Efficacy and Safety of Switching From Oral Bisoprolol to Transdermal Patch in Japanese Patients With Chronic Heart Failure

Abstract

Background: TY-0201 (TY) is a transdermal formulation of bisoprolol that is the free base of bisoprolol fumarate (BO), a drug widely used to treat chronic heart failure (CHF). The objectives of this phase II study were to evaluate the efficacy and safety of TY when switching from oral BO to TY in patients with CHF whose drug therapy was optimized, and to determine the dose conversion rate of BO to TY.

Methods and Results: The efficacy and safety of once daily TY patch use for 16 weeks was investigated in 40 patients with CHF who were stabilized with an optimized drug treatment, including BO, after switching from BO to TY at the dose conversion rate of 5:8. The pre-switch left ventricular ejection fraction was 50.13±11.09% (mean±SD). The post-switch value was 50.87±10.79% after 16 weeks, which was not significantly different, with similar results for other efficacy and safety parameters. The 16-week study was continued for all patients without changing doses after switching to TY. No cardiovascular deaths, hospitalizations for worsening HF, or significant safety concerns were observed.

Conclusions: Efficacy was maintained without significant safety concerns in patients with CHF who were stabilized with BO treatment after switching to TY, suggesting the appropriateness of the dose conversion rate.

Beta-blockers are essential for the treatment of chronic heart failure (CHF) with reduced left ventricular ejection fraction (LVEF). They are recommended in the guidelines of Japan, the USA, and Europe. Among the β-blockers, only oral formulations are marketed worldwide as a treatment for CHF. CHF is common among elderly people who often have difficulty in using oral drugs due to impaired swallowing function and gastrointestinal dysfunction. In addition, the provision of a β-blocker other than an oral formulation for use in the aging population may be a useful treatment option for patients with HF and their caregivers.

TY-0201 (TY) is a transdermal formulation whose active ingredient is bisoprolol with β₁-blocking effects that functions with a more stable plasma concentration-time profile compared with bisoprolol fumarate (BO), an oral tablet. The anti-hypertensive and heart rate-lowering effects of TY 8 mg are similar to those of BO 5 mg,¹ and these effects are dose dependent in the range of TY 2–8 mg.²

BO improves the prognosis and LVEF in patients with CHF. Although TY may have similar effects as BO, the efficacy, safety, and dose of this drug are not known in patients with CHF. Therefore, this phase II study was designed to evaluate the efficacy and safety of TY in stabilized patients with CHF when switching from BO to TY. Based on the dose of BO in patients with CHF, we replaced BO with TY at the dose conversion rate of 5:8.

Methods

Study Design and Patients

This multi-center, open-label study was conducted from June 2014 to September 2015 in 10 centers in Japan. This study was conducted in male and female patients between 20 and 80 years of age with CHF caused by ischemic heart disease, dilated cardiomyopathy, or dilated-phase hypertrophic cardiomyopathy. Eligibility criteria included a diagnosis of CHF >3 months before the study, LVEF <40% of the measurement obtained more than 3 months before the study, and no change in the New York Heart Association (NYHA) functional class I–III during the observation period. Subjects were those for whom drug treatment for CHF was optimized, and who had no changes in the maintenance dose of BO (once daily, 1.25, 2.5, 3.75, or 5 mg) or other therapeutic drugs for CHF (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, diuretics, and mineralocorticoid receptor antagonists) >3 months before the study and during the observation period.

Patients without pacemakers whose seated pulse rate or systolic blood pressure were <50 beats/min or 90 mmHg, respectively, were excluded. Patients with hypertrophic obstructive cardiomyopathy, cardiogenic shock, severe valve stenosis or regurgitation, or secondary cardiomyopathy, and patients who developed unstable angina, coronary spastic angina, rest angina, or myocardial infarction within 3 months were also excluded. Additionally, patients with serious liver/renal disease, bronchial asthma, skin conditions at the patch application site, or clinically significant skin inflammation with exposure to topical formulations were excluded.

