Abstract
Background:
Despite mounting evidence of increased cardiovascular events in patients with peripheral arterial disease (PAD), the overall incidence of cardiovascular events in PAD patients has not been fully clarified in Japan. The prospective Surveillance of cardiovascular Events in Antiplatelet-treated arterioSclerosis Obliterans patients in JapaN (SEASON) is a prospective observational multicenter study and here we report the baseline clinical characteristics, including atherosclerosis risk factor prevalence, in PAD patients treated with antiplatelet agents.
Methods and Results:
The SEASON registry enrolled 11,375 patients in 1,745 institutions and the data for 10,322 patients were analyzed. At baseline, the average age was 73.8±9.9 years, 60.0% were male and 83.9% were in Fontaine stage I or II. They had arteriosclerosis risk factors, such as current smoking (16.2%), hypertension (61.5%), diabetes mellitus (38.3%) and dyslipidemia (38.8%). There were complications including heart disease (29.7%), cerebrovascular disease (17.1%) and chronic kidney disease (14.3%). A subpopulation analysis revealed that the proportions of patients with risk factors were high in patients with lower ankle-brachial pressure index value.
Conclusions:
The baseline characteristics of the SEASON population demonstrate that real-world PAD patients have cardiovascular risk factors and comorbidities next to definite PAD patients. Further analysis of this database will contribute to understanding the real-world situation of PAD patients receiving antiplatelet therapy in Japan.
Peripheral arterial disease (PAD) is chronic arterial occlusive disease of the lower extremities caused by atherosclerosis. Its prevalence seems to be increasing, reflecting the aging of society worldwide.1
Several reports suggest that PAD is related to cardiovascular events and poor prognosis.2–4
Therefore, increased attention has been paid to better treatment of patients with PAD and to their prognosis. Several population-based cohort studies and retrospective studies of the outcome of PAD have been performed.5–8
Recent surveys of patients with cardiovascular disease or stroke in Japan have yielded significant interest in the effects of low ankle-brachial pressure index (ABPI) and symptoms of intermittent claudication on prognosis.9,10
However, systematic epidemiological approaches are not sufficient yet.
The REduction of Atherothrombosis for Continued Health (REACH) Registry is an international, prospective, observational study of patients at risk for atherothrombotic events.11
The REACH registry enrolled almost 69,055 outpatients in 44 countries, including 5,048 patients in Japan.12
The studies of this registry produced striking findings, such as patients with PAD having a higher risk of cardiovascular events than those with coronary artery disease,13
and that improved risk factor control was associated with a positive effect on cardiovascular event rates in PAD patients.14
A global baseline data analysis revealed that cardiovascular risk factors are largely under-treated and under-controlled in many regions of the world.12
The subgroup analysis of Japanese patients’ baseline data also showed the prevalence and under-treatment of cardiovascular risk factors in PAD patients.15
However, the sample size of PAD patients was limited. Moreover, only relatively severe PAD patients were eligible for REACH registry enrollment. Therefore, adequate analysis of a practical PAD population containing asymptomatic or mildly symptomatic patients has not have been performed in the past studies.
Ameliorators of circulation, including antiplatelet agents, are widely used for the treatment of PAD. It is important to collect and analyze more information concerning symptoms, treatments, cardiovascular events and outcomes in the real-world situation of PAD patients receiving antiplatelet therapy. These results would lead to better therapy for PAD. Therefore, we planned and carried out the large-scale Surveillance of cardiovascular Events in Antiplatelet-treated arterioSclerosis Obliterans patients in JapaN (SEASON)16
study in order to create a nationwide database of the incidence of cardiovascular events in arteriosclerosis obliterans (ASO) patients. Because ASO has recently been used as a synonym for PAD in Japan,17
this surveillance will contribute to understand the real-world situation of PAD patients treated with antiplatelet therapy.
The aims of the SEASON study were to determine (1) the current status of the management of ASO and (2) the incidence of cardiovascular events in patients with ASO undergoing antiplatelet therapy. The purpose of this study was to clarify the patients’ baseline clinical characteristics in a nationwide observational prospective study. We evaluated the baseline characteristics of 2 populations: patients diagnosed with ASO under treatment with antiplatelet drugs, and definite ASO patients defined as ABI <0.9 and intermittent claudication or history of limb revascularization.
Methods
The methods of the SEASON registry have been previously published,16
but are briefly described.
Study Design
The SEASON registry is a nationwide observational prospective cohort study with a 2-year period of follow-up. The study protocol was approved by the ethics review board of each institution, if necessary. All patients received an explanation about the study before enrollment. The protocol was registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000003385).
Study Population
Patients who met both of the following criteria were eligible for enrollment in the SEASON registry: (1) diagnosed with ASO and scheduled to receive long-term oral antiplatelet therapy and (2) not received sarpogrelate at the time of registration, and meeting either of the following conditions: (1) newly scheduled to receive one of the antiplatelet agents under study or (2) scheduled to change to sarpogrelate or another of the oral antiplatelet agents under study or to receive it in addition to other continuing antiplatelet therapies.
The diagnosis of ASO was confirmed by ABPI or comparison of bilateral lower limb arteries by palpation. Patients were excluded from enrollment if any of the following criteria were met: (1) contraindications to the use of antiplatelet agents, such as hemorrhagic tendency and confirmed/possible pregnancy; and (2) inappropriateness for the study as determined by a patient’s physician in charge.
