Study protocols
diabetic retinopathy, malignancies, myocardial ischemia, angina
DIABETIC RETINOPATHY, MALIGNANCIES, MYOCARDIAL ISCHEMIA
We enrolled patients with refractory angina without indication of PCI or CABG despite optimal medical therapy, who had angina episode at least once a week. Specifically, on the premise that existing optimal medical therapy has been performed, we enrolled patients who were found to be difficult to apply PCI or CABG due to the lack of graftability or complexity of lesions at the heart team conference. Angiography was performed in all enrolled patients, and only patients who have evidence of myocardial ischemia by invasive functional evaluation or stress myocardial perfusion imaging were enrolled. They were enrolled in 2013–2018, and were able to regularly visit an outpatient clinic. The registration of this study was extended from 3 years to 6 years because of the interruption of funding source midway through. All the patients were given informed consent and they were obtained by written form. They were randomly and automatically assigned to either the LIPUS group or the placebo group in a 1:1 fashion, according to the following 4 allocation factors; Canadian Cardiovascular Society (CCS) class score (II, III or IV), weekly use of nitroglycerin (4 times a week or less, or 5 times a week or more), left ventricular ejection fraction (40% or more, or less than 40%), and participating hospital. In this trial including 10 participating institutes, because 4 stratification factors were used, our first sample size setting was 80 patients. However, it was redesigned to enroll 60 patients in the middle of the trial due to delays in patient enrollment. In order to avoid any possible pathological angiogenesis, patients with malignancies or uncontrolled diabetic retinopathy were excluded. The diagnosis and approval of enrollment were made by a third-party committee. After we confirmed patient’s eligibility, subject information was sent to the registration center, randomized allocation was performed, and then the allocation results were documented to the open-label treatment physicians at each institution. In this study, all participating physicians and supporting staff except un-blinded physician who handled the LIPUS or placebo procedure were blinded. Authors could not access to the information that could identify individual participants during data collection. This study was conducted at 10 major cardiovascular institutes in Japan, including Kumamoto University Hospital, Kurume University Hospital, Hyogo Medical University Hospital, Fujita Health University Hospital, Tokyo Women’s Medical University Hospital, Nihon University Hospital, Tokyo Medical University Hospital, Juntendo University Hospital, National Cerebral and Cardiovascular Center, and Tohoku University Hospital. This study was approved by the institutional review board of each institute under the Good Clinical Practice and was conducted with the ethical principles under the Declaration of Helsinki. The protocol of the present study was approved by the institutional review board of the Tohoku University Hospital (No. 133004) and was registered as UMIN Trial ID: UMIN000012369. All the clinical data obtained in this trial can be disclosed upon appropriate request.