Concomitant use of other β-blockers and αβ-blockers was prohibited during the study. Those undergoing surgical procedures or use of mechanical circulatory support that might affect drug evaluation were excluded. This study was approved by each center’s institutional review board, and was conducted in accordance with the Good Clinical Practice (GCP), the principles of the Declaration of Helsinki, and the approved protocol. All patients were fully informed of the purpose and methods of this study, and all subjects provided written informed consent before participating in the study. This study is registered with the Japan Pharmaceutical Information Center Clinical Trials Information (JapicCTI; http://www.clinicaltrials.jp/user/cteSearch.jsp; JapicCTI-142644).

Procedure

As shown in Figure 1, this study consisted of a 2–4-week observation period and a 16-week treatment period. Based on a previous study in patients with hypertension,¹ we estimated that the effect of TY 8 mg for CHF patients corresponded to that of BO 5 mg. Therefore BO 1.25-, 2.5-, 3.75-, or 5-mg doses were switched to TY 2-, 4-, 6-, or 8-mg doses, respectively, at the conversion rate of 5:8 in patients fulfilling the enrollment criteria. The doses were given once per day for 16 weeks during the treatment period.

Figure 1.

Study design. Although eligible participants were ideally maintained on the converted dose, dose adjustment was permitted if the dose was not tolerated, or if the blood pressure and/or pulse rate were poorly controlled after switching. Patients were followed up at each center after 0, 2, 4, 8, 12, and 16 weeks of the treatment period. Clinical evaluation was conducted at each visit. TY-0201, transdermal formulation of bisoprolol.

Endpoints

Efficacy The primary endpoint was a change in LVEF at 16 weeks after the treatment period compared with baseline. The secondary efficacy endpoints were changes in left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) at 16 weeks after the treatment period compared with baseline, change in NYHA functional class, change in quality of life (QOL) score on the Minnesota Living with Heart Failure (MLwHF) questionnaire, and proportion of subjects who did not undergo TY dose adjustment. LVEDV and LVESV were measured by 2D echocardiography in the apical 2- and 4-chamber views using the modified biplane Simpson’s method.³ LVEF, a primary efficacy endpoint, was calculated as LV systolic function using the following formula: 100×(LVEDV−LVESV)/LVEDV. Echocardiography was performed according to the specified procedure for this study at each center. Additionally, a cardiac imaging evaluation committee member assessed the appropriateness of echocardiographic data submitted by each center.

The MLwHF questionnaire is a validated^4,5 and established tool used for QOL evaluations for clinical studies in patients with HF.⁶ For a Japanese translation of the MLwHF, a linguistically validated version created by the Health Outcome Group (San Francisco, CA, USA) was used, with the permission of the University of Minnesota (Minneapolis, MN, USA).

Safety Safety endpoints were incidence of cardiovascular events (cardiovascular death and admission to hospital for worsening HF), a change in brain natriuretic peptide (BNP) compared to baseline, and the incidence of adverse events and adverse reactions observed during the TY treatment period. The appropriateness of the classification of cardiovascular events was ultimately assessed by the event evaluation committee.

Statistical Analysis

The target sample size was 40, which was the minimum necessary and an adequate level for investigation of the efficacy and safety of TY. All subjects who were given TY were included in the efficacy analysis set and safety analysis set. A 2-sided significance level of 5% was applied. The baseline characteristics between starting doses were compared using an analysis of variance for continuous variables, Fisher’s exact test for categorical variables, and Kruskal-Wallis rank test for BNP concentration. LVEF was expressed as mean±SD, and a paired t-test was performed to compare the measurements at 16 weeks with baseline. For other efficacy endpoints, the same analysis was conducted. A comparison of BNP concentration between each visit after switching and that of baseline was tested using Wilcoxon signed rank test. Adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 17.1. All statistical analyses were performed using SAS version 9.3 (SAS Institute Japan, Tokyo, Japan) by the staff of the sponsor.

Results

Patient Characteristics

Of the 42 subjects who provided informed consent for this study, 40 received TY. These included 14, 12, 3, and 11 subjects with doses of 2, 4, 6, and 8 mg, respectively. All subjects who were treated with TY completed a 16-week study period. Except for hyperuricemia, no statistically significant change was observed and there was no significant difference in subject profile according to starting dose (Table 1).

