We conducted a multicenter, nonblinded, randomized trial at 127 clinical sites in 26 countries.15
The trial was sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. Additional support was provided by Abbott Laboratories, Chase Medical, and CV Therapeutics, which had no role in the design, conduct, or reporting of the trial. The trial protocol was designed by the authors in collaboration with the NHLBI and was approved by the appropriate institutional review board or ethics committee at each study center. Trial operations, site management and monitoring, and data collection and analysis were coordinated by the Duke Clinical Research Institute. Oversight was provided by an independent data and safety monitoring board. A clinical events committee whose members were unaware of study-group assignments adjudicated primary outcome events. The authors wrote the manuscript and vouch for the completeness and accuracy of the data and the analyses.
SELECTION OF PATIENTS AND RANDOMIZATION
Patients were eligible for enrollment if they had coronary artery disease that was amenable to CABG and if they had a left ventricular ejection fraction of 35% or less (). Exclusion criteria were a recent myocardial infarction, a need for aortic-valve replacement, a planned percutaneous coronary intervention (PCI), and coexisting noncardiac disease resulting in a life expectancy of less than 3 years. All patients provided written informed consent.
Enrollment and Outcomes in the STICH Hypothesis 1 and Hypothesis 2 Trials
After initial determination of overall eligibility for the trial, patients were evaluated to determine which component of the STICH program was appropriate for them on the basis of suitable therapeutic options for that patient (medical therapy alone, CABG alone, or CABG plus surgical ventricular reconstruction) (). Patients who had stenosis of the left main coronary artery of 50% or more or who had angina of Canadian Cardiovascular Society (CCS) class III or IV while receiving medical therapy were not eligible for medical therapy alone. All patients underwent cardiac imaging for assessment of left ventricular function and wall motion. Patients who were found to have dominant anterior akinesia or dyskinesia of the left ventricle were considered to have disease that was amenable to surgical ventricular reconstruction.
Using these guidelines, physicians who were responsible for the conduct of the trial selected the randomization stratum for each patient that appeared to offer treatment possibilities with equivalent potential risks and benefits. Permuted-block randomization was used, with stratification according to clinical site and according to whether the patient was a candidate for SVR, for medical therapy alone, or for both ().
The resulting trial included two major components. Patients in the Hypothesis 1 component were randomly assigned to receive either medical therapy alone or medical therapy plus CABG. The Hypothesis 1 component of the trial is ongoing. Patients in the Hypothesis 2 component were randomly assigned to receive either medical therapy plus CABG or medical therapy plus CABG and surgical ventricular reconstruction. The results of the Hypothesis 2 component are the subject of this report.
Guideline-based recommendations for drug and device use were emphasized for all patients. The lead cardiologist at each site was responsible for monitoring to ensure that ACE inhibitors, angiotensin-receptor blockers, beta-blockers, aldosterone antagonists, antiplatelet agents, statins, diuretics, digitalis, pacemakers (for bradyarrhythmias or for cardiac resynchronization), and implantable cardioverter–defibrillators were used properly throughout the study.
Cardiac surgeons were individually certified to participate in the trial if they met prespecified performance criteria. For CABG certification, surgeons were required to provide data on at least 25 patients with a left ventricular ejection fraction of 40% or less who underwent CABG, with a death rate of 5% or less. Education in the operative technique for surgical ventricular reconstruction and perioperative management was made available before patient enrollment and during investigator meetings. Certification of individual surgeons for performing surgical ventricular reconstruction required evidence of a consistent postoperative decrease in left ventricular volume in five consecutive patients who survived the operation.
During CABG, arterial grafting for stenosis of the left anterior descending coronary artery was required for all patients without specific contraindications. The use of additional arterial conduits supplemented by vein grafts was recommended for revascularization of all major vessels with clinically significant stenoses. Concurrent mitral-valve surgery for regurgitation was performed at the discretion of the surgeon.
The technique of surgical ventricular reconstruction has been described previously.11,12,17
For patients who were assigned to undergo surgical ventricular reconstruction, this component of the operation was most commonly performed during a single period of cardioplegic arrest after construction of bypass grafts. However, the procedure could also be performed with the heart beating in order to facilitate identification of the noncontractile zone of scarring. In this procedure, after an anterior left ventriculotomy is centered in the zone of anterior asynergy, a suture is placed in the interior of the ventricle to encircle the scar at the boundary between the akinetic and viable tissue. Tightening of this suture brings the healthy portions of the ventricular walls together. Visual inspection and palpation facilitate the judgment of whether a patch is needed to optimize the chamber size without deforming the left ventricle during closure of the ventriculotomy.
PRIMARY AND SECONDARY OUTCOMES
Major perioperative events and specified end points were recorded at discharge or at 30 days for patients remaining in the hospital. Patients were evaluated at 4-month intervals after randomization during the first year and thereafter at 6-month intervals.
Symptoms of angina and heart failure were assessed at each follow-up visit. All patients who were able to do so performed a 6-minute walk test at baseline, at 4 months, and annually thereafter. Left ventricular volumes and function were assessed with the use of echocardiography, cardiac magnetic resonance imaging, or single photon emission computed tomography at baseline, at 4 months, and at 2 years.
The primary outcome was the time to death from any cause or hospitalization for cardiac causes. Secondary outcomes included death from any cause at 30 days, hospitalization for any cause and for cardiovascular causes, myocardial infarction, and stroke.
We calculated that we would need to enroll 1000 patients in the trial for a power of 90% to detect a 20% reduction in the relative risk of death or hospitalization for cardiac causes, assuming a 3-year event rate in the CABG-only group of 45% or more and allowing for a crossover rate of up to 20%.
All major study-group comparisons were performed according to the intention-to-treat principle. Supplementary analyses
tabulated postoperative complications and clinical events occurring within 30 days, according to the type of operation that was performed. All statistical tests were two-tailed. Cumulative event rates from the time of randomization were calculated with the use of the Kaplan–Meier method.18
The log-rank test for time-to-event data was used for the statistical comparison of study groups with respect to the primary outcome and overall mortality.19
Hazard ratios with associated 95% confidence intervals were derived with the use of the Cox proportional-hazards model.20
The Cox model was also used to assess the consistency of treatment effects by testing for interactions between the type of surgery and prespecified baseline characteristics.
Eight interim analyses of the data were performed and reviewed by the data and safety monitoring board. Interim comparisons between study groups were monitored with the use of two-sided, symmetric O’Brien–Fleming boundaries generated with the alpha-spending-function approach to group-sequential testing.21,22
A P value of 0.05 or less was considered to indicate statistical significance. Because of the sequential monitoring, the level of significance that was required for the primary analysis at the completion of the study was 0.04.