The patient populations for the main analysis of enrolled patients were defined as follows: (1) a “real-world population (RWP)”, comprising patients whose case report forms (CRFs) were available and who were administered antiplatelet agents at least once; and (2) a “definite PAD population (DPP)” comprising patients in the RWP who met either of the following criteria: (1) current intermittent claudication with ABPI <0.9, or (2) history of lower limb revascularization.16
Antiplatelet Agents
Physicians designated 1 antiplatelet agent as an “investigated drug”, which was newly administered at the time of enrollment, from the following 6 oral antiplatelet agents: sarpogrelate, cilostazo1, ticlopidine, prostaglandin I2 (beraprost sodium), prostaglandin E1 (limaprost alfadex), and eicosapentaenoic acid. All these agents were approved for the treatment of ASO or thromboangitis obliterans (TAO, Buerger disease) in Japan. No restrictions were placed on pretreatment with antiplatelet medication, or on concomitant use of antiplatelet agents. If antiplatelet agents other than the investigated drugs (ie, aspirin, clopidogre1, and dipyridamole) were used, they were to be recorded as concomitant antiplatelet agents. The target allocation ratio of patients administered with sarpogrelate and other antiplatelet agents was 4:1.
Evaluations (Baseline Data Collection)
At the time of registration, patients were assessed at baseline for demographics, risk factors/comorbidities, premedication, current concomitant medications, medical history of ASO (disease duration, Fontaine classification, ABPI, history of revascularization, amputation), severity of ischemic symptoms, physical examination (blood pressure (BP) etc), laboratory values (low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides, hemoglobin A1c (HbAlc), serum creatinine or estimated glomerular filtration rate (eGFR)), intima-media thickness, and endothelial function. After registration, patients were followed every 6 months for a period of 2 years.
The RWP was divided into “normal” (ABPI ≥1.0), “borderline” (0.90≤ABPI<1.0) and “abnormal” (ABPI <0.90) groups to compare each risk proportions among the populations subdivided by ABPI. The following values were used as primary boundary lines for definition of the control status of patients, including well-controlled or not: 140 mmHg of systolic BP and 90 mmHg of diastolic BP for hypertension, 7.0% of HbA1c for diabetes mellitus, 100 mg/dl of LDL-C for dyslipidemia.18
Data Management
The SEASON registry implemented an electric data capture (EDC) system to register patients and collect their data via the internet. For security purposes, investigators received their own ID and password to access the SEASON database after completing study participation. The data for a patient were electronically sent to the SEASON database and automatically exposed to edit checks at the time of data entry, and then the system replied to queries to confirm discrepancies in data, unconfirmed missing data, implausible data, inconsistent data, typographical errors, and so on. Some investigators chose to use a paper CRF. In that case, the data manager of the SEASON registry entered CRF data into the database and performed the same edit checks as the EDC. Cleaned data without discrepancies were locked electronically. A data manager of the SEASON registry is in charge of ensuring data quality.
Statistical Analysis
All analysis data were extracted from the SEASON database. Descriptive analysis was applied to patient characteristics, risk factors/comorbidities, concomitant medication, medical history of ASO, physical examination and laboratory values at baseline. Pairwise comparisons between subpopulations by ABPI were performed using Pearson Chi-square test or t-test without adjustment for statistical test multiplicity. Statistical significance was considered as a 2-tailed probability of less than 0.05. All analyses were performed using SAS, version 9.3 (SAS Institute Inc, Cary, NC, USA).
Results
The
Figure
shows the disposition of patients in the SEASON registry. The registry enrolled 11,375 patients in 1,745 institutions from September 2009 to September 2011. Of these, 10,322 patients were included in the RWP. Of the 1,053 patients excluded, 283 had no CRF, 733 had no safety data reported, 33 did not have an investigated drug administered, and 4 did not meet the inclusion criteria. All the baseline data for the RWP were available for analysis. From the RWP, 3,992 patients were included in the DPP.
Table 1
shows the baseline characteristics of the patients in the RWP and DPP. The ratios of male/female, the mean values and the distributions of age and BMI were similar between groups. The proportion of current smokers in the RWP was 16.2%, and the proportion in the DPP was 22.2%, showing a higher proportion in the DPP. The proportion of patients with diagnosed hypertension, diabetes mellitus or dyslipidemia was 61.5%, 38.3% or 38.8% in the RWP, and 68.4%, 45.2% or 44.0% in the DPP, respectively, again showing higher proportions in the DPP. The proportion of patients with disease duration ≥1 year was almost 40% in the RWP, and >50% in the DPP, a longer duration in the DPP. Based on Fontaine classification, the proportions of stages I and II in the RWP were 40.8% and 43.1%. In the DPP, the proportion of stage II was 69.6%, and of stage IV was almost 2-fold that in the RWP, showing a more severe Fontaine classification stage in the DPP.
Table 1.