Table 1. Subject Characteristics at Baseline

	All (n=40)	Starting dose				P-value
		2 mg (n=14)	4 mg (n=12)	6 mg (n=3)	8 mg (n=11)
Age (years)	66.1±10.0	67.0±12.6	68.7±7.3	56.3±10.2	64.9±8.0	0.2758
Male sex	33 (82.5)	13 (92.9)	8 (66.7)	3 (100.0)	9 (81.8)	0.3309
BMI (kg/m2)	24.9±4.3	24.1±5.4	24.7±3.4	26.4±3.1	25.8±4.2	0.7356
SBP (mmHg)	130.3±15.8	126.6±17.0	132.1±16.3	128.0±13.1	133.6±15.3	0.7090
DBP (mmHg)	73.3±12.3	73.9±12.9	69.8±12.6	78.3±11.0	74.9±12.4	0.6605
PR (beats/min)	70.7±11.1	68.6±8.9	71.1±13.0	75.3±15.3	71.8±11.5	0.7763
LVEF (%)	50.1±11.1	51.0±9.5	53.8±9.2	40.7±12.3	47.6±13.7	0.2515
LVEDV (mL)	110.7±48.6	109.6±35.1	94.4±28.5	164.2±117.6	115.4±52.6	0.1650
LVESV (mL)	58.0±38.7	55.6±28.5	44.4±17.9	101.0±85.0	64.2±46.5	0.1351
NYHA functional class
I	24 (60.0)	9 (64.3)	8 (66.7)	1 (33.3)	6 (54.5)	0.7820
II	15 (37.5)	5 (35.7)	4 (33.3)	2 (66.7)	4 (36.4)
III	1 (2.5)	0 (0.0)	0 (0.0)	0 (0.0)	1 (9.1)
MLwHF score	10.1±13.4	13.3±19.2	7.5±8.7	5.0±8.7	10.3±9.5	0.6569
BNP (pg/mL)	137.8±233.4	134.9±129.6	61.5±45.2	62.0±14.2	245.4±408.6	0.5844
Duration of HF (years)	5.9±6.6	7.7±9.3	3.9±3.3	4.3±4.9	6.4±5.5	0.5085
Etiology
IHD	15 (37.5)	8 (57.1)	4 (33.3)	0 (0.0)	3 (27.3)	0.2226
DCM	25 (62.5)	6 (42.9)	8 (66.7)	3 (100.0)	8 (72.7)
Comorbidity
Hypertension	30 (75.0)	11 (78.6)	8 (66.7)	2 (66.7)	9 (81.8)	0.8289
Atrial fibrillation	13 (32.5)	3 (21.4)	4 (33.3)	2 (66.7)	4 (36.4)	0.4772
Angina pectoris	5 (12.5)	2 (14.3)	1 (8.3)	1 (33.3)	1 (9.1)	0.6581
Dyslipidemia	32 (80.0)	12 (85.7)	9 (75.0)	3 (100.0)	8 (72.7)	0.7924
Diabetes mellitus	23 (57.5)	8 (57.1)	9 (75.0)	1 (33.3)	5 (45.5)	0.4183
Hyperuricemia	16 (40.0)	10 (71.4)	3 (25.0)	1 (33.3)	2 (18.2)	0.0258
Prior MI	13 (32.5)	6 (42.9)	4 (33.3)	0 (0.0)	3 (27.3)	0.6602
Concomitant medications
ACEI	11 (27.5)	5 (35.7)	1 (8.3)	0 (0.0)	5 (45.5)	0.1447
ARB	20 (50.0)	4 (28.6)	7 (58.3)	3 (100.0)	6 (54.5)	0.1218
Diuretics	23 (57.5)	9 (64.3)	7 (58.3)	2 (66.7)	5 (45.5)	0.8196
MRA	14 (35.0)	5 (35.7)	3 (25.0)	2 (66.7)	4 (36.4)	0.6489
Inotropic agents	4 (10.0)	1 (7.1)	2 (16.7)	0 (0.0)	1 (9.1)	0.8686
Nitrates	6 (15.0)	3 (21.4)	2 (16.7)	0 (0.0)	1 (9.1)	0.9139
Devices
ICD	3 (7.5)	1 (7.1)	1 (8.3)	0 (0.0)	1 (9.1)	1.0000
CRT	1 (2.5)	0 (0.0)	0 (0.0)	0 (0.0)	1 (9.1)	0.3500

