Abstract
Background:
Guidelines for peripheral arterial disease (PAD) recommend long-term antiplatelet therapy in symptomatic patients to reduce cardiovascular morbidity and mortality risk. Although diabetes is a known risk factor for PAD, PAD has been undertreated in these patients. This study aimed to evaluate risk factors for major amputation in patients with diabetes undergoing antiplatelet therapy for PAD.
Methods and Results:
This retrospective analysis of a 2-year observational cohort study (1,745 clinics in Japan, September 2009–2013) evaluated predictors of amputation in patients with diabetes undergoing antiplatelet therapy for PAD. Among 4,016 eligible patients, 52 had an amputation during follow-up. Amputation risk (Cox regression analysis) was predicted at baseline by history of lower extremity revascularization/amputation (hazard ratio [HR]: 2.92; 95% confidence interval [CI]: 1.39, 6.14), chronic kidney disease (HR: 4.19; 95% CI: 1.95, 8.97), and comorbid cerebrovascular and heart disease (HR: 3.32; 95% CI: 1.19, 9.30), and was unaffected by choice of oral antiplatelet therapy. In patients with PAD and diabetes, amputation event rate was highest for those with ankle-brachial pressure index (ABI) <0.40 and progressively decreased at higher ABI cut-offs.
Conclusions:
These findings inform real-world understanding of PAD in diabetic patients receiving antiplatelet therapy in Japan, and showed that ABI <0.4 was the strongest risk factor for amputation.
Peripheral arterial disease (PAD), a secondary manifestation of systemic atherosclerosis that affects the aorta, its branches and the lower limb arteries, is associated with a high risk of death from cardiovascular and cerebrovascular causes.1,2
PAD is a major macrovascular complication of diabetes mellitus (DM) that is often associated with early manifestation, asymptomatic presentation (contributing to delayed diagnosis), rapid clinical progression, and a poorer outcome compared with patients without DM.3,4
Editorial p 1840
In most studies, ankle-brachial pressure index (ABI), calculated as the ratio of systolic blood pressure (SBP) in the brachial artery to that of the dorsalis pedis artery as well as the posterior tibial artery after resting in a supine position, is the standard for identifying PAD.4
An ABI <0.90 is strongly associated with major modifiable cardiac risk.5
When claudication appears, symptoms become aggravated in up to 20% of patients within 5 years, progressing to critical limb ischemia (CLI) in around 1–2% of patients.6
Patients with CLI have poor prognoses, with major amputation rates as high as 40% in those who have exhausted all treatment options.7
International guidelines on the management of PAD recommend the long-term prescription of antiplatelet therapy in symptomatic patients to reduce the risk of cardiovascular morbidity and mortality.8–10
Notwithstanding this guidance, PAD in general has been under-recognized and undertreated;11–13
moreover, despite DM being an independent predictor of ABI status, PAD has been undertreated in this high-risk population.14–16
The Surveillance of cardiovascular Events in Antiplatelet-treated arterioSclerosis Obliterans patients in JapaN (SEASON) registry was a prospective, observational, multicenter cohort study designed to provide a real-world database of over 10,000 patients across Japan with asymptomatic and symptomatic PAD treated with sarpogrelate hydrochloride or other oral antiplatelet therapy.17–19
The aim of this post hoc analysis was to evaluate the risk factors for major amputation in patients with DM undergoing antiplatelet therapy for PAD.
Methods
Study Design and Patients
SEASON (UMIN Clinical Trials registry: UMIN000003385) was a 2-year nationwide observational prospective cohort study conducted at 1,745 surgical, internal medicine and other medical clinics in Japan between September 2009 and September 2013. The study design,17
baseline characteristics,19
and primary analysis18
have been published previously. Patients were diagnosed with PAD (by physicians), as confirmed by ABI or bilateral palpation of the lower limb arteries, and scheduled to receive long-term oral antiplatelet therapy with a designated agent (of which, 1 possible medication was sarpogrelate), or modification of existing long-term antiplatelet therapy by switching to or adding one of the designated agents. For the purposes of this post hoc analysis, patients with DM were identified based on a history/complication of type 1 DM or type 2 DM recorded in the case report form. The study protocol was approved by the ethics review board at each representative site, with the study conducted in accordance with the Good Post-marketing Study Practice guidelines of the Japanese Ministry of Health, Labour and Welfare. The study was explained to all patients before they enrolled and informed consent was given by all enrolled patients. Patient registration, data collection and management, and statistical analysis were performed by CMIC Co., Ltd. (Tokyo, Japan).
