation of the study outcome at the ACC March 8, 2004, all remaining SCD-HeFT patients (1855 out of 2521 enrolled) were instructed to receive an ICD. Within 3 months of that announcement, only 25 patients in the placebo and amiodarone arms of the trial had availed themselves of free ICD therapy. This is both bad and good. It is bad in that approximately two-thirds of the remaining 1855 patients, those on placebo and amiodarone, were not protected from SCD. On the other hand, for the purposes of examining comparative outcomes, it is good in that it is likely that relatively few of the placebo and amiodarone patients ultimately received ICD therapy. Consequently, the Challenge Grant offers a perfect opportunity for a one- time, long-term follow-up of the remaining 1855 SCD-HeFT patients since our last follow-up of October 31, 2003. The 2-year funding opportunity represents an ideal amount of time and money to obtain human subjects approval at the participating institutions and to track down and question the remaining patients or to access their medical records for a one-time, comprehensive questionnaire regarding key outcome data. Because we had 100 per cent vital status follow-up at the close of the study and 99 per cent data completion on the remaining outcome measures, we believe we can approach this same high quality follow-up. The primary goals of this application are: 1. To compare 10-year mortality data on the remaining 1855 SCD-HeFT patients since the close of follow- up from October 31, 2003 in the 3 arms of the trial (ICD, placebo and amiodarone) to allow the generation of 10-year Kaplan-Meier survival curves based upon an intent-to-treat and an on-treatment analysis. The data on the 666 deaths from the original study will be integrated with the new data. 2. To obtain outcome data in the major subgroups of SCD-HeFT: ischemic versus non-ischemic and NYHA Class II versus Class III heart failure, and in woman and minorities. 3. To obtain 10-year ICD use rates, complication rates, lead failure rates and replacement rates. 4. To validate or refute the observation that amiodarone increases mortality in NYHA Class III patients. 5. To obtain 10-year hospitalization and major procedure data. 6. To obtain 10-year quality of life data. Investigation will be conducted by the same principals involved in the original SCD-HeFT work. Gust Bardy will be the principal investigator, Kerry Lee will oversee the biostatistical aspects of the trial, Dan Mark will oversee the economics and quality of life aspects of the study and Jeanne Poole will oversee the ICD data. The Seattle Institute for Cardiac Research (SICR), will, as before, serve as the coordinating center.
The relevance of this comparative effectiveness research trial builds on the quality, numbers, and duration of follow-up of the largest ICD trial ever undertaken: the NHLBI sponsored Sudden Cardiac Death in Heart Failure Trial that compared ICD therapy to placebo and amiodarone to placebo (double blind). By increasing follow-up to 10-years for the entire SCD-HeFT population, we will provide a unique data set on the long-term mortality and morbidity related to ICD therapy as well as deeper and broader insights into therapy costs and ICD replacement and complication rates from a non-industry source.
