ACC 2009: REVERSE at 24 Months: CRT Modifies Disease Progression And Improves Clinical Outcomes

from <a href="" target="_blank">Heart<i>wire</i></a> &#151; a professional news service of WebMD

March 31, 2009

March 31, 2009 (Orlando, Florida) — The data at 12 and 18 months didn't provide it, but two-year results from the European cohort of the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial has shown that cardiac resynchronization therapy (CRT) added to optimal medical therapy in patients with initially mild heart failure modifies disease progression and improves clinical outcomes.

Presented today during the late-breaking clinical-trials session here at the American College of Cardiology 2009 Scientific Sessions, investigators reported that patients with mild heart failure, impaired left ventricular function, and a wide QRS duration randomized to CRT had significantly less clinical worsening than patients who did not receive the resynchronization therapy.

The results contrast with findings at 12 months, which were presented last year and showed no statistically significant difference in clinical worsening between the two arms, although there was an improvement in symptoms that encouraged investigators.

"It's mostly a question of time, because it takes time to have an effect in mild or asymptomatic heart failure," said Dr Cecilia Linde (Karolinska Hospital, Stockholm, Sweden) during a morning press conference announcing the results. "Of course, if you follow patients for 24 months, you find more benefit than if you follow patients for 12 months. I think if we were designing the study all over again we would certainly have two-year follow-up for all patients."

REVERSE at Two Years in European Patients

Presented last year, the 12-month results from REVERSE provided some evidence suggesting that CRT benefited patients with ventricular dyssynchrony and the mildest forms of heart failure--that is, those who are asymptomatic as a result of therapy or are only mildly symptomatic.

As reported by heartwire, the trial missed its primary end point, a clinical composite response that assessed worsening of heart failure through subjective and objective measures that included all-cause mortality, heart-failure hospitalizations, crossover due to worsening heart failure, NYHA class, and the patient global assessment. However, device therapy did improve left ventricular end-systolic volumes (LVESV) and end-diastolic volumes (LVEDV), which translated into higher left ventricular ejection fractions.

In this prospectively planned 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 LVESV and LVEDV at 24 months, compared with those in the "CRT-off" group. In contrast to the 12-month results, investigators also report that those randomized to CRT had less clinical worsening, and there was also a 62% relative risk reduction in time to first hospitalization or death, when compared with those not receiving therapy.

European Analysis at 24 Months in REVERSE

End point CRT-off (n=82) CRT-on (n=180) p
Clinical worsening* (%) 34 19 0.01
LVESV (mL/m2) 94.5 69.7 <0.0001
LVEDV (mL/m2) 132 103 <0.0001
LVEF (%) 29.9 34.8 <0.0001
First hospitalization or death (%) 24.0 11.7 0.003

Presenting the results during the late-breaking clinical-trials session, Dr Jean-Claude Daubert (Centre Hospitalier Universitaire, Rennes, France) noted that the difference in the progression in clinical worsening occurred early, at six months, compared with the overall cohort, and persisted to 24 months. He pointed out that these European patients differed significantly from the overall patient population in that they were younger, had less ischemic etiology, had larger ventricles, and wider QRS durations.

Overall, there was no change in the functional parameters, including the Minnesota Living with Heart Failure Questionnaire, the six-minute-walk test, and NYHA class.

"When you focus on severe heart failure like we did during the CRT trials, it was a matter of proving really quickly that you had some benefit," Linde told reporters. "Now we're dealing with the vast majority of patients who come in with heart failure, they get put on drugs, such as beta blockers, and they come back to the clinic feeling well. They're in functional class 1 or 2, and you want to keep them there. The way to do that, in our mind, is with CRT in patients with the broad QRS complex and the presence of poor left ventricular function. This will keep them asymptomatic so much longer."

Commenting on the results of the study, Dr Richard Page (University of Washington, Seattle) noted the study moves beyond the current indication for a biventricular device and said he had trouble "reconciling the data" in terms of the lack of functional benefit despite the modification of disease progression and reverse-remodeling effect.

"I'm having some trouble being convinced of true improvement in functional capacity, especially when you put that into context of some downside, and not just cost, of having the device," said Page.

During the clinical-trials session, Daubert said he has no explanation for the lack of improvement in functional capacity but suggested, as did Linde, that because patients included in REVERSE were asymptomatic or only mildly symptomatic, they were unlikely to see changes in functional capacity.

The increasing number of pacing leads did result in complications, noted investigators. In REVERSE, complications arose in roughly 10% of patients and were confined to the left lead, including lead dislocation and perforation of the coronary sinus, in the first year, and to the right lead in year two.

Although the larger morbidity and mortality trials testing the value of CRT in these patients are still ongoing, the REVERSE investigators believe the results have the potential to lower the threshold for who is eligible for CRT.

"I think the study results go hand-in-hand with what is about to emerge from other morbidity and mortality trials, like MADIT-CRT and RAFT, and, provided they show exactly the same results, I think these three trials will change therapy so that New York Heart Association class 1 and 2 patients will be indicated for CRT provided they have poor left ventricular function and broad QRS," said Linde.

Linde told the media that a cost-effective analysis is currently being done and will be presented shortly.

Medtronic sponsored the REVERSE trial. Linde reports consulting fees and research grants from Medtronic and St Jude Medical. Daubert reports speaker's and consulting fees from St Jude and Medtronic. Page reports speaker's and consulting fees from Sanofi Aventis, Astellas Pharma, and Pfizer.

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