Study Assessments and Outcomes
All follow-up data were collected from outpatients by physicians and reported to the Efficacy Endpoint Review Committee for adjudication according to prespecified criteria. Vascular events were included as outcome (SEASON) events and reported for the current analysis as both minor and major amputations. Major amputation was defined as above the ankle, and was further categorized according to location above or below the knee. Minor amputations were below the ankle (toe or metatarsal). Amputations arising from tumors or trauma were excluded. The vascular outcome of interest to the present analysis was the event rate of amputation in patients with PAD and DM during 2 years of follow-up.
Statistical Analysis
The rationale for the planned sample size for the overall cohort of approximately 10,000 patients with PAD, together with statistical methods, has been described elsewhere.17
Descriptive data were used for continuous and categorical data. Data are expressed as means (standard deviation [SD]). Cox regression analysis was performed to identify predictors of amputation in patients with DM, and adjusted hazard ratio (HR) and 95% confidence interval (CI) were calculated. No imputation method was used for missing values. Variables included in the Cox model were sex, body mass index (BMI), smoking history, lower extremity revascularization (LER)/amputation, chronic kidney disease (CKD), DM (glycated hemoglobin A1c [HbA1c] <53 mmol/mol [<7.0%] vs. ≥53 mmol/mol [≥7.0%]), dyslipidemia (low-density lipoprotein cholesterol [LDL-C] <100 vs. ≥100 mg/dL), hypertension (SBP <140 vs. ≥140 mmHg or diastolic blood pressure [DBP] <90 vs. ≥90 mmHg), multiple risk factors (none, cerebrovascular disease, heart disease, and cerebrovascular disease+heart disease), and medication (sarpogrelate vs. other antiplatelet agents). The amputation event rates per 100 patient-years were calculated by dividing the total number of patients with events at 2 years by the total duration (years) of patient participation in the registry, multiplied by 100, and expressed with 95% CI (calculated based on the assumption of a Poisson distribution). Patients with DM were stratified according to ABI score (cut-offs: 0.0≤ABI<0.4; 0.4≤ABI<0.7; 0.7≤ABI<0.9; 0.9≤ABI<1.0; and 1.0 ≤ABI), and whether the amputation was major (above or below the knee) or minor (toe or metatarsal). All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC, USA).
Results
Patient Disposition and Baseline Characteristics
Of 10,322 eligible patients with PAD and available case report forms who received at least 1 dose of the designated oral antiplatelet drug, 4,016 patients had a diagnosis of DM and were included in the present retrospective analysis of SEASON (Figure 1).
Baseline demographics and clinical characteristics were compared for patients with DM according to the absence (n=3,964) or presence (n=52) of amputation (Table 1). At baseline, compared with patients without amputation, patients with amputation during the 2-year follow-up period had a lower mean BMI at baseline (23.4 kg/m2
vs. 21.6 kg/m2), fewer had a BMI ≥25 kg/m2
(26.1% vs. 15.4%) or dyslipidemia (55.8% vs. 38.5%), and more were taking ≥2 antiplatelet medications (16.1% vs. 28.8%). In addition, more patients with amputation had Fontaine stage ≥II classification (60.7% vs. 88.5%), a history of LER/amputation (18.1% vs. 48.1%), hypertension (77.4% vs. 86.5%), heart disease (35.6% vs. 63.5%), cerebrovascular disease (20.3% vs. 34.6%), and 0.4≤ABI<0.7 (22.0% vs. 46.2%) and DBP (73.8 vs. 69.7 mmHg) and LDL-C (106.1 vs. 91.0 mg/dL) were concurrently lower for patients with amputation. The demographics and baseline characteristics of all eligible patients are provided in
Supplementary Table 1.
Table 1.
