First large-scale study of cardiac resynchronization therapy in advanced heart failure patients
Study shows that therapy improves exercise capacity and quality of life
Cardiologists meeting here today heard results of a landmark clinical trial showing that heart failure patients receiving a breakthrough new therapy to augment their standard medications exhibited marked improvement in exercise capacity and quality of life.
Presenters at the 50th annual Scientific Sessions of the American College of Cardiology (ACC) estimated that the new device-based cardiac resynchronization therapy from Medtronic, Inc., could potentially benefit as many as 750,000 seriously ill heart failure patients.
The Multicenter InSync Randomized Clinical Evaluation trial, known as MIRACLE, evaluated the therapeutic benefits of the Medtronic InSync Model 8040 atrial synchronous biventricular pacing device, the Model 9880 E software system, and the Attain LV and Attain CS pacing leads, in delivering cardiac resynchronization therapy.
William Abraham, MD, Chief, Division of Cardiovascular Medicine, University of Kentucky Hospital, and principal clinical investigator for the MIRACLE study, said after his presentation this morning, "The InSync cardiac resynchronization system improved the functional status of heart failure patients in New York Heart Association (NYHA) Class III and IV with concomitant left ventricular dysynchrony. These study results should bring hope to thousands of patients whose quality of life has been severely affected by heart failure. Cardiac resynchronization therapy may allow many patients who are not helped by drugs alone to resume many of their normal activities."
William George, Chairman and CEO of Medtronic, said, "The MIRACLE study results herald the beginning of a new era in device-based therapies designed to treat advanced heart failure. The InSync system delivers cardiac resynchronization therapy to patients who are not otherwise indicated for either pacing or ICD implantation. This means that an entirely new patient population - one that could only be managed with drugs or through major surgical intervention in the past - may have the option of benefiting from this unique, breakthrough treatment."
Steve Mahle, president, Medtronic Cardiac Rhythm Management, commented that the MIRACLE study results demonstrate the soundness of Medtronic's approach to heart failure management. "We intend to provide a variety of therapeutic combinations for clinicians treating heart failure so that they can select the most appropriate ones for their particular patients. The InSync family of cardiac resynchronization products -- including InSync, InSync ICD, and InSync III -- along with the Attain family of leads that Medtronic has developed specifically for these applications, will give physicians and heart failure patients multiple options in their quest to improve cardiac function, exercise capacity and quality of life."
Medtronic has filed a pre-market approval (PMA) application with the FDA for the InSync cardiac resynchronization system, which is investigational in the U.S. and commercially available in Europe.
Results Demonstrate Functional Improvement
The MIRACLE trial is the first rigorous study statistically powered to measure therapeutic benefits of cardiac resynchronization in a large number of patients with advanced systolic heart failure and ventricular dysynchrony. As a randomized, double-blind parallel controlled trial, the study design controls for the placebo effect of receiving an implanted therapeutic device. The MIRACLE study was designed to primarily measure therapeutic benefits as determined by changes in New York Heart Association (NYHA) functional classification, distance walked in six minutes and patients' perceptions of improvements in quality of life.The study results reported by Dr. Abraham show that a statistically significant proportion of patients in the treatment group responded positively to cardiac resynchronization therapy delivered by the InSync system as compared to the control group, with improvements noted in all of the study's primary efficacy endpoints. These include:
- An improvement in NYHA functional class: Compared to baseline, 69 percent of patients in the treatment group experienced an improvement in NYHA functional status by one or more class at six months, versus 34 percent in the control group. This metric represents the physician's assessment of changes observed in patients at six months. NYHA Class III heart failure patients are considered to be exercise-limited; Class IV heart failure patients are symptomatic at rest. Improvements of one or more class indicate an improved ability to perform the activities of daily life.
- Improvement in exercise capacity, as evidenced by an increase in six-minute hall walk distance of fifty meters or greater: Compared to baseline, 50 percent of patients in the treatment group walked 50 meters or more at 6 months versus 30 percent of patients in the control group. The six-minute hall walk represents a standard and valid measure of exercise capacity in evaluating treatment for heart failure patients.
