Title of Trial:
Multicenter InSyncRandomized Clinical Evaluation (MIRACLE)
Background:
Cardiac resynchronization therapy (CRT) has emerged as a new treatment for heart failure in patients with intraventricular conduction delays or ventricular dysynchrony. Previous studies have demonstrated improvements in patients âsymptoms and exercise capacity.
The purpose of the study was to compare the effect of CRT versus no CRT on quality of life and functional capacity in patients with chronic heart failure and ventricular dysynchrony and to assess the safety of CRT using Medtronic InSYNC system in patients with chronic heart failure.
Inclusion criteria included: 18+ years of age, NYHA Class III or IV, QRS duration 130 ms or greater, EF 35 % or less, LVEDD 55mm or greater, a stable heart failure regiment for 1 month or more including an ACE inhibitor, and if patient prescribed a beta-blocker for 3 months.
Following baseline assessment, patients underwent implantation within 1 week. Following successful implant, patients underwent a pre-discharge randomization to control group (no CRT) or CRT. The patient underwent a 6 month period of double-blinded study with follow-up at 1, 3, and 6 months. The patients in the control arm were then given the opportunity to go into the resynchronization mode. Patients were followed at 9 months and all patients continued to be followed at 6 month intervals.
The electrophysiologist serves as unblinded third party. The heart failure specialist, the managing physician, and the patient were blinded to the study assignment during the 6 months of the study randomization.
The primary efficacy endpoints: improvements in quality oflife using the Minnesota Living with Heart Failure Questionnaire, improvements in NYHA functional class, and improvement in 6 minute hall walk.
The power calculations resulted in a sample size of 224 patients followed for 6 months. The safety objectives included electrical function of the system, implant success of 80% or greater, and complications ofthe device, leads or system as a whole. Secondary efficacy endpoints included metabolic exercise evaluation, echocardiographic measures of systolic and diastolic heart function and structure, neurohormonal evaluation, and acomposite response in which patients were judged to be improved, unchanged, or worsened.
Enrollment of the patients in the pivotal phase was concluded in June, 2000 but enrollment continued through December, 2000 in anexpansion phase. In the pivotal phase, 266 patients were randomized to control or CRT. There were only 22 exits during the 6 month period of controlled evaluation. Eighteen patients died, 2 patients from the control group crossed over to CRT, and 1 patient from each arm were lost due to miscellaneous causes. The number of deaths, 10 in the control group and 8 in the CRTgroup, were not different but the study was underpowered to detect a difference in mortality.
There were 119 patients completing the control arm and 125 patients completing the CRT arm. The demographics of the patients included:
| | Control | CRT |
| Number | N=119 | N=125 |
| Age | 65+11 | 63+11 |
| NYHA II | 92% | 90% |
| QRS Duration (ms) | 165 | 165 |
| EF | 21% | 22% |
| LV EDD mm | 69 | 69 |
| Heart Rate bpm | 76 | 74 |
| ACE Inhibitor | 87% | 94% |
| Beta-blockers | 48% | 60% |
There was an implant success of 93%. All device, lead, and system, performance criteria were exceeded.
CRT improved the 6 minute hall walk distance with an average improvement of 39 meters at the end of 6 months. The improvements were highly significant (1 month p=0.032, 3months p=0.004, 6 months p= 0.033).
CRT resulted in an improved Minnesota Living with Heart Failure score with an average of 19 points with an marked placebo effect observed as well. The treatment effect was highly significant.
CRT had a significant improvement in NYHA Class with an average improvement of 0.8 class. There was a change in the distribution of NYHA Class. At 6 months, 65% of patients in CRT had improved to Class I or II while only 30% of patients in the control group had such improvement.
A pre-specified clinical levels of significance were 1Class, 13 points, and 50 meter in the primary endpoints. For each combination of the endpoints, all 3 endpoints, hall walk plus quality of life, hall wall plus NYHA Class, and quality of life plus NYHA, the proportion in the CRT group exceeded the proportion in the control group. For example, 12% of the control group had clinically significant improvements in all three endpoints while 33% of the CRT group had such changes.
In the control group there was no change in the Peak VO2 while there was a borderline significant on average 1 ml/kg/min improvement was seen in the CRT group. There was a 100 second average increase I the Naughton protocol duration.
Echocardiography demonstrated a significant decrease in the LVEDD dimension 0.5cm on average (0<0.001) and an increase in LVEF on average 6% improvement (p<0.001).
A major secondary endpoint was the composite clinicalresponse. Patients were defined as improved if they have had an improvement in NYHA or in global clinical assessment , as worse if the patient had died, had worsening heart failure leading to hospitalization or permanent withdrawal of therapy, or worsening of NYHA or global assessment, or unchanged if the patient met none of these criteria.In the CRT group 63% were classified as improved while 38% of the control group were improved.
In summary in NYHA III and IV systolic heart dysfunction with intraventricular conduction delays biventricular pacing ( cardiac resynchronization ) is safe and well-tolerated, improves quality of life, functional class, exercise capacity, and heart failure composite response.
Review written by Paul J. Wang, M.D.