Demographics and Baseline Disease Characteristics of Patients With PAD and Diabetes
| Characteristic |
Without amputation
(n=3,964) |
With amputation |
| All (n=52) |
Major (n=27) |
Minor (n=26) |
| Sex |
| Male, n (%) |
2,649 (66.8) |
36 (69.2) |
17 (63.0) |
20 (76.9) |
| Age, years |
| Mean (SD) |
72.2 (9.6) |
71.8 (7.9) |
72.3 (6.7) |
70.7 (9.4) |
| ≥70, n (%) |
2,560 (64.6) |
30 (57.7) |
17 (63.0) |
13 (50.0) |
| BMI, kg/m2 |
| Mean (SD) |
23.4 (3.8) |
21.6 (3.5) |
21.5 (3.5) |
21.6 (3.7) |
| ≥25, n (%) |
1,033 (26.1) |
8 (15.4) |
5 (18.5) |
3 (11.5) |
| Disease duration ≥1 year, n (%) |
1,787 (45.1) |
23 (44.2) |
13 (48.1) |
10 (38.5) |
| Fontaine classification, stage ≥II, n (%) |
2,407 (60.7) |
46 (88.5) |
23 (85.2) |
24 (92.3) |
| LER/amputation, n (%) |
| No |
3,226 (81.4) |
26 (50.0) |
13 (48.1) |
13 (50.0) |
| Yes |
719 (18.1) |
25 (48.1) |
13 (48.1) |
13 (50.0) |
| Comorbidities, n (%) |
| Hypertension |
3,067 (77.4) |
45 (86.5) |
24 (88.9) |
22 (84.6) |
| Dyslipidemia |
2,213 (55.8) |
20 (38.5) |
10 (37.0) |
11 (42.3) |
| Heart disease |
1,412 (35.6) |
33 (63.5) |
17 (63.0) |
17 (65.4) |
| Cerebrovascular disease |
804 (20.3) |
18 (34.6) |
11 (40.7) |
7 (26.9) |
| HbA1c, mmol/mol |
55.5 (19.6) |
57.0 (18.9) |
58.9 (13.8) |
56.1 (22.7) |
| HbA1c, % |
7.2 (1.8) |
7.4 (1.7) |
7.5 (1.3) |
7.3 (2.1) |
| SBP, mmHg |
137.6 (20.1) |
136.2 (25.3) |
139.0 (20.8) |
133.1 (29.2) |
| DBP, mmHg |
73.8 (12.3) |
69.7 (12.5) |
69.8 (11.8) |
70.0 (13.5) |
| LDL-C, mg/dL |
106.1 (33.0) |
91.0 (42.2) |
90.9 (18.1) |
89.8 (52.9) |
| ABI, n (%) |
| 0.0≤ABI<0.4 |
138 (3.5) |
10 (19.2) |
6 (22.2) |
4 (15.4) |
| 0.4≤ABI<0.7 |
874 (22.0) |
24 (46.2) |
10 (37.0) |
14 (53.8) |
| 0.7≤ABI<0.9 |
1,000 (25.2) |
10 (19.2) |
6 (22.2) |
5 (19.2) |
| 0.9≤ABI<1.0 |
311 (7.8) |
2 (3.8) |
1 (3.7) |
1 (3.8) |
| ABI ≥1.0 |
480 (12.1) |
2 (3.8) |
1 (3.7) |
1 (3.8) |
| Unknown |
1,161 (29.3) |
4 (7.7) |
3 (11.1) |
1 (3.8) |
| Current smoker, n (%) |
712 (18.0) |
11 (21.2) |
6 (22.2) |
6 (23.1) |
| ≥2 antiplatelet medications, n (%) |
637 (16.1) |
15 (28.8) |
10 (37.0) |
5 (19.2) |
| Antiplatelet medication, n (%) |
| Sarpogrelate |
3,248 (81.9) |
47 (90.4) |
24 (88.9) |
24 (92.3) |
| Others |
716 (18.1) |
5 (9.6) |
3 (11.1) |
2 (7.7) |
All values are mean (SD) unless otherwise indicated. ABI, ankle-brachial pressure index; BMI, body mass index; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin A1c; LDL-C, low-density lipoprotein cholesterol; LER, lower extremity revascularization; PAD, peripheral arterial disease; SBP, systolic blood pressure; SD, standard deviation.
