Saichi Hosoda

Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina : a multicenter study

Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.

Effect of Trapidil on Cardiovascular Events in Patients With Coronary Artery Disease (Results from the Japan Multicenter Investigation for Cardiovascular Diseases-Mochida (JMIC-M))

A large-scale study was conducted to assess the effect of long-term administration of trapidil on the prognosis of patients with angiographic evidence of coronary artery disease (CAD). A large-scale, multicenter study, the Japan Multicenter Investigation for Cardiovascular Diseases-Mochida was an open-label, randomized trial of 1,743 patients with CAD who were < or =70 years old and had angiographic evidence of >25% stenosis in any coronary artery. We randomly assigned the patients to receive medical treatment either with trapidil 100 mg 3 times daily (trapidil group, n = 873) or without trapidil (control group, n = 870). The mean follow-up period was 924 days. The incidence of cardiovascular events, including cardiac death, nonfatal myocardial infarction, angina pectoris/heart failure requiring hospitalization, and cerebrovascular events was 11.1% in the trapidil group and 14.9% in the control group (relative risk 0.75, 95% confidence interval 0.58 to 0.98, p = 0.036). Thus, long-term intervention with trapidil in CAD reduces the incidence of cardiovascular events and improves the prognosis of patients with CAD.

Nifedipine retard prevents hospitalization for angina pectoris better than angiotensin-converting enzyme inhibitors in hypertensive Japanese patients with previous myocardial infarction (JMIC-B substudy)

Objectives and background We previously reported that nifedipine retard showed comparable efficacy to angiotensin-converting enzyme (ACE) inhibitors for the prevention of cardiac events in hypertensive patients with coronary artery disease during the Japan Multicenter Investigation for Cardiovascular Diseases B study. In the nifedipine group, patients with a history of myocardial infarction (MI) showed a significant reduction in hospitalization for angina pectoris compared with the ACE inhibitor group. We investigated whether this difference was related to the progression of coronary arteriosclerosis. Methods To evaluate coronary arteriosclerosis, we performed coronary angiography (CAG) and a quantitative analysis of coronary angiograms. Results The cumulative incidence of hospitalization for angina was significantly lower in the nifedipine group (log-rank test P = 0.013). The etiology of angina requiring hospitalization was determined on the basis of CAG findings. Its incidence secondary to the development of new lesions or the progression of existing lesions was significantly lower in the nifedipine group than in the ACE inhibitor group (log-rank test P = 0.042 and P = 0.028, respectively). Using quantitative coronary analysis, changes in the coronary artery luminal diameter were compared between the nifedipine and ACE inhibitor groups. The minimum coronary lumen diameter did not show a significant change in the nifedipine group, whereas it decreased significantly in the ACE inhibitor group (paired t-test P = 0.002), and there was a significant difference between the two groups by analysis of covariance (P = 0.047). Conclusion These results indicate that nifedipine more effectively prevented admission for angina pectoris by inhibiting the progression of coronary artery disease in patients with a history of MI.

Estimated Glomerular Filtration Rate Reversal by Blood Pressure Lowering in Chronic Kidney Disease: Japan Multicenter Investigation for Cardiovascular DiseaseB CKD Study

Patients are diagnosed as having chronic kidney disease (CKD) if estimated glomerular filtration rate (eGFR) is <60u2003mL/min/1.73u2003m2. Low eGFR is likely to increase the incidence of cardiovascular events and lead to dialysis. Therefore, it is important to prevent eGFR from decreasing eGFR. However, it still remains unknown whether antihypertensive therapy can prevent low eGFR from becoming even lower and improve eGFR in hypertensive patients with CKD. The authors analyzed the results of the Japan Multicenter Investigation for Cardiovascular DiseaseB (JMIC‐B) and investigated the effects of antihypertensive therapy on eGFR. In hypertensive patients with CKD (eGFR <60), eGFR was significantly increased from 51.87±6.21 (n=98) to 57.55±19.00 (P<.001) after 3 years of antihypertensive therapy. In patients without CKD (eGFR ≥60), eGFR was significantly decreased from 91.84±23.27 (n=682) to 88.95±23.67 (P<.001). Regardless of the type of antihypertensive drugs used, eGFR was significantly increased in patients with CKD and was significantly decreased in patients without CKD. This paper shows that antihypertensive therapy can improve eGFR in hypertensive patients with CKD. J Clin Hypertens (Greenwich). 2012;00:00–00. ©2012 Wiley Periodicals, Inc.

Reverse remodeling and improved function by antihypertensive treatment in hypertensive patients with coronary artery disease.

Background Although antihypertensive therapy reduces cardiovascular events, it is unclear whether there are differences in cardiac remodeling and function between treatments with nifedipine retard and angiotensin-converting enzyme inhibitors (ACE-Is). It is also not clear how antihypertensive therapy influences cardiac remodeling and function. Methods Hypertensive patients with coronary artery disease were randomly assigned to the nifedipine retard (n = 108) or ACE inhibitors groups (n = 102) and treated for 3 years. The primary endpoints were changes in end-diastolic volume index (EDVI) and end-systolic volume index (ESVI) as indices of cardiac remodeling, whereas the secondary endpoints were changes in ejection fraction (EF), stroke volume index (SVI), cardiac index (CI) and regional wall motion as indices of cardiac function. Left ventriculography was performed at baseline and after 3 years of treatment. Fifty-eight and 61 patients, respectively, were subjected to the final analysis. Results Comparable changes in remodeling and function were obtained in the nifedipine retard group and the ACE-Is group. Both groups showed a significant reduction of EDVI and ESVI, and a significant increase in EF, SVI, and CI, whereas the decreased regional wall motion significantly improved. In both groups, weak but significant correlations were noted between treatment-induced changes of systolic blood pressure and those of primary and secondary endpoints. Conclusion The above findings show that treatments with nifedipine retard or ACE-Is cause a comparable change in remodeling and cardiac function. Lowering of the blood pressure by either drug leads to reverse remodeling or improvement of cardiac function. In addition to alleviation of coronary artery damage by reducing blood pressure, there is a favorable effect on the left ventricular structure and function. Reducing the blood pressure is critically important for hypertensive patients with coronary artery disease.