Data given as n (%) or mean±SD. Comorbidities are described using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (Ver. 17.1). Analysis of variance (continuous variable) and Fisher’s exact test (qualitative variable) were used for the comparison between starting doses. Kruskal-Wallis rank test was used for BNP concentration, a continuous variable. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BMI, body mass index; BNP, brain natriuretic peptide; CRT, cardiac resynchronization therapy; DBP, diastolic blood pressure; DCM, dilated cardiomyopathy; HF, heart failure; ICD, implantable cardioverter defibrillator; IHD, ischemic heart disease; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MI, myocardial infarction; MLwHF, Minnesota Living with Heart Failure; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; PR, pulse rate; SBP, systolic blood pressure.

Efficacy

Primary Efficacy Endpoint LVEF, a primary efficacy endpoint, changed from the pretreatment level of 50.13±11.09% to 50.87±10.79% after the 16-week treatment period for all doses. The difference from baseline (week 0) was 0.75±5.03% (P=0.3547; Figure 2). Similarly, no significant difference compared with baseline was observed after the 16-week treatment period for each starting dose.

Figure 2.

Change in left ventricular ejection fraction (LVEF) during the 16-week treatment period both for all doses and for each starting dose (TY-0201 2, 4, 6, and 8 mg). Data are expressed as mean±SD. Paired t-test was conducted for measurements after the 16-week treatment period compared with baseline both for all doses and for each starting dose. TY-0201, transdermal formulation of bisoprolol.

Secondary Efficacy Endpoints Secondary efficacy endpoints are listed in Table 2. Changes in LVEDV and LVESV after the 16-week treatment period were not significantly different, both for all doses and for each starting dose. No significant change in NYHA functional class was observed after TY treatment (Figure 3). No significant difference was observed in any change in the MLwHF score after the 16-week treatment period compared with baseline, both for all doses and for each starting dose (Table 2). The proportion of subjects who did not adjust their TY dose was 100% during the treatment period, with no subjects having any remarkable clinical symptoms after switching to TY.

Table 2. Secondary Efficacy Endpoints

	All (n=40)	Starting dose
		2 mg (n=14)	4 mg (n=12)	6 mg (n=3)	8 mg (n=11)
LVEDV (mL)
Baseline	110.73±48.64	109.61±35.08	94.43±28.50	164.23±117.61	115.35±52.59
16 weeks	107.46±34.33	107.50±30.49	94.34±28.24	130.57±63.57	115.41±35.58
Change	−3.28±23.28	−2.11±17.64	−0.09±12.00	−33.67±57.30	0.06±24.30
P-value (vs. baseline)	0.3790	0.6612	0.9794	0.4159	0.9932
LVESV (mL)
Baseline	58.02±38.72	55.61±28.51	44.42±17.90	101.00±84.98	64.19±46.54
16 weeks	54.85±27.93	54.45±24.48	45.00±19.23	73.17±46.10	61.11±34.23
Change	−3.17±17.23	−1.16±13.86	0.58±6.67	−27.83±40.84	−3.08±17.90
P-value (vs. baseline)	0.2524	0.7597	0.7677	0.3592	0.5806
MLwHF
Baseline	10.1±13.4	13.3±19.2	7.5±8.7	5.0±8.7	10.3±9.5
16 weeks	9.7±14.2	14.0±21.0	6.9±7.8	5.3±9.2	8.5±9.5
Change	−0.4±12.9	0.7±21.5	−0.6±5.7	0.3±0.6	−1.8±3.4
P-value (vs. baseline)	0.8460	0.9030	0.7302	0.4226	0.1039

Data given as mean±SD. Paired t-tests for measurements after the 16-week treatment period compared with baseline were conducted both for all doses and for each starting dose. Abbreviations as in Table 1.

Figure 3.

Change in New York Heart Association (NYHA) functional class during the 16-week treatment period.