In the cohort of 4,016 patients with DM, 3 potential risk factors for any amputation event were identified: history of LER/amputation (HR: 2.92; 95% CI: 1.39, 6.14); CKD (HR: 4.19; 95% CI: 1.95, 8.97); and comorbid cerebrovascular and heart disease (HR: 3.32; 95% CI: 1.19, 9.30) (Figure 2). HbA1c
cut-off at baseline was not a risk factor for amputation. The risk of amputation was also unaffected by sex or the choice of oral antiplatelet medication, with similar HRs for sarpogrelate and other antiplatelet drugs (Figure 2).
Event Rate
In the cohort of 4,016 patients with DM, there were 52 amputation events over a risk exposure period of 6,485 patient-years, giving an event rate of 0.80 per 100 patient-years (95% CI: 0.60, 1.05). This event rate was 4.43-fold higher than for patients with PAD alone (i.e., without DM;
Supplementary Table 2). The amputation event rate was also assessed in patients with DM following stratification according to baseline ABI. The event rate per 100 patient-years of either a major or minor amputation was highest for patients with baseline ABI <0.4: 2.64 per 100 patient-years (95% CI: 0.97, 5.74) and 1.77 per 100 patient-years (95% CI: 0.48, 4.52), respectively (Table 2). At higher ABI cut-offs, the event rate progressively decreased, with the lowest risk observed for patients with ABI ≥1.0.
Table 2.
Rates of Major and Minor Amputation Events in Patients With PAD and Diabetes
| Risk factor |
n |
Major amputation |
Minor amputation |
No. of
events |
Event rate per 100
patient-years
(95% CI) |
No. of
events |
Event rate per 100
patient-years
(95% CI) |
| LER/amputation |
| No |
3,252 |
13 |
0.25 (0.13, 0.42) |
13 |
0.25 (0.13, 0.42) |
| Yes |
744 |
13 |
1.08 (0.58, 1.85) |
13 |
1.09 (0.58, 1.86) |
| CKD |
| No |
3,199 |
9 |
0.17 (0.08, 0.32) |
12 |
0.23 (0.12, 0.4) |
| Yes |
817 |
18 |
1.49 (0.88, 2.35) |
14 |
1.16 (0.63, 1.94) |
| Diabetes |
| HbA1c <53 mmol/mol (<7.0%) |
1,812 |
8 |
0.26 (0.11, 0.52) |
13 |
0.43 (0.23, 0.74) |
| HbA1c ≥53 mmol/mol (≥7.0%) |
1,463 |
11 |
0.47 (0.23, 0.84) |
8 |
0.34 (0.15, 0.67) |
| Multiple risk factors |
| None |
2,119 |
7 |
0.2 (0.08, 0.41) |
6 |
0.17 (0.06, 0.37) |
| Cerebrovascular disease |
452 |
3 |
0.42 (0.09, 1.22) |
3 |
0.42 (0.09, 1.22) |
| Heart disease |
1,075 |
9 |
0.52 (0.24, 0.98) |
13 |
0.75 (0.4, 1.28) |
| Cerebrovascular+heart disease |
370 |
8 |
1.43 (0.62, 2.81) |
4 |
0.71 (0.19, 1.83) |
| ABI |
| 0.0≤ABI<0.4 |
148 |
6 |
2.64 (0.97, 5.74) |
4 |
1.77 (0.48, 4.52) |
| 0.4≤ABI<0.7 |
898 |
10 |
0.71 (0.34, 1.31) |
14 |
1.01 (0.55, 1.69) |
| 0.7≤ABI<0.9 |
1,010 |
6 |
0.36 (0.13, 0.79) |
5 |
0.3 (0.1, 0.71) |
| 0.9≤ABI<1.0 |
313 |
1 |
0.19 (0, 1.04) |
1 |
0.19 (0, 1.04) |
| ABI ≥1.0 |
482 |
1 |
0.12 (0, 0.69) |
1 |
0.12 (0, 0.69) |
CKD, chronic kidney disease. Other abbreviations as in Table 1.
