Boston, MA - Although some questions remain, the publication of the Cardiac Resynchronization-Heart Failure (CARE-HF) trial should eliminate most doubts about the value of cardiac resynchronization therapy (CRT) for many patients with moderate-to-severe heart failure.[1] CARE-HF, which appears in the April 14, 2005 issue of the New England Journal of Medicine, culminates years of randomized trials that ultimately show that CRT not only improves symptoms and functional outcomes, it also reduces mortality and HF hospitalizations in patients initially with LV dysfunction and ventricular dyssynchrony of either ischemic or nonischemic etiology.

The trial extends the landmark findings of the previously published COMPANION trial by showing a significant all-cause mortality reduction for CRT pacing without defibrillator backup (CRT-P) in similar medically treated HF patients.

In COMPANION, CRT-P or CRT with defibrillator capability (CRT-D) significantly reduced a composite one-year end point of all-cause mortality or hospitalization.[2] But while CRT-D also significantly lowered all-cause mortality as a solo end point, the corresponding CRT-P reduction fell short of significance.

"It is thus now firmly established that [CRT] not only reduces symptoms and improves objective measures of left ventricular function but also prolongs survival in patients with moderate-to-severe [HF] and ventricular dyssynchrony," writes Dr John A Jarcho, deputy editor at the Journal, in an accompanying editorial published for the first time.[3] [CARE-HF had been reported in March at the American College of Cardiology 2005 Scientific Sessions and covered by heartwire, at which time it was also formally published online.]

Retarding the progression of cardiac dysfunction to prevent malignant arrhythmias may be a better strategy than treating [them] once they occur, because defibrillation is stressful to the patient and associated with an adverse prognosis.

CARE-HF randomized 813 patients with NYHA class 3-4 HF despite standard drug therapy, an LVEF <35%, and QRS duration of at least 120 ms. Those with a QRS duration of less than 150 ms were also required to have echocardiographic confirmation of ventricular dyssynchrony. Patients either continued with their medical therapy or were given CRT-P on top of it.

Over a mean follow-up of nearly 30 months, CRT was associated with significant, deep reductions in the risk of the primary end point—all-cause mortality or an unplanned CV hospitalization—and of the secondary end point of all-cause mortality.

Those in the CRT group also benefited significantly with improved LVEF, NYHA class, end-systolic volume, mitral-valve function, blood pressure, quality-of-life indices, and levels of an emerging CV-risk biomarker, N-terminal pro-B-type natriuretic peptide (NT-proBNP).

"The data are consistent with a resynchronization-induced reduction in cardiac dyssynchrony, leading to a sustained increase in left ventricular performance and a diminution of mitral regurgitation and, in turn, a rise in perfusion pressure, a fall in cardiac filling pressure, and favorable left ventricular remodeling," write CARE-HF authors Dr John GF Cleland (University of Hull, Kingston-upon-Hull, UK) and associates.

The CRT-P-related all-cause mortality reduction in CARE-HF was very similar to what was observed in COMPANION for CRT-D, observe Cleland and associates. In their trial, they write, the superior survival of patients who received CRT-P owed to reductions in both sudden death and death from worsening HF. Although the addition of a defibrillator to CRT-P might further reduce overall mortality, they write, "Retarding the progression of cardiac dysfunction to prevent malignant arrhythmias may be a better strategy than treating malignant arrhythmias once they occur, because defibrillation is stressful to the patient and associated with an adverse prognosis."

According to Jarcho's editorial, CARE-HF also supports the use of CRT in NYHA class 4 patients "who do not desire an [ICD] but who do desire a treatment to improve their quality of life without the risk of painful shocks from a cardioverter-defibrillator."

Questions about CRT-P that remain, according to Jarcho, include uncertainty over whether it can benefit patients in NYHA class 2, how best to identify LV dyssynchrony in candidates, whether the strategy can work well in patients with atrial fibrillation, and why it doesn't benefit some patients who meet the eligibility criteria. For the last question, he speculates that such failures may result from unsuccessful lead placement or overestimation of LV dyssynchrony when screening for CRT eligibility.