Safety Endpoint

No cardiovascular deaths and no hospital admissions due to worsening of HF were observed during the treatment period. Overall, no significant difference was observed in the change from baseline BNP concentration both after the 4-week and after the 16-week treatment periods after switching from BO to TY (Table 3). For each starting dose, a significant decrease was observed after the 16-week treatment period in subjects treated with TY 2 mg, while a significant increase was observed after the 4-week treatment period in subjects treated with TY 4 mg. Both changes were mild.

Table 3. BNP Measurements

	All (n=40)	Starting dose
		2 mg (n=14)	4 mg (n=12)	6 mg (n=3)	8 mg (n=11)
Baseline	137.78±233.42	134.86±129.56	61.47±45.18	62.03±14.21	245.40±408.57
4 weeks	143.57±222.56	116.32±105.99	87.83±76.09	110.83±60.16	247.98±392.93
16 weeks	122.64±159.43	88.07±56.04	70.48±49.97	94.37±35.88	231.25±271.82
Change at 4 weeks	5.79±69.69	−18.54±86.17	26.36±46.63	48.80±46.38	2.58±67.57
P-value (vs. baseline)	0.2555	0.2958	0.0425	0.2500	0.7646
Change at 16 weeks	−15.14±126.53	−46.79±95.06	9.02±19.86	32.33±26.82	−14.15±217.57
P-value (vs. baseline)	0.7315	0.0308	0.2334	0.2500	0.4131

Data given as mean±SD. Paired t-tests for measurements after the 4-week and the 16-week treatment period compared with baseline were conducted both for all doses and for each starting dose. BNP, brain natriuretic peptide.

As shown in Figure 4, blood pressure and pulse rate were well controlled during the treatment period. Systolic blood pressure significantly decreased from 130.3±15.8 mmHg at baseline to 124.4±14.6 mmHg at 8 weeks, and to 125.6±14.4 mmHg at 16 weeks, but those changes were not clinically relevant.

Figure 4.

Changes in blood pressure and pulse rate during the 16-week treatment period. (A) Systolic blood pressure (SBP) and diastolic blood pressure (DBP), and (B) pulse rate (PR). Data are given as mean±SD. Paired t-tests for measurements after the 2-week, 4-week, 8-week, 12-week, and 16-week treatment period compared with baseline were conducted. *P<0.05 vs. 0 weeks.

Overall, adverse events were observed in 19 subjects (47.5%). Adverse events were observed in 7 (50.0%), 6 (50.0%), 0 (0.0%), and 6 subjects (54.5%) with a starting dose of 2, 4, 6, and 8 mg, respectively. Overall, adverse reactions were observed in 5 subjects (12.5%). Adverse reactions were observed in 2 (14.3%), 1 (8.3%), 0 (0.0%), and 2 subjects (18.2%) with a starting dose of 2, 4, 6, and 8 mg, respectively (Table 4). All adverse events are listed in Table S1. Clinically significant bradycardia was not observed. All adverse events were mild in intensity, and no subjects discontinued their participation in the study due to adverse events. As a serious adverse event, cardiac failure was observed in 1 subject (8.3%) who was treated with a starting dose of 4 mg. That subject, however, continued the dose without change and recovered during treatment.

Table 4. AE and Drug-Related AE

	All (n=40)	Starting dose
		2 mg (n=14)	4 mg (n=12)	6 mg (n=3)	8 mg (n=11)
Any AE†	19 (47.5)	7 (50.0)	6 (50.0)	0	6 (54.5)
Any drug-related AE	5 (12.5)	2 (14.3)	1 (8.3)	0	2 (18.2)
SOC‡
PT‡
Cardiac disorders	2 (5.0)	1 (7.1)	0	0	1 (9.1)
Cardiac failure	1 (2.5)	1 (7.1)	0	0	0
Ventricular extrasystoles	1 (2.5)	0	0	0	1 (9.1)
General disorders and treatment site conditions	3 (7.5)	1 (7.1)	1 (8.3)	0	1 (9.1)
Application site erythema	1 (2.5)	0	1 (8.3)	0	0
Application site pruritus	2 (5.0)	1 (7.1)	0	0	1 (9.1)

Data given as n (%). ^†A list of all AE is given in Table S1. ^‡Medical Dictionary for Regulatory Activities (MedDRA) ver. 17.1. AE, adverse event; PT, preferred term; SOC, system organ class.

Discussion

In this study, the efficacy and safety of TY were evaluated when switching from BO to TY at the dose conversion rate of 5:8, which was shown in a previous study to have a similar anti-hypertensive and heart rate-lowering effect in patients with hypertension as well as in patients with CHF who were being treated with BO.

Compared with baseline, no significant difference was observed in the change in LVEF after the 16-week treatment period after switching from BO to TY for all doses and for each starting dose. Similar results were obtained for other secondary efficacy endpoints. Since no patients required dose adjustment of TY after switching, we concluded that the dose conversion rate from BO to TY was appropriate.

According to the J-CHF study in Japanese patients with HF, in which the change in LVEF was evaluated when carvedilol was used for approximately 1 year, LVEF was 41.6±1.3% at the 24-week time point when the dose was fixed, and was maintained at 42.8±1.4% at the 48-week time point.⁷ In the J-CHF study, the mean duration of dose titration was 52.9 days, and carvedilol was used for >3 months on average after dose fixation at the 24-week time point. Although a recent study was conducted in patients with CHF who had been treated with BO for >3 months after dose titration, LVEF was maintained after switching to TY, thereby confirming the maintenance of LVEF on β-blockers that had been observed in the J-CHF study.

Previous clinical studies switching between different β-blockers with equivalent efficacy reported good tolerability after switching.^8,9 Meanwhile, a study of switching in patients with HF and chronic obstructive pulmonary disease by Jabbour et al reported that forced expiratory volume in 1 s was lower on carvedilol compared with bisoprolol, and that N-terminal proBNP was higher on bisoprolol. Therefore, when switching between different β-blockers, we should consider the difference in characteristics of each β-blocker.⁹ In the present study, we found no major safety concerns in switching from BO to TY. However, given that it was a small study, further assessment of the differences in formulations may be needed for using TY in the clinical setting.

There are several benefits of using TY in its transdermal formulation. First, the TY patch can contribute to improve drug adherence because patients or caregivers can check for the presence or absence of the TY patch through direct visual observation to appropriately monitor drug therapy. Since a larger proportion of elderly people have HF, including those who need support from families and caregivers because of cerebrovascular disorders or dementia, it is useful for patients and caregivers to verify that the patient is using their medicine.

Second, TY can be used in patients for whom oral treatment is difficult, including those whose swallowing function has been impaired, those with gastrointestinal disease, and those who require tracheal intubation for an operation or pneumonia. To date, only an oral formulation of β-blockers has been indicated for the treatment of CHF; discontinuation of therapeutic drugs, however, is a contributing factor to the worsening of HF, as described in the guidelines in Japan.¹⁰ Therefore, ensuring the continuation of therapeutic drugs for CHF, including β-blockers, is important. When oral treatment becomes difficult for any reason, switching from an oral formulation to TY can prevent the worsening of prognosis of CHF that is caused by the discontinuation of β-blockers.

The present results suggest that TY can be used safely by switching from BO in patients with CHF whose disease is stabilized. The efficacy and safety of TY should be further investigated using a control group and including a larger number of patients with HF.

Study Limitations

The major limitations of this open-label study include the small sample size and the lack of a control group, therefore careful interpretation of the effect and safety results is required.

Conclusions

We studied the effect of TY in patients with CHF who had been treated with BO and other therapeutic drugs for more than 3 months and whose disease had been stable. Treatment efficacy was maintained and no significant safety problems were observed when switching from BO to TY at a dose conversion rate of 5:8, thereby suggesting the validity of this dose conversion rate in patients with CHF. TY may therefore provide a new treatment option for CHF.

Acknowledgments

We thank the physicians and staff at each study site for helping with patient enrollment and data collection.