In addition to low ABI, other risk factors associated with higher event rates for major amputation during the 2-year follow-up period were CKD (1.49 per 100 patient-years; 95% CI: 0.88, 2.35), comorbid cerebrovascular and heart disease (1.43; 95% CI: 0.62, 2.81), and a history of LER/amputation (1.08; 95% CI: 0.58, 1.85) (Table 2). Achieving glycemic control (HbA1c
<53 mmol/mol [<7.0%]) halved the event rate of a major amputation compared with HbA1c
≥53 mmol/mol [≥7.0%]) (0.47 vs. 0.26 events per 100 patient-years). The presence of CKD was associated with an almost 9-fold higher event rate ratio of a major amputation compared with no CKD (1.49 vs. 0.17), whereas comorbid cerebrovascular and heart disease tripled the relative event rate of major amputation compared with either cerebrovascular disease or heart disease alone (1.43 vs. 0.42 vs. 0.52). In the case of a minor amputation, the highest relative risk was again attributed to CKD (1.16 per 100 patient-years; 95% CI: 0.63, 1.94), which was followed by a history of LER/amputation (1.09; 95% CI: 0.58, 1.86), heart disease alone (0.75; 95% CI: 0.4, 1.28), and comorbid cerebrovascular and heart disease (0.71; 95% CI: 0.19, 1.83).
Discussion
In this post hoc analysis of SEASON, which focused on patients with PAD who were receiving oral antiplatelet therapy, the greatest risk for amputation was among patients with an ABI <0.40. The factors that predicted an increased risk of major amputation in patients with DM over the 2-year follow-up period were a history of LER/amputation, CKD, and comorbid cerebrovascular disease and heart disease. The risk factors were similar for a major or minor amputation, but our data suggested a higher event rate associated with major amputation compared with minor amputation when one of these risk factors was present. Finally, the present data suggested that the type of oral antiplatelet agent prescribed was not a risk factor for amputation.
Overall, these findings contribute to the real-world understanding of patients with PAD who receive antiplatelet therapy in clinical practice in Japan and are consistent with those of other studies that have shown a greater risk of adverse outcomes in patients with both PAD and DM compared with those with PAD only.20–24
Studies conducted in Japanese patients with PAD have shown that, compared with patients without DM, patients with DM have a higher risk of poor outcomes following vascular therapy for CLI.21,23,24
This is consistent with the current study, which confirmed that the amputation event rate for patients with PAD was 4.43-fold higher for those with DM compared with those without DM. In the Canagliflozin Cardiovascular Assessment (CANVAS) study, patients with type 2 DM had an increased risk of amputation of the toes, feet, or legs when treated with the sodium-glucose cotransporter-2 (SGLT2) inhibitor, canagliflozin, compared with placebo.22
In CANVAS, 71% of patients with amputation had an amputation at the toe or metatarsal, and the risk of amputation was highest among those with a history of amputation or PAD. This is a surprising result, given that canagliflozin decreased the risk of cardiovascular events compared with placebo.22
Currently, the reason for this unexpected risk of amputation in patients receiving canagliflozin is not well understood, but emerging evidence suggests that it may be an SGLT2 inhibitor class effect.22,25–27
To minimize the risk of amputation in patients with DM and established PAD, it is important to be able to identify those patients taking antidiabetic drugs who are at risk of amputation and to understand the pathophysiology involved in progression of PAD.28
Recently, in a cohort of 10,322 patients with PAD who were undergoing antiplatelet therapy over a 2-year follow-up period, we confirmed that Fontaine IV classification and an ABI <0.4 were independent predictors of amputation, including minor amputations of the toe or metatarsal.18
In the present post hoc analysis, the presence of DM in general and DM with an ABI <0.4 in particular were strong predictors of major amputation. In addition, CKD, comorbid cerebrovascular and heart disease, and a history of LER/amputation contributed to the risk of both major and minor amputation, suggesting that clinicians need to consider the risk of amputation in patients with DM and established cardiovascular disease. Baseline findings of the SEASON cohort showed that as well as DM, common comorbidities among patients with PAD included hypertension (61.5%), dyslipidemia (38.8%), heart disease (29.7%), cerebrovascular disease (17.1%), current smoking (16.2%), and CKD (14.3%).19
Collectively, these results highlighted that patients with DM and PAD require effective management of all aspects of vascular risk. However, management of vascular risk in patients with DM is often suboptimal,14,29
most likely because of the focus on glycemic control in patients with DM. In one study of 12,106 patients with type 2 DM, fewer than 25% had received an antiplatelet agent or statin, and those with DM and PAD who had undergone lower limb amputation were no more likely to receive such agents than those without amputation.14
