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Abstract & Commentary
Synopsis: Cardiac resynchronization using biventricular pacing improves a broad range of measures of cardiac function and clinical status in patients with moderate-to-severe heart failure and a prolonged QRS interval.
Source: Abraham WT, et al. N Engl J Med. 2002;346: 1845-1853.
The multicenter insync randomized clinical Evaluation (MIRACLE) trial was a double blind study of biventricular pacing, also referred to as "cardiac resynchronization" in patients with moderate-to-severe heart failure and a prolonged QRS duration. Patients could be included in the study if they had Class III or IV chronic heart failure. All patients had an ejection fraction of 35% or less, a left ventricular and diastolic dimension of 55 mm or more, a QRS interval of 130 msec or greater, and a 6-minute walking distance of 450 m or less. Patients were treated with a full pharmacologic regimen for heart failure including a diuretic, an angiotensin converting enzyme inhibitor, or an angiotensin receptor blocker, a beta blocker, and digitalis. At baseline, patients underwent a 6-minute walking test, a maximum treadmill exercise test using a modified Norton protocol, a quality of life evaluation, and 2 dimensional Doppler flow echocardiography. Patients then underwent implantation of a biventricular pacemaker (InSync model 8040, Medtronic, Minneapolis, Minn) using a right atrial lead, a right ventricular lead, and a left ventricular placed in the distal coronary sinus using a guiding catheter. If the implant was successful, patients were randomly assigned to atrial synchronized, biventricular pacing, or to no pacing for 6 months, during which time medications for heart failure were to be kept constant. The physicians managing the patients’ heart failure and the patients themselves were not aware of the treatment assignment. An electrophysiologist who was not otherwise involved in patient care or the symptom and quality of life evaluations did the pacemaker programming. Three end points were assessed: New York Heart Association class, quality-of-life score, and the 6-minute walk distance. Secondary end points included peak oxygen consumption, treadmill time, left ventricular ejection fraction, left ventricular and diastolic dimension, and a composite response of several clinical parameters.
A total of 453 patients who underwent successful device implant are described in the study, 225 patients in the control group, and 228 patients in the cardiac resynchronization group. The mean age was about 64 years with 68% male and 90% white. More than half of the patients had ischemic cardiomyopathy with 90% in the New York Heart Association functional class III. The mean QRS duration was 166 msec and the left ventricular ejection fraction was 21.7%. A small number of patients did not complete 6 months of follow-up. In the control group, 16 patients died, 2 received a heart transplant, 1 had complications with the device, and 5 missed the 6-month visit. In the cardiac resynchronization group, 12 died and 1 had complications related to the device. There were 7 patients in the control group who crossed over to cardiac resynchronization because of either worsening heart failure (7), or bradycardia (3).
In comparison to the control group, patients assigned to cardiac resynchronization improved their 6-minute walk distance (+39 vs +10 meters) and their living with heart failure score (-18 vs -9). More patients in the resynchronization group improved by 2 or more New York Heart Association functional classes (16% vs 6%) and by at least one class (68% vs 38%). In the cardiac resynchronization group, 79% of the patients recorded themselves as slightly, moderately, or markedly improved vs. 57% of the control group. There were 50 hospitalizations for heart failure in 34 control patients for a total of 363 hospital days vs 25 hospitalizations for heart failure for a total of 83 days in 18 patients in the resynchronization group. Complications were noted in approximately 7% of implant procedures. This included 2 deaths, 2 episodes of complete heart block that required permanent pacing, 23 patients with coronary sinus dissection, and 12 patients with cardiac perforation. Any acute complications were noted in 30 patients and 7 patients developed a late pacemaker related infection.
Abraham and colleagues conclude that cardiac resynchronization using biventricular pacing improves a broad range of measures of cardiac function and clinical status in patients with moderate to severe heart failure and a prolonged QRS interval.
Comment by John P. DiMarco, MD, PhD
Earlier short-term or uncontrolled studies had shown hemodynamic and symptomatic improvement with biventricular pacing. It had been noted that some patients are sensitive to negative hemodynamic effects from right ventricular apical pacing and from delayed activation of one ventricle due to bundle branch block. This clinical study is the first large-scale randomized trial to assess the short-term benefits of biventricular pacing. This study clearly shows overall improvement with biventricular pacing. However, it must be noted that a significant proportion of patients in the control group also reported some improvement. Although it is hoped that ventricular pacing would also improve mortality, this study was too small to detect a mortality difference. Further large trials of biventricular pacing and devices that combine both biventricular pacing and fibrillation capacity are now underway.
Current techniques for biventricular pacing remain cumbersome but there has been rapid progress in the tools available to implanting physicians. If, as expected, these tools further improve, biventricular pacing may become the standard approach in patients with systolic dysfunction whether they have symptomatic bradycardia.
As should be expected with any new therapy, significant questions remain about cardiac resynchronization with biventricular pacing. We need to know if the symptomatic benefits persist long term or do they dissipate over a relatively short time. Does biventricular pacing reduce the risk of atrial and ventricular arrhythmias or should most devices also include defibrillation capability? How wide must the baseline QRS be to derive benefit? Should everyone with a wide QRS improve if the left ventricular lead is optimally placed or are there some patients who will not respond? We can expect to see many more studies on cardiac resynchronization that should shed light on these important questions.
Dr. DiMarco is Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville.