September 8, 2008 (Munich, Germany) — An additional six months of data from the European cohort of the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial supports secondary conclusions from its previously reported main analysis, that cardiac resynchronization therapy (CRT) added to optimal medical therapy in patients with initially mild heart failure can turn the tide of the heart's remodeling changes known to contribute to HF progression [ color="blue">1]. The analysis at 18 months also suggested a favorable effect of CRT on clinical outcomes in this population.
However, as clinical outcomes at 12 months in the trial's overall population, from both sides of the Atlantic, constituted the trial's primary end point, which CRT failed to improve, there remains something of a disconnect in the evidence base between the clinical and cardiac-structural benefits of CRT in mild heart failure.
In the prospectively planned extended follow-up of the 262 European participants, those who had been randomized to having the CRT function of their devices programmed "on" showed significantly reduced LV end-systolic and end-diastolic volumes (LVESV and LVEDV, respectively) at 18 months, compared with those in the "CRT-off" group. Their LVEF improved significantly as well, as did their time to first HF hospitalization, reported REVERSE principal investigator Dr Cecilia Linde (Karolinska Hospital, Stockholm, Sweden) here at the European Society of Cardiology Congress 2008.
Those secondary end points had also improved with CRT at one year in the trial's overall population of 610 patients from both Europe and North America, as Linde presented at and heartwire reported from the American College of Cardiology 2008 Scientific Sessions. The patients, who entered the trial with NYHA 1 or 2 heart failure, a QRS duration >120 ms, an LVEF <40%, and echocardiographic evidence of LV dilatation, had been randomized to receive (n=419) or not receive (n=191) CRT.
REVERSE investigators had also announced at the Heart Rhythm Society 2008 Scientific Sessions, and heartwire then reported, that CRT was not associated with a reduction in ventricular arrhythmias at one year.
In the current subanalysis, the "CRT-on" patients also showed a reduction (p=0.007) in a "composite clinical score" consisting of all-cause mortality, heart-failure hospitalizations, CRT activation due to worsening heart failure, worsened NYHA class, and patient global assessment--in contrast to the overall population at one year, for whom it was the primary end point.
In fact, the failure of REVERSE to show a significant difference in its primary end point disappointed some who had hoped that the clinical benefits seen in NYHA class 3-4 heart failure would apply to milder disease as well, as had been suggested in observational studies. Others were heartened by CRT's apparent benefits in the secondary end points and point to the solid reverse-remodeling data as evidence that CRT may be appropriate in mild heart failure.
European Subanalysis at 18 Months in the REVERSE Trial
|End Point||CRT-Off, n=82||CRT-On, n=180||p|
|Clinical composite score* (% worsened)||29||15||0.007|
*Primary end point of the 12-month analysis: all-cause mortality, heart-failure hospitalizations, CRT activation due to worsening heart failure, worsened NYHA class, and a patient global assessment
Rates of first HF hospitalization at 18 months were 11.2% for CRT-off and 3.9% for CRT-on patients, for an adjusted hazard ratio in the CRT-on group of 0.34 (p=0.03).
There were no significant differences between the groups in quality-of-life findings on the Minnesota Living with Heart Failure Questionnaire or functionally according to six-minute-walk distance. In both groups, both measures improved dramatically during the first six months, after which there was little further change. Nor did the groups differ with respect to change in NYHA class or mortality, which at 18 months was 4.9% for CRT-off patients and 2.3% for the CRT-on group.
Discussant Dr Panos E Vardas (Heraklion University Hospital, Crete, Greece), president-elect of the European Heart Rhythm Association, lauded REVERSE for showing that CRT, consistent with earlier, smaller studies, can reverse cardiac remodeling associated with heart failure and probably reduce hospitalizations in patients with mild heart failure. "But we have to accept that there are some questions raised," he said, that should be explored in further trials.
Those questions, according to Vardas, include unknowns about CRT cost-effectiveness and the potential for implantation-related complications in patients who aren't as sick as those in NYHA 3-4, for whom the devices are currently indicated. "Do the benefits observed justify the implantation of an expensive and potentially risky device in patients with mild heart failure?"
REVERSE was sponsored by Medtronic. Linde reports that she has received consulting fees and research grants from Medtronic and consulting fees from St Jude Medical. Vardas had no disclosures.
Linde C. Progressive reverse remodeling in patients with mild or asymptomatic heart failure with previous symptoms in the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study. European Society of Cardiology Congress 2008; September 3, 2008; Munich, Germany. Clinical trials update 3.
Heartwire from Medscape © 2008 Medscape
Cite this: Steve Stiles. REVERSE at 18 Months: Questions About CRT for Mild Heart Failure Remain - Medscape - Sep 08, 2008.