In addition, despite evidence showing the benefits of lifelong antiplatelet therapy on reductions in vascular risk beyond that achieved with exercise, smoking cessation, and aggressive blood pressure and lipid control, there is no consensus regarding an optimal antiplatelet regimen.5,30
Of note, in Italy, which has one of the lowest prevalence rates of major amputation among patients with DM in Europe, local consensus guidelines do acknowledge the need for antiplatelet therapy in the treatment of PAD in patients with DM.31
The findings from this large cohort of patients in Japan give insight into the risk of major amputation in patients with DM and PAD in real-world clinical practice. Because of the large sample size, the findings are likely to be representative of patients with PAD who receive antiplatelet therapy in Japan. In addition, because this subgroup analysis was post hoc, the differences observed between the cohorts with and without DM may have occurred by chance and should be confirmed. The Fukuoka Diabetes Registry has reported an incidence rate of limb amputation of 0.47 per 1,000 patient-years (0.05% per year) in a Japanese cohort of 4,870 patients with type 2 DM, but as these patients did not have PAD, any comparison with the present findings would be inappropriate.32
The SEASON Study was conducted to determine the prognosis of patients with PAD receiving antiplatelet therapy, to explore the relationships between prognosis, patient characteristics and the risk factors for cardiovascular events, and to compare the effectiveness of sarpogrelate in decreasing cardiovascular events with those of other antiplatelet agents.17
Because of the observational nature of this study, it was difficult to select patients with PAD who were not receiving antiplatelet therapy. Evaluation of risk factors in patients who were not receiving antiplatelet therapy would enable a more direct assessment of risk factors for amputation.
Conclusions
The large-scale SEASON registry provided an opportunity to evaluate real-world aspects of PAD in patients receiving antiplatelet therapy. In the present post hoc analysis of Japanese patients with PAD, the risk factors for amputation in patients with DM were a history of LER/amputation, CKD, and comorbid cerebrovascular disease and heart disease. Knowledge of these risk factors and their mitigation will contribute to improved understanding and management of patients with PAD in clinical practice.
Acknowledgments
The authors thank all patients and physicians who participated in this study. Hiroaki Matsuda, a former employee of Mitsubishi Tanabe Pharma Corporation, was responsible for the statistical analyses; analysis co-programming was performed by Y. Suzuki of Personal Tempstaff Co., Ltd. (funded by Mitsubishi Tanabe Pharma Corporation). In addition, we thank M. Wakisaka, M. Kumiji, K. Kawano, and S. Michiyama for their excellent secretarial assistance; T. Hidaka, MD, PhD; S. Nakamura, MD, PhD; J. Soga, MD, PhD; Y. Fujii, MD, PhD; N. Idei, MD; N. Fujimura, MD, PhD; T. Maruhashi, MD, PhD; S. Mikami, MD, PhD; Y. Iwamoto, MD; A. Iwamoto, MD, PhD; T. Matsumoto, MD, PhD; N. Oda, MD, PhD; S. Kishimoto, MD; S. Matsui, MD; H. Hashimoto, MD; and Y. Kihara, MD, PhD (Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan); K. Kanai, PhD; Y. Aibara, MS; H. Morimoto, PhD; F.B.M. Yusoff, MD; K. Noma, MD, PhD; A. Nakashima, MD, PhD, and Y. Higashi, MD, PhD, FAHA (Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan); T. Sakashita, MD, PhD; and Y. Kudo, MD, PhD (Department of Obstetrics and Gynecology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan); T. Sueda, MD, PhD (Department of Surgery, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan); M. Kajikawa, MD, PhD; S. Miyaki, PhD; N. Kamei, MD, PhD; Y. Urabe, MD, PhD; Y. Sanada, PhD; and M. Ohira, MD, PhD (Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan); Y. Matsuishi, MD, PhD (Matsuishi Hospital, Hiroshima, Japan) for acquisition of data; E. Hida, PhD (Center for Integrated Medical Research, Hiroshima University Hospital, Hiroshima, Japan); C. Goto, PhD (Hiroshima International University, Hiroshima, Japan); K. Chayama, MD, PhD (Department of Medicine and Molecular Science, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan); T. Miyata, MD, PhD (Sanno Hospital and Sanno Medical Center, International University of Health and Welfare, Tokyo); H. Shigematsu, MD, PhD (Sanno Hospital and Sanno Medical Center, International University of Health and Welfare, Tokyo); H. Origasa, PhD (Division of Biostatistics and Clinical Epidemiology, University of Toyama School of Medicine, Toyama); M. Fujita, MD, PhD (Department of Cardiovascular Medicine, Uji Hospital, Uji, Kyoto); H. Matsuo, MD, PhD (Matsuo Clinic, Osaka); and H. Naritomi, MD, PhD (Senri Chuo Hospital, Osaka) for comments on the manuscript.