Disclosures

S.M. received consultancy/speaker honoraria from Daiichi Sankyo, Bayer Yakuhin, Nippon Boehringer Ingelheim, and Pfizer Japan, and scholarship funds from Daiichi Sankyo, MSD, Mitsubishi Tanabe Pharma, Medtronic Japan, and Teijin Pharma. Y. Saito received consultancy/speaker honoraria from Otsuka Pharmaceutical, Kowa Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Pfizer Japan, and Novartis Pharma, research fund from Novartis Pharma, and scholarship funds from Takeda Pharmaceutical, Teijin Pharma, Ono Pharmaceutical, Mitsubishi Tanabe Pharma, Eisai, Shionogi, ZERIA Pharmaceutical, Otsuka Pharmaceutical, Sumitomo Dainippon Pharma, Kyowa Hakko Kirin, Boston Scientific Japan, Astellas Pharma, and Daiichi Sankyo, and is affiliated with endowed departments sponsored by MSD. Y.Y. received consultancy/speaker honorarium from Otsuka Pharmaceutical. K.Y. received consultancy/speaker honoraria from Ono Pharmaceutical, Otsuka Pharmaceutical, Bristol-Myers Squibb, and Abbott Vascular Japan, research fund from Astellas Pharma, and scholarship funds from St. Jude Medical Japan, Otsuka Pharmaceutical, Daiichi Sankyo, Boston Scientific Japan, Johnson & Johnson, BIOTRONIK Japan, Japan Lifeline, Astellas Pharma, Teijin Pharma, Mitsubishi Tanabe Pharma, Fukuda Denshi, Takeda Pharmaceutical, Ono Pharmaceutical, Public Health Research Foundation, Nihon Kohden, and Novartis Pharma. Y. Sakata received consultancy/speaker honorarium and scholarship fund from Mitsubishi Tanabe Pharma. I.K. received consultancy/speaker honoraria from Astellas Pharma, Shionogi, Daiichi Sankyo, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Toa Eiyo, Nippon Boehringer Ingelheim, Pfizer Japan, Bunkodo, and Medical Review, and scholarship funds from Edwards Lifesciences, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Teijin Pharma, and Bayer Yakuhin. M.D., K.K., and H.O. have no conflict of interest to disclose. N.D. is an employee of Toa Eiyo.

Author Contributions

This study was planned and conducted by a sponsor (Toa Eiyo Ltd.), with advice from the Protocol Review Committee. The sponsor collected and analyzed data. The authors and the sponsor were both involved in interpretation of the data. The first draft manuscript was written by the sponsor. All authors reviewed and revised the article.

Name of Grant

This study was funded by Toa Eiyo.

Appendix

Protocol Review Committee

Shin-ichi Momomura (Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University), Yoshihiko Saito (First Department of Internal Medicine, Nara Medical University), Yoshio Yasumura (Department of Cardiology, Amagasaki Chuo Hospital), Kazuhiro Yamamoto (Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics).

Cardiac Imaging Evaluation Committee

Masao Daimon (Department of Clinical Laboratory, The University of Tokyo).

Event Evaluation Committee

Koichiro Kinugawa (Second Department of Internal Medicine, University of Toyama), Hiroshi Okamoto (Department of Cardiovascular Medicine, Hokkaido University), Katsuya Kajimoto (Department of Cardiology, Sekikawa Hospital).

Medical Specialist

Issei Komuro (Department of Cardiovascular Medicine, The University of Tokyo).

Coordinating Investigator

Yasushi Sakata (Department of Cardiovascular Medicine, Osaka University).

Institutions and Investigators

Yasushi Sakata, Osaka University Hospital; Takayuki Inomata, Kitasato University Hospital; Koichi Nakao, Saiseikai Kumamoto Hospital; Masayoshi Ajioka, Tosei General Hospital; Naoki Sato, Nippon Medical School Musashi Kosugi Hospital; Masahiko Nakamura, Yamanashi Prefectural Central Hospital; Hideyuki Tsuboi, Ogaki Municipal Hospital; Shinichi Hirotani, Hyogo College of Medicine; Yasuyo Taniguchi, Hyogo Brain and Heart Center; Hitoshi Adachi, Gunma Cardiovascular Center.

Supplementary Files

Supplementary File 1

Table S1. Adverse event

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-0532

References

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