- Improvement in Quality of Life, as measured by the Minnesota Living With Heart Failure Questionnaire. Patients receiving cardiac resynchronization therapy experienced a greater improvement in their quality of life. The improvements exceed similar measurements of advanced heart failure patients using standard medications such as beta-blockers and ACE inhibitors. This means that patients in the MIRACLE study, who were already receiving standard drug therapy, felt better as a result of cardiac resynchronization therapy.
- Reduction in systolic and diastolic volumes
- Increase in left ventricular ejection fraction
- Reduction in severity of mitral regurgitation
"There were no measures of efficacy for which the control group did better than the treatment group," said Dr. Abraham. "Measures of effectiveness that are generally viewed as resistant or less susceptible to placebo effect (e.g., six-minute hall walk, metabolic exercise testing, echocardiographic assessment of left ventricular structure and function, plasma norepinephrine levels) were significantly improved. The improvements in left ventricular ejection fraction and ventricular volumes demonstrated in this study represent a further improvement over those achieved with standard heart failure medications."
Heart Failure a Growing Problem
Heart failure is a major and growing health problem, with nearly five million Americans currently diagnosed, and up to 500,000 new cases each year, contributing to the estimated $38 billion to $40 billion expended to manage the disease in the United States alone. Researchers investigating the underlying pathophysiological mechanisms responsible for heart failure have identified several critical factors that contribute to its progression. Up to 50 percent of advanced heart failure patients have interventricular conduction delay or ventricular dysynchrony, which results in abnormal contraction of the heart. In addition, prolonged QRS duration in these patients causes abnormal septal wall motion, decreased contractility, reduced diastolic filling time and prolonged duration of mitral regurgitation, all of which contribute to deterioration of quality of life and are associated with increased mortality.Recent advances in drug therapy have improved cardiac function and survivability in these patients, but the great majority continues to suffer from poor exercise capacity and quality of life. While some have benefited from aggressive surgical interventions such as left ventricular assist devices and cardiac transplants, these have been restricted to a highly selected patient population.
Since 1994, investigators have used cardiac resynchronization to demonstrate acute and chronic improvements in cardiac function, hemodynamic parameters and symptoms. However, most studies to date were either non-randomized or smaller, single-blinded studies.
The MIRACLE Study is designed to determine whether initial positive reports from pilot studies concerning cardiac resynchronization therapy would be upheld in a prospective, multicenter, one-to-one, randomized, double-blinded, controlled trial using Medtronic's InSync system. Patients who met inclusion criteria (heart failure of at least one month duration, NYHA Class III or IV, QRS duration > 130 ms, left ventricular ejection fraction of < 35 percent, and not indicated for pacing or ICD therapy) were implanted with the InSync system within seven working days of their baseline evaluation. Patients were then randomized within 3 days after implant to either the control arm (cardiac resynchronization OFF) or the treatment arm (cardiac resynchronization ON) for a period of six months. All patients were programmed to ON following completion of the six-month follow-up visit and testing in their randomized mode.
Forty four (44) centers, 39 in the U.S. and five in Canada, provided data obtained from 266 implanted, randomized patients in the pivotal phase of the study. A total of 132 patients were randomized to the control group (therapy OFF), while 134 were in the treatment group (therapy ON). Of these 266 patients, 244 completed their six-month follow-up at the time of Dr. Abraham's report: 119 in the control group and 125 in the treatment group. The InSync device continues under clinical investigation in the U. S.
Useful in a New Patient Population
"Improvements in each of the primary objectives established for the study demonstrate the value of cardiac resynchronization therapy for this particular class of heart failure patient," Dr. Abraham told the ACC audience. "The MIRACLE trial is unique in that patients selected for the study are not currently indicated for a pacemaker or an ICD."The InSync and the InSync ICD cardiac resynchronization systems, along with several models of Attain leads, are commercially available in Europe. The InSync III device and the Attain Over The Wire lead are both under clinical evaluation in Europe and Canada. InSync, InSync ICD and InSync III devices, along with the Attain leads, are currently under clinical evaluation in the United States. Those interested in additional information on clinical trials involving these devices should call Medtronic at 800-930-9374.
Medtronic, Inc., headquartered in Minneapolis, is the world's leading medical technology company, providing lifelong solutions for people with chronic disease. Its Internet address is www.medtronic.com.
Source: Medtronic, Inc.