Disclosures
Conflicts of Interest
Y.H. received honoraria and grants from Teijin Pharma Ltd., Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corporation, Sanofi KK, AstraZeneca KK, Kyowa Hakko Kirin Co., Ltd., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nihon Kohden Corporation, Shionogi Co., Ltd., Nippon Sigmax Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Unex Corporation, and Kao Corporation, and honoraria from Radiometer Ltd., Omron Corporation, Sumitomo Dainippon Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Torii Pharmaceutical Co., Ltd., Kowa Co., Ltd., Fujiyakuhin Co., Ltd., Amgen Astellas BioPharma KK, Nippon Shinyaku Co., Ltd., Itamar Medical Ltd, Bayer Holding Ltd., Eli Lilly KK, and Ono Pharmaceutical Co., Ltd.
T.M. received remuneration and research funding from Daiichi Sankyo Co., Ltd and Bayer Holding Ltd.
H.S. received honoraria from Mitsubishi Tanabe Pharma Corporation, Sanofi KK, Otsuka Pharmaceutical Co., Ltd., Cook Japan Ltd., Kaken Pharm Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Astellas Pharm Co., Nihon Shinyaku Co., Ltd., Toray Medical Co., Ltd., Bayer Pharm Co Ltd., Daiichi Sankyo Co., Ltd., Mitsubishi Rayon Clinsui Co., Ltd., Nihon Gore KK, Integural Co., Ltd., Life Science Co., Ltd., AnGes MG Co., Ltd., Terumo BSN KK, and Kowa Co., Ltd., and event support from Sanofi KK, Cook Japan Ltd., Nihon Gore KK, Integural Co., Ltd., and LimbFix Co Ltd.
H.O. and M.F. have no disclosures to report.
H.M. received honoraria from Mitsubishi Tanabe Pharma Corporation, Aspen Japan KK, Otsuka Pharmaceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd., General Electric Company, Kowa Pharmaceutical Co., Ltd., Zeria Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Toshiba Medical Systems Corporation, Mitsubishi Tanabe Pharma Corporation, Nippon Sigmax Co., Ltd., Japanese Society of Sonographers, Novartis Pharma KK, Bayer Holding Ltd., Hitachi Aloka Medical Ltd., Fukuda Denshi Co., Ltd., and Medicus Suppan Publishers Co., Ltd.
H.N. received honoraria from Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., and Boehringer Ingelheim Japan Inc.
M.N. and S.Y. are employees of Mitsubishi Tanabe Pharma Corporation.
H.A. was an employee of Mitsubishi at the time the work was conducted.
Funding
This study was sponsored by Mitsubishi Tanabe Pharma Corporation, manufacturer/licensee of sarpogrelate. Patient registration, data collection and management, and statistical analysis were performed by CMIC Co., Ltd. and funded by Mitsubishi Tanabe Pharma Corporation. Mitsubishi Tanabe Pharma was involved in the study design, data collection, data analysis and preparation of the manuscript.
Medical writing assistance was provided by H. Christian, PhD, CMPP and S. Stretton, PhD, CMPP of ProScribe – Envision Pharma Group, and funded by Mitsubishi Tanabe Pharma Corporation. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP3).
Author Contributions
All authors participated in the study design, the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. Y.H., T.M., H.S., M.F., H.M., and H.N. were investigators in the study, M.N. and H.A. were involved in the data collection, and H.O. conducted the statistical analyses. Y.H. is the guarantor of this work and accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Availability of Data and Material
The data that support the findings of this study are available on request from the corresponding author, Yukihito Higashi. The data are not publicly available because this was a postmarketing observational study and release of the information could compromise study participant consent.
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-19-0088
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