Baseline Characteristics of the RWP Patients and Subpopulations of the RWP and DPP
| |
RWP |
Subpopulation by ABPI |
P value* |
DPP |
Normal
(ABPI ≥1.0) |
Borderline
(0.90≤ABPI<1.0) |
Abnormal
(ABPI <0.90) |
Borderline
vs. Normal |
Abnormal
vs. Normal |
| Total |
10,322 (100.0) |
1,300 (100.0) |
776 (100.0) |
4,489 (100.0) |
– |
– |
3,992 (100.0) |
| Sex |
| Male |
6,189 (60.0) |
728 (56.0) |
435 (56.1) |
3,093 (68.9) |
0.9799 |
<0.0001 |
2,939 (73.6) |
| Female |
4,133 (40.0) |
572 (44.0) |
341 (43.9) |
1,396 (31.1) |
|
|
1,053 (26.4) |
| Age (years) |
| <40 |
36 (0.3) |
9 (0.7) |
2 (0.3) |
5 (0.1) |
|
|
5 (0.1) |
| 40’s |
151 (1.5) |
32 (2.5) |
10 (1.3) |
44 (1.0) |
|
|
49 (1.2) |
| 50’s |
639 (6.2) |
111 (8.5) |
49 (6.3) |
233 (5.2) |
|
|
231 (5.8) |
| 60’s |
2,245 (21.7) |
334 (25.7) |
147 (18.9) |
1,014 (22.6) |
|
|
948 (23.7) |
| 70’s |
4,165 (40.4) |
530 (40.8) |
320 (41.2) |
1,830 (40.8) |
<0.0001 |
<0.0001 |
1,644 (41.2) |
| 80’s |
2,758 (26.7) |
258 (19.8) |
230 (29.6) |
1,236 (27.5) |
|
|
1,028 (25.8) |
| ≥90 |
328 (3.2) |
26 (2.0) |
18 (2.3) |
127 (2.8) |
|
|
87 (2.2) |
| N |
10,322 |
1,300 |
776 |
4,489 |
|
|
3,992 |
| Mean |
73.8 |
71.6 |
74.2 |
74.1 |
<0.0001** |
<0.0001** |
73.5 |
| SD |
9.9 |
10.2 |
9.5 |
9.2 |
|
|
9.3 |
| BMI (kg/m2) |
| <25.0 |
6,951 (67.3) |
901 (69.3) |
522 (67.3) |
3,292 (73.3) |
|
|
2,967 (74.3) |
| 25.0–30.0 |
1,902 (18.4) |
275 (21.2) |
185 (23.8) |
856 (19.1) |
|
|
710 (17.8) |
| 30.0–35.0 |
258 (2.5) |
38 (2.9) |
25 (3.2) |
111 (2.5) |
0.2036 |
0.0259 |
86 (2.2) |
| ≥35.0 |
51 (0.5) |
11 (0.8) |
3 (0.4) |
20 (0.4) |
|
|
7 (0.2) |
| Unknown |
1,160 (11.2) |
75 (5.8) |
41 (5.3) |
210 (4.7) |
|
|
222 (5.6) |
| N |
9,162 |
1,225 |
735 |
4,279 |
|
|
3,770 |
| Mean |
22.81 |
23.08 |
23.28 |
22.65 |
0.2329** |
0.0003** |
22.49 |
| SD |
3.66 |
3.74 |
3.63 |
3.63 |
|
|
3.47 |
| Smoking history |
| No |
4,445 (43.1) |
655 (50.4) |
365 (47.0) |
1,466 (32.7) |
|
|
1,120 (28.1) |
| Past smoker |
2,594 (25.1) |
251 (19.3) |
204 (26.3) |
1,500 (33.4) |
|
|
1,471 (36.8) |
| Current smoker |
1,677 (16.2) |
180 (13.8) |
125 (16.1) |
948 (21.1) |
0.159 |
<0.0001 |
888 (22.2) |
| Unknown |
1,606 (15.6) |
214 (16.5) |
82 (10.6) |
575 (12.8) |
|
|
513 (12.9) |
| Hypertension |
6,349 (61.5) |
738 (56.8) |
512 (66.0) |
3,098 (69.0) |
<0.0001 |
<0.0001 |
2,731 (68.4) |
| SBP (mmHg) |
| <140 |
5,457 (52.9) |
770 (59.2) |
467 (60.2) |
2,381 (53.0) |
|
|
2,097 (52.5) |
| ≥140 |
3,625 (35.1) |
452 (34.8) |
275 (35.4) |
1,905 (42.4) |
0.7572 |
<0.0001 |
1,674 (41.9) |
| Unknown |
1,240 (12.0) |
78 (6.0) |
34 (4.4) |
203 (4.5) |
|
|
221 (5.5) |
| DBP (mmHg) |
| <90 |
8,107 (78.5) |
1,057 (81.3) |
662 (85.3) |
3,808 (84.8) |
|
|
3,356 (84.1) |
| ≥90 |
961 (9.3) |
164 (12.6) |
79 (10.2) |
468 (10.4) |
0.095 |
0.0258 |
405 (10.1) |
| Unknown |
1,254 (12.1) |
79 (6.1) |
35 (4.5) |
213 (4.7) |
|
|
231 (5.8) |
| Diabetes mellitus/related complications |
| Diabetes mellitus |
3,953 (38.3) |
473 (36.4) |
310 (39.9) |
2,028 (45.2) |
0.105 |
<0.0001 |
1,805 (45.2) |
| Diabetic retinopathy |
932 (9.0) |
103 (7.9) |
67 (8.6) |
517 (11.5) |
– |
– |
450 (11.3) |
| Neuropathy |
1,102 (10.7) |
158 (12.2) |
81 (10.4) |
536 (11.9) |
– |
– |
493 (12.3) |
| Nephropathy |
1,296 (12.6) |
128 (9.8) |
101 (13.0) |
745 (16.6) |
– |
– |
633 (15.9) |
| Other diabetic complications |
787 (7.6) |
102 (7.8) |
56 (7.2) |
430 (9.6) |
– |
– |
393 (9.8) |
| HbA1c |
| <7.0 |
4,365 (42.3) |
583 (44.8) |
383 (49.4) |
2,178 (48.5) |
|
|
1,910 (47.8) |
| ≥7.0 |
1,496 (14.5) |
187 (14.4) |
116 (14.9) |
838 (18.7) |
0.7248 |
0.0004 |
746 (18.7) |
| Unknown |
4,461 (43.2) |
530 (40.8) |
277 (35.7) |
1,473 (32.8) |
|
|
1,336 (33.5) |
| Dyslipidemia |
4,006 (38.8) |
544 (41.8) |
357 (46.0) |
1,989 (44.3) |
0.0643 |
0.1151 |
1,758 (44.0) |
| LDL-C (mg/dl) |
| <100 |
2,820 (27.3) |
415 (31.9) |
223 (28.7) |
1,403 (31.3) |
|
|
1,253 (31.4) |
| ≥100 |
3,994 (38.7) |
507 (39.0) |
352 (45.4) |
1,930 (43.0) |
0.0044 |
0.0102 |
1,636 (41.0) |
| Unknown |
3,508 (34.0) |
378 (29.1) |
201 (25.9) |
1,156 (25.8) |
|
|
1,103 (27.6) |
| HDL-C (mg/dl) |
| <40 |
1,425 (13.8) |
136 (10.5) |
122 (15.7) |
798 (17.8) |
0.0004 |
<0.0001 |
702 (17.6) |
| ≥40 |
5,466 (53.0) |
810 (62.3) |
469 (60.4) |
2,542 (56.6) |
|
|
2,201 (55.1) |
| Unknown |
3,431 (33.2) |
354 (27.2) |
185 (23.8) |
1,149 (25.6) |
|
|
1,089 (27.3) |
| Triglycerides (mg/dl) |
| <150 |
5,343 (51.8) |
713 (54.8) |
461 (59.4) |
2,482 (55.3) |
|
|
2,157 (54.0) |
| ≥150 |
2,211 (21.4) |
297 (22.8) |
182 (23.5) |
1,158 (25.8) |
0.7506 |
0.0308 |
1,029 (25.8) |
| Unknown |
2,768 (26.8) |
290 (22.3) |
133 (17.1) |
849 (18.9) |
|
|
806 (20.2) |
| PAD duration (years) |
| <1 |
4,286 (41.5) |
581 (44.7) |
311 (40.1) |
1,743 (38.8) |
|
|
1,406 (35.2) |
| 1–3 |
2,166 (21.0) |
260 (20.0) |
162 (20.9) |
963 (21.5) |
0.9082 |
0.0049 |
918 (23.0) |
| ≥3 |
2,192 (21.2) |
256 (19.7) |
148 (19.1) |
1,016 (22.6) |
|
|
1,114 (27.9) |
| Unknown |
1,678 (16.3) |
203 (15.6) |
155 (20.0) |
767 (17.1) |
|
|
554 (13.9) |
| Fontaine classification |
| Stage I |
4,215 (40.8) |
797 (61.3) |
392 (50.5) |
1,172 (26.1) |
<0.0001 |
<0.0001 |
414 (10.4) |
| Stage II |
4,445 (43.1) |
368 (28.3) |
311 (40.1) |
2,611 (58.2) |
|
|
2,778 (69.6) |
| Stage III |
1,090 (10.6) |
100 (7.7) |
53 (6.8) |
389 (8.7) |
|
|
412 (10.3) |
| Stage IV |
570 (5.5) |
35 (2.7) |
20 (2.6) |
316 (7.0) |
|
|
387 (9.7) |
| Unknown |
2 (0.0) |
0 (0.0) |
0 (0.0) |
1 (0.0) |
|
|
1 (0.0) |
| ABPI |
| <0.4 |
331 (3.2) |
0 (0.0) |
0 (0.0) |
331 (7.4) |
– |
– |
303 (7.6) |
| 0.4–0.7 |
1,953 (18.9) |
0 (0.0) |
0 (0.0) |
1,953 (43.5) |
– |
– |
1,680 (42.1) |
| 0.7–0.9 |
2,205 (21.4) |
0 (0.0) |
0 (0.0) |
2,205 (49.1) |
– |
– |
1,515 (38.0) |
| 0.9–1.0 |
776 (7.5) |
0 (0.0) |
776 (100.0) |
0 (0.0) |
– |
– |
117 (2.9) |
| 1.0–1.4 |
1,296 (12.6) |
1,296 (99.7) |
0 (0.0) |
0 (0.0) |
– |
– |
132 (3.3) |
| ≥1.4 |
4 (0.0) |
4 (0.3) |
0 (0.0) |
0 (0.0) |
– |
– |
0 (0.0) |
| Unknown |
3,757 (36.4) |
0 (0.0) |
0 (0.0) |
0 (0.0) |
– |
– |
245 (6.1) |
| History of limb revascularization |
| Without |
8,885 (86.1) |
1,180 (90.8) |
659 (84.9) |
3,513 (78.3) |
<0.0001 |
<0.0001 |
2,597 (65.1) |
| With |
1,387 (13.4) |
114 (8.8) |
113 (14.6) |
972 (21.7) |
|
|
1,387 (34.7) |
| Unknown |
50 (0.5) |
6 (0.5) |
4 (0.5) |
4 (0.1) |
|
|
8 (0.2) |
| History of limb amputation |
| Without |
10,117 (98.0) |
1,279 (98.4) |
768 (99.0) |
4,400 (98.0) |
0.2723 |
0.4489 |
3,788 (94.9) |
| With |
202 (2.0) |
21 (1.6) |
8 (1.0) |
87 (1.9) |
|
|
202 (5.1) |
| Unknown |
3 (0.0) |
0 (0.0) |
0 (0.0) |
2 (0.0) |
|
|
2 (0.1) |
| Heart disease |
| Any heart disease |
3,064 (29.7) |
263 (20.2) |
234 (30.2) |
1,667 (37.1) |
<0.0001 |
<0.0001 |
1,546 (38.7) |
Ischemic heart disease
(myocardial infarction/
angina pectoris) |
2,089 (20.2) |
168 (12.9) |
154 (19.8) |
1,190 (26.5) |
– |
– |
1,116 (28.0) |
| Atrial fibrillation |
638 (6.2) |
51 (3.9) |
45 (5.8) |
362 (8.1) |
– |
– |
343 (8.6) |
| Other heart diseases |
724 (7.0) |
81 (6.2) |
61 (7.9) |
344 (7.7) |
– |
– |
288 (7.2) |
| Cerebrovascular disease |
Any cerebrovascular
disease |
1,767 (17.1) |
163 (12.5) |
121 (15.6) |
897 (20.0) |
0.0501 |
<0.0001 |
779 (19.5) |
| Stroke |
1,443 (14.0) |
122 (9.4) |
102 (13.1) |
731 (16.3) |
– |
– |
640 (16.0) |
| TIA |
206 (2.0) |
24 (1.8) |
14 (1.8) |
101 (2.2) |
– |
– |
91 (2.3) |
Other cerebrovascular
diseases |
212 (2.1) |
27 (2.1) |
18 (2.3) |
116 (2.6) |
– |
– |
96 (2.4) |
| Chronic kidney disease |
Any chronic kidney
disease |
1,473 (14.3) |
137 (10.5) |
97 (12.5) |
834 (18.6) |
0.1715 |
<0.0001 |
734 (18.4) |
Chronic
glomerulonephritis |
206 (2.0) |
25 (1.9) |
11 (1.4) |
89 (2.0) |
– |
– |
75 (1.9) |
| Nephrosclerosis |
523 (5.1) |
45 (3.5) |
30 (3.9) |
327 (7.3) |
– |
– |
294 (7.4) |
Other chronic kidney
disease |
808 (7.8) |
77 (5.9) |
61 (7.9) |
446 (9.9) |
– |
– |
392 (9.8) |
| Hemodialysis |
644 (6.2) |
60 (4.6) |
37 (4.8) |
330 (7.4) |
– |
– |
291 (7.3) |
| eGFR (ml/min/1.73 m2) |
| <30 |
973 (9.4) |
80 (6.2) |
66 (8.5) |
559 (12.5) |
<0.0001 |
<0.0001 |
476 (11.9) |
| 30–60 |
2,754 (26.7) |
299 (23.0) |
234 (30.2) |
1,471 (32.8) |
|
|
1,294 (32.4) |
| 60–90 |
3,524 (34.1) |
562 (43.2) |
297 (38.3) |
1,584 (35.3) |
|
|
1,415 (35.4) |
| ≥90 |
729 (7.1) |
112 (8.6) |
76 (9.8) |
291 (6.5) |
|
|
274 (6.9) |
| Unknown |
2,342 (22.7) |
247 (19.0) |
103 (13.3) |
584 (13.0) |
|
|
533 (13.4) |
| No. of oral antiplatelet agents used |
| 0 |
6,299 (61.0) |
909 (69.9) |
472 (60.8) |
2,212 (49.3) |
<0.0001 |
<0.0001 |
1,736 (43.5) |
| 1 |
3,002 (29.1) |
324 (24.9) |
226 (29.1) |
1,595 (35.5) |
|
|
1,519 (38.1) |
| 2 |
868 (8.4) |
57 (4.4) |
66 (8.5) |
577 (12.9) |
|
|
613 (15.4) |
| ≥3 |
153 (1.5) |
10 (0.8) |
12 (1.5) |
105 (2.3) |
|
|
124 (3.1) |
*For numeric or ordered measurements, Pearson Chi-square tests were applied after creating a 2×2 table with unknown data combined with non-risk side (age: <70, ≥70; BMI: <25.0, ≥25.0; SBP: <140, ≥140; DBP: <90, ≥90; HbA1c: <7.0, ≥7.0; LDL-cholesterol: <100, ≥100; HDL-cholesterol: <40, ≥40; triglycerides: <150, ≥150; PAD duration: <1, ≥1; Fontaine classification: Stage I, ≥Stage II; eGFR: <60, ≥60; no. of oral antiplatelet agents used: ≤1, ≥2). For smoking history, 2×2 table was created with current smoker, others. **Student’s t-test. Subpopulations of RWP based on ABPI values. ABPI, ankle-brachial pressure index; BMI, body mass index; DBP, diastolic blood pressure; DPP, definite peripheral arterial disease population; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PAD, peripheral arterial disease; RWP, real-world population; SBP, systolic blood pressure; TIA, transient ischemic attack.
The proportion of patients having ABPI <0.9 in the RWP was approximately 40%, and approximately 90% in the DPP, more severe in the DPP. The proportions of a history of revascularization and limb amputation in the DPP were 34.7% and 5.1%, more than 2-fold higher than the respective 13.4% and 2.0% in the RWP. The proportions of heart disease, cerebrovascular disease and chronic kidney disease were 38.7%, 19.5% and 18.4% in the DPP, higher than the respective 29.7%, 17.1% and 14.3% in the RWP. The proportion of patients with eGFR <60 was 44.3% in DPP, higher than the 36.1% in the RWP.
As shown in
Table 1, the RWP was subdivided by ABPI values into a normal (ABPI ≥1.0), borderline (0.9<ABPI<1.0) and abnormal (ABPI ≤0.9) subpopulation. The proportions of male patients, aged patients (≥70 years), current smoker, hypertension (systolic and diastolic BPs), diabetes mellitus, long PAD duration (≥1 year), Fontaine stage II/III/IV, history of limb revascularization, heart disease, cerebrovascular disease, chronic kidney disease and multiple antiplatelet treatment (≥2) in the abnormal subpopulation were statistically higher than in the normal subpopulation (P<0.05). The proportion of obese patients (BMI ≥25.0) in the abnormal subpopulation was statistically lower than in the normal group (P<0.05). The proportions of aged patients, hypertension, Fontaine stage II/III/IV, history of limb revascularization, heart disease and multiple antiplatelet treatment (≥2) in the borderline subpopulation were statistically higher than in the normal subpopulation (P<0.05). Each proportion of patients within each category of the baseline characteristics of the abnormal subpopulation of RWP was similar to that of the DPP.
Table 2
shows the concomitant medications of patients in the RWP, DPP and 3 subpopulations. At baseline, several antiplatelet agents, antihypertensive agents, hypolipidemic agents and antidiabetic agents were already being administered to patients in all and the subpopulations. The proportions of patients with antiplatelet, antihypertensive, hypolipidemic and antidiabetic agents in the DPP were 56.5%, 71.4%, 39.0 and 37.2%, higher than the respective 39.0%, 64.8%, 34.2% and 31.1% in the RWP. Those values in the ABPI normal/abnormal subpopulations were 30.1%/50.7%, 59.2%/72.2%, 35.5%/39.2% and 29.8%/37.1%, respectively, All proportions in the abnormal subpopulation were statistically higher than those in the normal subpopulation (P<0.05). The proportions in the borderline group were also statistically higher than those in the normal subpopulation (P<0.05), except for antidiabetic medication.
Table 2.
Concomitant Medications of PAD Patients in the Total and Subpopulations
| |
RWP |
Subpopulation by ABPI |
P value* |
DPP |
Normal
(ABPI ≥1.0) |
Borderline
(0.90≤ABPI<1.0) |
Abnormal
(ABPI <0.90) |
Borderline
vs. Normal |
Abnormal
vs. Normal |
| Total |
10,322 (100.0) |
1,300 (100.0) |
776 (100.0) |
4,489 (100.0) |
|
|
3,992 (100.0) |
| Oral antiplatelet agents |
Any oral antiplatelet
agent used |
4,023 (39.0) |
391 (30.1) |
304 (39.2) |
2,277 (50.7) |
<0.0001 |
<0.0001 |
2,256 (56.5) |
| Aspirin |
2,450 (23.7) |
224 (17.2) |
217 (28.0) |
1,446 (32.2) |
– |
– |
1,468 (36.8) |
| Cilostazol |
669 (6.5) |
63 (4.8) |
41 (5.3) |
462 (10.3) |
– |
– |
503 (12.6) |
| Clopidogrel sulfate |
528 (5.1) |
55 (4.2) |
37 (4.8) |
339 (7.6) |
– |
– |
333 (8.3) |
| Limaprost |
454 (4.4) |
48 (3.7) |
30 (3.9) |
254 (5.7) |
– |
– |
240 (6.0) |
| Eicosapentaenoic acid |
449 (4.3) |
36 (2.8) |
24 (3.1) |
199 (4.4) |
– |
– |
212 (5.3) |
| Beraprost |
318 (3.1) |
21 (1.6) |
23 (3.0) |
177 (3.9) |
– |
– |
181 (4.5) |
| Ticlopidine |
283 (2.7) |
19 (1.5) |
14 (1.8) |
168 (3.7) |
– |
– |
167 (4.2) |
| Dipyridamole |
65 (0.6) |
4 (0.3) |
8 (1.0) |
34 (0.8) |
– |
– |
31 (0.8) |
| Antihypertensive agents |
Any antihypertensive
agent used |
6,686 (64.8) |
770 (59.2) |
542 (69.8) |
3,240 (72.2) |
<0.0001 |
<0.0001 |
2,851 (71.4) |
| CCB |
4,302 (41.7) |
496 (38.2) |
367 (47.3) |
2,163 (48.2) |
– |
– |
1,931 (48.4) |
| ARB |
4,121 (39.9) |
471 (36.2) |
362 (46.6) |
2,011 (44.8) |
– |
– |
1,732 (43.4) |
| Hydragogue |
1,315 (12.7) |
123 (9.5) |
89 (11.5) |
700 (15.6) |
– |
– |
569 (14.3) |
| β-blocker |
988 (9.6) |
96 (7.4) |
75 (9.7) |
546 (12.2) |
– |
– |
508 (12.7) |
| ACEI |
813 (7.9) |
74 (5.7) |
45 (5.8) |
482 (10.7) |
– |
– |
407 (10.2) |
| α-blocker |
368 (3.6) |
32 (2.5) |
28 (3.6) |
221 (4.9) |
– |
– |
188 (4.7) |
| Antihyperlipidemic agents |
Any hypolipidemic agent
used |
3,531 (34.2) |
461 (35.5) |
313 (40.3) |
1,760 (39.2) |
0.0263 |
0.0145 |
1,557 (39.0) |
| Statin |
3,164 (30.7) |
405 (31.2) |
278 (35.8) |
1,606 (35.8) |
– |
– |
1,427 (35.7) |
| Fibrate |
264 (2.6) |
40 (3.1) |
33 (4.3) |
113 (2.5) |
– |
– |
102 (2.6) |
| Ezetimibe |
226 (2.2) |
33 (2.5) |
26 (3.4) |
107 (2.4) |
– |
– |
89 (2.2) |
| Probucol |
17 (0.2) |
1 (0.1) |
1 (0.1) |
8 (0.2) |
– |
– |
7 (0.2) |
| Ion exchange resin |
11 (0.1) |
0 (0.0) |
0 (0.0) |
8 (0.2) |
– |
– |
5 (0.1) |
| Antidiabetic agents |
Any diabetes mellitus
medication used |
3,213 (31.1) |
388 (29.8) |
254 (32.7) |
1,665 (37.1) |
0.1687 |
<0.0001 |
1,484 (37.2) |
| Oral hypoglycemic agent |
2,506 (24.3) |
309 (23.8) |
210 (27.1) |
1,257 (28.0) |
– |
– |
1,112 (27.9) |
| Insulin |
1,042 (10.1) |
123 (9.5) |
66 (8.5) |
586 (13.1) |
– |
– |
535 (13.4) |
*Pearson Chi-square test. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium-channel blocker. Other abbreviations as in Table 1.
The proportion of antiplatelet-treated patients with ABPI ≥1.0 was lowest among the subpopulations. On the other hand, each proportion of patients with each of the medications in the abnormal subpopulation was, at a higher proportion, close to that of the DPP.
Table 3
shows the control status of patients with diabetes mellitus, dyslipidemia and hypertension. The proportions of patients with well-controlled diabetes mellitus, dyslipidemia and hypertension in the RWP/DPP were 44.9%/43.0%, 34.6%/37.5% and 48.9%/48.7%, respectively. Those values in the ABPI normal/abnormal subpopulations were 50.1%/44.3%, 36.4%/36.9% and 52.8%/48.8%, respectively. The proportions of well-controlled diabetes mellitus and hypertension patients in the abnormal subpopulation were statistically lower than those in the normal subpopulation (P<0.05).
Table 3.
Control Status of PAD Patients With Diabetes Mellitus/Dyslipidemia/Hypertension in the RWP and Subpopulations of the RWP and DPP
| |
RWP |
Subpopulation by ABPI |
P value* |
DPP |
Normal
(ABPI ≥1.0) |
Borderline
(0.90≤ABPI<1.0) |
Abnormal
(ABPI <0.90) |
Borderline
vs. Normal |
Abnormal
vs. Normal |
| Total no. of patients |
10,322 (100.0) |
1,300 (100.0) |
776 (100.0) |
4,489 (100.0) |
|
|
3,992 (100.0) |
| Diabetes mellitus |
3,953 (38.3) |
473 (36.4) |
310 (39.9) |
2,028 (45.2) |
– |
– |
1,805 (45.2) |
| HbA1c <7.0 |
1,774 (44.9) |
237 (50.1) |
164 (52.9) |
899 (44.3) |
0.4437 |
0.0231 |
777 (43.0) |
| HbA1c ≥7.0 |
1,445 (36.6) |
182 (38.5) |
115 (37.1) |
817 (40.3) |
|
|
719 (39.8) |
| HbA1c unknown |
734 (18.6) |
54 (11.4) |
31 (10.0) |
312 (15.4) |
|
|
309 (17.1) |
| Dyslipidemia |
4,006 (38.8) |
544 (41.8) |
357 (46.0) |
1,989 (44.3) |
– |
– |
1,758 (44.0) |
| LDL-C <100 |
1,386 (34.6) |
198 (36.4) |
122 (34.2) |
734 (36.9) |
0.4952 |
0.8283 |
659 (37.5) |
| LDL-C ≥100 |
1,818 (45.4) |
259 (47.6) |
175 (49.0) |
916 (46.1) |
|
|
767 (43.6) |
| LDL-C unknown |
802 (20.0) |
87 (16.0) |
60 (16.8) |
339 (17.0) |
|
|
332 (18.9) |
| Hypertension |
6,349 (61.5) |
738 (56.8) |
512 (66.0) |
3,098 (69.0) |
– |
– |
2,731 (68.4) |
SBP <140 and
DBP <90 mmHg |
3,103 (48.9) |
390 (52.8) |
280 (54.7) |
1,512 (48.8) |
0.5208 |
0.0485 |
1,329 (48.7) |
SBP ≥140 or
DBP ≥90 mmHg |
2,728 (43.0) |
316 (42.8) |
221 (43.2) |
1,478 (47.7) |
|
|
1.280 (46.9) |
| SBP or DBP unknown |
518 (8.2) |
32 (4.3) |
11 (2.1) |
108 (3.5) |
|
|
122 (4.5) |
*For numeric measurements, Pearson Chi-square tests were applied after creating a 2×2 table with unknown data combined with uncontrol side. Abbreviations as in Table 1.
Each proportion of patients with well-controlled disease in the abnormal subpopulation of the RWP was similar to that in the DPP. Therefore, the DPP had a lower proportion of well-controlled disease, despite a higher proportion of concomitant medications.
We compared the baseline characteristics by statistical tests among the 3 subpopulations of the RWP by ABPI, but only numerically between the RWP and DPP, because the RWP contained all the elements of the DPP and the 2 populations were not independent of each other.
Discussion
The SEASON registry is a nationwide surveillance of cardiovascular events in more than 10,000 antiplatelet-treated ASO patients in Japan. The baseline data analysis in the SEASON registry showed that the RWP had considerable proportions of cardiovascular risk factors and comorbidities next to the DPP in general. The analysis also revealed that the control status of comorbidities in both the RWP and DPP was almost the same, and that the status in the ABPI normal subpopulation was better than that in the ABPI abnormal subpopulation despite more medications in the ABPI abnormal subpopulation. The proportions of patients with well-controlled diabetes mellitus, dyslipidemia and hypertension were less than 50% in both the RWP and DPP, suggesting that cardiovascular risk factors are probably not under-controlled in the majority of Japanese PAD patients.
PAD is a chronic arterial occlusive disease of the lower extremities caused by atherosclerosis, and its prevalence increases with age.1
A recent systematic review revealed that from 2000 to 2010 the number of individuals with PAD increased by 28.7% in low-income or middle-income countries and by 13.1% in high-income countries.19
Previous reports suggest that PAD is related to cardiovascular events, cardiovascular mortality and all-cause mortality.2–4
Modifiable risk factors for PAD are not different from those for patients with coronary artery disease.1,20
Therefore, increased attention has been paid to the treatment of patients with PAD.
The REACH registry is an international, prospective, observational study of patients at risk for atherothrombotic events.11
A global baseline data analysis revealed that cardiovascular risk factors were largely under-treated and under-controlled in many regions of the world.12
However, the REACH registry population does not contain asymptomatic or mildly symptomatic PAD patients. Only relatively severe PAD patients were eligible for the REACH registry, fulfilling either of 2 criteria: (1) current intermittent claudication with ABPI <0.9, or (2) history of lower limb revascularization.16
Those criteria are almost the same as those for the DPP in the SEASON registry.
On the other hand, there are a large number of diagnosed PAD patients who are asymptomatic or mildly symptomatic in the clinical setting. Coldness and numbness of the lower extremities caused by occlusion of lower limb arteries are considered to be early symptoms of PAD in Japan. In order to investigate diagnosed PAD patients in practical clinical settings in Japan, we needed a different registry. Therefore, we planned and carried out the large-scale SEASON registry16
to create a nationwide database and analyze the real-world situation of PAD patients with associated antiplatelet therapy in Japan. In the present study, we defined a RWP as patients who fulfilled the SEASON criteria. It contained not only definite PAD patients but also asymptomatic or mildly symptomatic PAD patients, making it similar to the PAD population in real-world clinical settings in Japan.
