Abstract & Commentary
Comments by John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco is on the Editorial Board of Clinical Cardiology Alert.
Synopsis: In patients with heart failure and cardiac dyssynchrony, cardiac resynchronization improves symptoms and the quality of life and reduces complications and the risk of death.
Source: Cleland JGF, et al. The Effect of Cardiac Resynchronization on Morbidity and Mortality in Heart Failure. N Engl J Med. 2005 (online edition).
Dr. John Cleland presented data from the Cardiac Resynchronization-Heart Failure (CARE-HF) study at the ACC meeting. CARE-HF was a multicenter, international trial comparing standard pharmacologic therapy for heart failure with the combination of standard therapy and cardiac resynchronization without a defibrillator in patients with left ventricular systolic dysfunction, cardiac dyssynchrony, and class III or IV heart failure. Patients were eligible for inclusion if they had New York Heart Association class III or IV heart failure, despite standard pharmacologic therapy. In addition, each had a left ventricular ejection fraction of no more than 35%, a left ventricular and diastolic dimension of at least 30mm, and a QRS interval of at least 120 m/sec. Patients who had a QRS between 120 and 149 m/sec were required to meet 2 of 3 additional criteria for dyssynchrony: an aortic pre-ejection delay of more than 140 m/sec, an interventricular mechanical delay of more than 40 m/sec, or a delayed activation of the posterior lateral ventricular wall. These parameters were assessed by an echocardiography core lab. Patients with a major cardiovascular event within the previous 6 weeks, those with conventional indications for pacing or an implantable defibrillator, and those with heart failure requiring continuous intravenous therapy were excluded. The study also excluded patients with atrial arrhythmias. Patients were randomly assigned to either standard pharmacologic therapy or pharmacologic therapy plus a cardiac resynchronization using a biventricular pacemaker. Attempts were made to position the left ventricular lead on the lateral or the posterolateral wall. Back-up atrial pacing was set at 60 bpm. The interventricular delay was set at 0 m/sec, and the AV delay was echocardiographically optimized. Patients were evaluated at 1, 3, 6, 9, 12, and 18 months, and every 6 months thereafter. Standard medications could be adjusted as appropriate. The primary end point was a composite of death from any cause or an unplanned hospitalization for a major cardiovascular event. Patients who underwent elective heart transplantation were censored 7 days after the procedure. Emergency transplantation was counted as a death.
Hospitalizations were adjudicated in a blinded fashion by an end points committee. Secondary outcome events included death from any cause and a composite of death from any cause and all hospitalizations. Serial changes in several quality of life measurements were also followed. Several echocardiographic and biochemical variables were assessed, including changes in the severity of dyssynchrony, ventricular dysfunction, mitral regurgitation, and terminal brain natriuretic peptide (BNP).
The study assigned 404 patients to medical therapy alone, and 409 patients received medical therapy plus cardiac resynchronization. The mean follow-up duration was 29 ± 4 months, with a range of 18-44.7 months. The study patients had a median age of 66, and approximately three-quarters were male. Seven percent of the patients were in New York Heart Association class IV. Fifty-eight percent of the patients had ischemic heart disease. Forty-five percent had idiopathic dilated cardiomyopathy, and 17% had heart disease of other causes. The median QRS duration was 160 m/sec, with an interquartile range of 152-180. The interventricular mechanical delay was 50 m/sec. A high percentage of patients were on ACE inhibitors, beta blockers, high dose loop diuretics, digoxin, and spironolactone in both groups.
In the cardiac resynchronization group, 82 patients died, compared to 120 patient deaths in the medical therapy group (20% vs 30%; hazard ratio 0.64, 95% confidence interval 0.48 to 0.85; P less than 0.002). The principal cause of death was classified as cardiovascular in 143 patients (71%), noncardiovascular in 34 patients (17%), and of unknown cause in 25 patients (12%). There were 38 sudden deaths in the medical therapy group and 29 sudden deaths in the cardiac resynchronization group. The mortality rate in the medical therapy group was 12.6% at 1 year and 25.1% at 2 years, compared with 9.7% and 18.0% in the cardiac resynchronization group.
As compared with patients in the medical therapy group, patients in the cardiac resynchronization group had less severe symptoms and a better quality of life. At the 18-month follow-up point, improvement in New York Heart Association class was noted in both groups, but the degree of improvement was greater in the cardiac resynchronization group. At that time point, in the resynchronization group, 105 patients were in New York Heart Association class I, 150 patients were in New York Heart Association class II, and 80 patients were in New York Heart Association class III or IV. In the medical therapy group, there were 39 patients in class I, 112 in class II, and 152 in class III or IV. At both 3 and 18 months, the left ventricular ejection fraction increased, the left ventricular end systolic volume index decreased, and the mitral regurgitation area reduction were greater in the cardiac resynchronization group. BNP levels were lower among patients in the cardiac resynchronization group.
Of the 409 patients assigned to cardiac resynchronization, the initial implant was successful in 349 (85%). An additional 41 patients had successful implantation on a subsequent attempt. The median duration of hospitalization for the initial implant was 5 days. During follow-up, the number of adverse device or procedure related events were noted. These included lead displacement (24 patients), coronary sinus dissection (10 patients), pocket erosion (8 patients), pneumothorax (6 patients), and device related infections (3 patients).
Cleland and colleagues conclude that cardiac resynchronization produced favorable effects on both symptoms and mortality in class III heart failure patients from all causes.
Cardiac resynchronization has become an important therapeutic option in patients with advanced heart failure and interventricular conduction delays. The early trials of CRT therapy typically showed a relatively short-term improvement in symptoms and functional status, but were not able to show an effect on mortality. The COMPANION trial, which compared resynchronization therapy only, resynchronization plus ICD therapy and optimal pharmacologic therapy showed an improved survival in the ICD group, but only a trend towards an improvement in mortality in the resynchronization only group. CARE-HF shows that CRT alone produces a benefit in mortality.
There are several features in this trial that should be recognized. Most of the patients had quite wide QRS durations. The median QRS duration was 160 m/sec.
Although patients could enroll with a QRS duration between 120 and 149, they had to have other measures of ventricular dyssynchrony to enter the trial. Therefore, we should be cautious when predicting benefit in patients, based only on a QRS duration of greater than 120 m/sec. In addition, this trial did not include a large number of very elderly patients. It still remains unknown whether CRT will show comparable benefits in patients late in life. Physicians must factor the patients’ ages into a decision of whether or not to prescribe CRT therapy. Finally, although all these patients had III or IV heart failure, patients who required intravenous infusions were not included, and renal function was relatively well preserved. Other centers now are beginning to report that patients who frequently or continuously require inotrope infusions, or who have significant renal dysfunction, respond poorly to resynchronization. Resynchronization should not be regarded as a rescue therapy for these patients with very advanced heart failure.
CARE-HF is an important study. It shows that resyncronization has an independent effect on mortality and symptoms. However, it seems unlikely that a large number of resynchronization only devices will be implanted. Recent changes in guidelines would include almost all of these patients as candidates for ICD therapy. Perhaps there will be occasional patients in whom symptom relief is needed, but sudden death protection may not be desirable.