CORRESPONDENCE: LETTER TO THE EDITOR
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Cecilia Linde, MD, PhD*,
William T. Abraham, MD,
Michael R. Gold, MD, PhD,
Martin St John Sutton, MD,
Stefano Ghio, MD,
Claude Daubert, MD REVERSE Study Group
* Karolinska Institute, Box 110, Stockholm, S-17176, Sweden (Email: cecilia.linde{at}ki.se).
We thank Dr. Osswald and colleagues for their interest in our paper (1). The REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) study was designed as one population of New York Heart Association (NYHA) functional class I to II heart failure (HF) patients. We agree that the primary end point did not reach statistical significance (2), with 16% of patients worsened in the cardiac resynchronization therapy (CRT) ON group and 21% in the CRT OFF group (p = 0.10). The clinical composite response was designed for severe HF patients and, to our knowledge, has not previously been used in mildly symptomatic or asymptomatic HF patients (3).
The fact that the primary end point did not reach statistical significance despite substantial improvement in left ventricular (LV) dimensions accompanied by a significantly reduced time to first HF related hospitalization might be due to the difference in utility of this end point or that the observation period was not long enough to demonstrate effects in NYHA functional class I to II patients. Dr. Osswald and colleagues are concerned about the subgroup analysis in a neutral study and more specifically by the "lack of benefit" in NYHA functional class I patients and in those not on diuretics (1). We understand their concern but want to point out that subgroup analyses are performed in larger studies to clarify whether a presumed treatment effect can be generalized over many clinically relevant conditions.
The main finding was an overall positive effect over nearly all subgroups, with an odds ratio of 0.70 in favor of CRT. The study was not powered to show a benefit in NYHA functional class I patients alone and, therefore, statistical significance for this small group of patients should not be expected. Nonetheless, the results indeed favor CRT ON in NYHA functional class I patients with an odds ratio of 0.87. Improvements in left ventricular end-systolic volume index between NYHA functional class I and II patients were substantial in both NYHA functional class I and II groups as well as for patients with and without diuretics. Diuretics were not randomized in any way. The on-diuretics group included both CRT ON and CRT OFF patients, so if "diuretics by themselves may have accounted for the documented beneficial effect," then both CRT ON and CRT OFF patients would have shown the same improvement. Therefore, this is not a confounding variable.
We thus believe that our conclusion, that CRT reduces the risk for HF hospitalization and reverses LV remodeling over the course of 12 months in patients with American College of Cardiology/American Heart Association stage C, NYHA functional class I and II HF, raising the possibility that CRT might delay disease progression in HF patients with mild HF through LV reverse remodeling, is valid. Because the REVERSE study was not dimensioned as a morbidity/mortality trial we will have to wait for the ongoing MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) and RAFT (Resynchronization/defibrillation for Ambulatory heart Failure Trial) studies and the 24-month REVERSE study results to obtain the final answer as to whether CRT may modify disease progression in mildly symptomatic HF patients (4,5).
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1. Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C, REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms J Am Coll Cardiol 2008;52:1834-1843.[Abstract/Free Full Text]2. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure J Card Fail 2001;7:176-182.[CrossRef][Web of Science][Medline] 3. Linde C, Gold MR, Abraham WT, Daubert JC. Rationale and design of a randomized controlled trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with asymptomatic left ventricular dysfunction with previous symptoms or mild heart failure—the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study Am Heart J 2006;151:288-294.[CrossRef][Web of Science][Medline] 4. Tang AS, Wells GA, Arnold M, et al. Resynchronization/defibrillation for ambulatory heart failure trial: rationale and trial design Curr Opin Cardiol 2009;24:1-8.[CrossRef][Web of Science][Medline] 5. Moss AJ, Brown MW, Cannom DS, et al. Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT): design and clinical protocol Ann Noninvasive Electrocardiol 2005;10(Suppl):34-43.[CrossRef][Web of Science][Medline]
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No Benefit From Cardiac Resynchronization Therapy in Asymptomatic Patients
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