From the SEASON baseline data analysis, the prevalence of cardiovascular risk factors, such as smoking, hypertension, diabetes mellitus, dyslipidemia and renal dysfunction, was numerically higher in the DPP or the ABPI abnormal subpopulation than in the RWP. These data seem reasonable, because risk factors are associated with disease severity and low ABPI in PAD patients.20–23
The mean age and the proportion of male PAD patients in the REACH subpopulation analysis of Japanese patients were 72.2 years and 83.7%, respectively,15
and those in the DPP of the SEASON registry were 73.5 years and 73.6%, respectively. The proportions of PAD patients with current smoking, diabetes mellitus, and hypertension were 21.7%, 41.2% and 77.8%, respectively, in the REACH subpopulation15
and 22.2%, 45.2% and 68.4%, respectively, in the DPP of the SEASON registry, suggesting that our results are consistent with those from the REACH subpopulation analysis.
In the present study, the proportions of patients with well-controlled diabetes mellitus, dyslipidemia and hypertension were less than 50% in both the RWP and DPP. Similar findings were obtained from the REACH registry.12,15
The poor prognosis of PAD patients is related to poor control of these risk factors.1,7,13
In the DPP, the proportion of patients receiving antihypertensive agents, hypolipidemic agents or antidiabetic agents was 71.4%, 39.0% or 37.2%, respectively. These values are similar to those for the Japanese PAD patients in the REACH registry.15
However, the proportion of patients with any antiplatelet agent in the DPP (56.5%) is different from the value for Japanese PAD patients in REACH (82.9%).15
In the SEASON registry, the eligible criteria included either of the following conditions: (1) scheduled to newly receive one of the antiplatelet agents under study or (2) scheduled to change to sarpogrelate or one of the other oral antiplatelet agents under study or to receive it in addition to other continuing antiplatelet therapies. Therefore, we speculate that recruiting antiplatelet agent-naïve patients would have been easier than recruiting patients already being administered antiplatelet agents.
In the DPP, the proportion of patients administered calcium-channel blockers (CCBs) was similar to that with angiotensin II receptor blockers (ARBs), whereas those with CCBs was almost double those with ARBs in the REACH Japanese PAD patients.15
These data indicate that the trend in the prescription of antihypertensive agents changed from the time of the REACH study (2004) to the time of the SEASON study (2009–2011).
The term “ASO” was formerly distinguished from PAD, because the latter includes TAO, which previously accounted for the majority of cases of PAD in Japan. With the dramatic decrease in the number of patients with TAO in recent decades, PAD has recently been regarded as the almost same as ASO.17
Oral antiplatelet agents are widely used to treat PAD patients and prevent cardiovascular ischemic events.24
Meta-analysis of Antithrombotic Trialists’ Collaboration showed that aspirin (or other oral antiplatelet agent) is protective in most types of patient at increased risk of occlusive vascular events, including those with PAD.25
However, limited information is available concerning the appropriate choice of an antiplatelet agent for PAD patients.
Sarpogrelate is a selective 5-HT2A
receptor antagonist, inhibiting thrombus formation, platelet aggregation, vasoconstriction and smooth muscle proliferation, and alleviating ischemic symptoms in ASO/PAD patients.26,27
However, clearly comparative data on the effect of sarpogrelate vs. other antiplatelet agents on cardiovascular events remain to be obtained. We plan to collect not only baseline data but also follow-up data of the outcomes of ASO/PAD patients treated with antiplatelet agents (mainly sarpogrelate) from the SEASON registry.16
Further observation will elucidate the effect of sarpogrelate on cardiovascular events in PAD patients in Japan.
Study Limitations
Even though the SEASON study is a large (>10,000 patients), nationwide registry designed to explore cardiovascular events in ASO/PAD patients receiving antiplatelet agents, it has several limitations. Limitations were previously described,16
but one of the main limitations is that SEASON is an observational cohort study, not a randomized controlled study. In particular, the analysis of the present study was based only on baseline data, not considering time-dependent factors. Moreover, this study has features of both an epidemiological investigation and an official post-marketing surveillance study. Institutions that were not using sarpogrelate could not participate in the SEASON registry, because an important purpose of the study was to evaluate the safety and effectiveness of sarpogrelate in ASO/PAD patients. Sampling bias might have occurred.
On the other hand, several types of oral antiplatelet agents have been used extensively for patients with diabetes mellitus and acute coronary syndrome and each agent possesses specific characters, both in efficacy and safety (side effect risks).28
Furthermore, not only medication therapies, including antiplatelet agents, but some nutrients and dietary patterns have been suggested as effective in the primary and secondary prevention of PAD.29
Therefore, additional analyses of multiple aspects of PAD patients are expected to be performed in the near future.
In conclusion, the baseline characteristics of the patients in the SEASON registry, a nationwide observational population study, demonstrate that real-world PAD patients have cardiovascular risk factors and comorbidities next to definite PAD patients. The data also show that cardiovascular risk factors and comorbidities in real-world PAD patients are not sufficiently controlled, even though medical treatments are given. Further analysis of this database, especially to clarify the relationship between prognosis (cardiovascular event occurrence) and patient characteristics, will contribute to understanding the real-world situation of PAD patients receiving antiplatelet therapy in Japan.
Acknowledgments
The authors thank all participating physicians and registered patients who contributed to this post-marketing surveillance study.
Names of Grants
No grants.
Disclosures
The present study was sponsored by Mitsubishi Tanabe Pharma Corporation.
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