Discussion
angina, chest pain, myocardial ischemia, treatment-resistant angina pectoris, chronic myocardial ischemia, deaths, chronic coronary syndrome
ACUTE MYOCARDIAL INFARCTION, REFRACTORY ANGINA PECTORIS, ADVERSE EVENTS, CHRONIC CORONARY SYNDROME, MYOCARDIAL ISCHEMIA, ADVERSE EFFECT, CHRONIC MYOCARDIAL ISCHEMIA, EVENTS
In the present study, we conducted a pilot trial to examine the efficacy and safety of the LIPUS therapy for patients with refractory angina. We found no significant differences in the primary subjective endpoints between the 2 groups. There was no serious adverse effect of the LIPUS therapy. To the best of our knowledge, this is the first clinical trial to address the efficacy and safety of the LIPUS therapy in patients with refractory angina.In the past clinical trials for chronic coronary syndrome, most of the investigators focused on 2 major outcomes, including frequency of chest pain and long-term prognosis [Based on these results, we consider that the efficacy of the LIPUS therapy was not shown in the present protocol. However, by analyzing myocardial perfusion imaging in individual cases, we found that some cases showed improvement in myocardial ischemia that could be regarded as a “responder”. In order to assess these cases, we performed an additional post-hoc analysis after adjusting the baseline myocardial ischemic volume. We found a significant correlation between the extent of baseline myocardial ischemia and the anti-ischemic effect of the LIPUS therapy. Furthermore, the LIPUS therapy tended to improve long-term prognosis as compared with the placebo group. From these results, we consider that a next pivotal trial with a larger number of patients and objective endpoints is required for future evaluation of the LIPUS treatment.Mechanistically, we need to consider whether the total amount of LIPUS irradiation in the present study was enough to exert sufficient therapeutic effects. In the present trial, LIPUS was applied for 3 cross-sections for 20 min each from the base to the apex of the heart 3 days in a week. The similar conditions of the LIPUS therapy have been shown to exert eNOS-mediated angiogenic effects in porcine model of chronic myocardial ischemia and mouse model of acute myocardial infarction [Several limitations should be mentioned for the present study. First, as discussed above, we need to define objective findings, especially myocardial flow-related data, as objective primary endpoint. Second, the number of patients was small for statistical validation. Third, as discussed above, in order to enhance the anti-ischemic effects, repetitive performance of the LIPUS therapy for the whole heart needs to be considered for the next pivotal trial. Fourth, in this study, patients with treatment-resistant angina pectoris were enrolled compared to the past studies shown above, and it is possible that the trial design was difficult to mining the effectiveness of the LIPUS therapy. Fifth, regarding the occurrence of competing risk events, only one or two deaths and discontinuation due to adverse events occurred, which was quite small. As a result, the need of using competing risk analysis has become less. All these considerations need to be included when designing the protocol of the next pivotal trial.In summary, in the present pilot trial, we demonstrate the safety but not the additional efficacy of the LIPUS therapy for patients with refractory angina pectoris treated with optimal medical therapy. The present findings need to be further examined in the next pivotal trial with a large number of patients and modified protocols of the LIPUS therapy with objective endpoints.