Long-term outcomes of peripheral arterial disease patients with significant coronary artery disease undergoing percutaneous coronary intervention

Byoung Geol Choi; Ji-Yeon Hong; Seung-Woon Rha; Cheol Ung Choi; Michael S Lee

doi:10.1371/journal.pone.0251542

. 2021 May 19;16(5):e0251542. doi: 10.1371/journal.pone.0251542

Long-term outcomes of peripheral arterial disease patients with significant coronary artery disease undergoing percutaneous coronary intervention

Byoung Geol Choi ^1,^*,^#, Ji-Yeon Hong ^2,^#, Seung-Woon Rha ^3,^*, Cheol Ung Choi ³, Michael S Lee ⁴

Editor: Xianwu Cheng⁵

PMCID: PMC8133421 PMID: 34010351

Abstract

Background

Patients with peripheral arterial disease (PAD) have known to a high risk of cardiac mortality. However, the effectiveness of the routine evaluation of coronary arteries such as routine coronary angiography (CAG) in PAD patients receiving percutaneous transluminal angioplasty (PTA) is unclear.

Methods

A total of 765 consecutive PAD patients underwent successful PTA and 674 patients (88.1%) underwent routine CAG. Coronary artery disease (CAD) was defined as angiographic stenosis ≥70%. Patients were divided into three groups; 1) routine CAG and a presence of CAD (n = 413 patients), 2) routine CAG and no CAD group (n = 261 patients), and 3) no CAG group (n = 91 patients). To adjust for any potential confounders that could cause bias, multivariable Cox-proportional hazards regression and propensity score matching (PSM) analysis was performed. Clinical outcomes were evaluated by Kaplan-Meier curved analysis at 5-year follow-up.

Results

In this study, the 5-year survival rate of patients with PAD who underwent PTA was 88.5%. Survival rates were similar among the CAD group, the no CAD group, and the no CAG group, respectively (87.7% vs. 90.4% vs. 86.8% P = 0.241). After PSM analysis between the CAD group and the no CAD group, during the 5-year clinical follow-up, there were no differences in the incidence of death, myocardial infarction, strokes, peripheral revascularization, or target extremity surgeries between the two groups except for repeat PCI, which was higher in the CAD group than the non-CAD group (9.3% vs. 0.8%, P<0.001).

Conclusion

PAD patients with CAD were expected to have very poor long-term survival, but they are shown no different long-term prognosis such as mortality compared to PAD patients without CAD. These PAD patients with CAD had received PCI and/or optimal medication treatment after the CAG. Therefore a strategy of routine CAG and subsequent PCI, if required, appears to be a reasonable strategy for mortality risk reduction of PAD patients. Our results highlight the importance for evaluation for CAD in patients with PAD.

Introduction

Peripheral arterial disease (PAD) reduces the quality of life and is associated with poor long-term clinical prognosis [1,2]. Also, coronary artery disease (CAD) is a leading cause of death in many geographies of the world [3]. It shares many risk factors with PAD including age, smoking, diabetes, and chronic kidney disease [2–4]. Because atherosclerosis is a systemic process that can affect multiple vascular territories, patients with either PAD or CAD commonly have the other condition [1,2,5,6]. The severe CAD has been observed in 54% to 69% of patients with PAD [7–10]. Patients with PAD have particularly a high mortality rate from cardiovascular events [6,11–13]. Thus, patients with both PAD and CAD are expected to have a particularly poor long-term prognosis.

Percutaneous transluminal angioplasty (PTA) is commonly used to improve claudication of the extremities and treat critical limb ischemia [7,14]. The use of cardio-protective drugs such as antiplatelet therapy, statin, and angiotensin-converting enzyme inhibitors in PAD helps to improve survival, but the introduction of these guidelines is more than a decade behind CAD [15]. Therefore, evaluating the presence of CAD, which can lead to coronary revascularization and optimal medical treatment, can improve both short- and long-term surviaval in patients receiving PTA [8,16,17]. However, the effective of routine evaluation of coronary arteries in patients receiving PTA is unclear [11,18]. In the present study, we evaluated the long-term clinical outcomes of the strategy of routine coronary angiography (CAG) and subsequent percutaneous coronary intervention (PCI) in patients with PAD who underwent PTA.

Methods

We obtained data from PTA registry of Korea University Guro Hospital (KUGH), Seoul, South Korea. This registry has been described in detail in previous studies [8,19,20]. In brief, this is a single-center, prospective, all-comers registry which started in 2006 and was designed to reflect “real world” practice. Data are collected by trained study-coordinators using standardized case report forms.

Ethical approval

Participants or their legal guardians were given a thorough literal and verbal explanation of the study procedures before asking for written consent to participate in the study. The study protocol was approved by the Medical Device Institutional Review Board (MD-IRB) of KUGH (IRB protocol #MD12018).

Data source and population

A total of 765 consecutive PAD patients underwent successful PTA and 674 patients underwent routine CAG. For the remaining 91 patients who did not receive the CAG, but the cardiac function was evaluated non-invasively by the cardiologist. CAD was defined as angiographic stenosis ≥70% in the main epicardial coronary vessels. Patients were divided into three groups; 1) routine CAG and a presence of CAD (the CAD group: 413 patients), 2) routine CAG without CAD (the no CAD group: 261 patients), and 3) no CAG group (91 patients).

Percutaneous transluminal angioplasty

Standard techniques were used for PTA. For below-the-knee lesions, a 5 Fr Heartrail guiding catheter (Terumo) was used, and a 0.014˝ guidewire was used to traverse the lesions. If intraluminal wiring failed, sub-intimal angioplasty or retrograde approach was performed. After guidewire crossing, prolonged balloon inflation with a balloon ranging in size from 1.5–3.0 mm was used for infra-popliteal vessels and 4–7 mm for femoro-popliteal vessels. Provisional stenting was performed using self-expanding nitinol stents (Xpert, Abbott Vascular, or Maris Deep; Medtronic-Invatec) if balloon angioplasty results were suboptimal. For the ilio-femoral lesion, 6 or 7 F guiding sheath was placed and true lumen angioplasty was attempted to treat chronic total occlusion (CTO) of the superficial femoral artery (SFA) and iliac artery using dedicated 0.018˝ CTO wires. If the intraluminal approach was unsuccessful, subintimal angioplasty using 0.035˝ soft Terumo wire (1.5 J curve) with a 5 Fr angiocatheter support was performed for longer CTO lesions with prolonged balloon inflation with adequate size. If balloon angioplasty results were favorable, PTA with drug-coated balloons (DCB) was performed. If the balloon angioplasty result was suboptimal, provisional stenting with self-expanding nitinol stents or drug-eluting stents was performed. Wiring of the true lumen was performed for shorter CTO lesions. Re-entry with CTO wires or a re-entry device (Outback catheter, Cordis) was used if the subintimal wiring failed to re-enter the distal true lumen for femoropopliteal CTO lesions. A retrograde approach from the distal SFA, popliteal, or infra-popliteal arteries was used in selected cases.

Study definitions [21,22]

PAD was defined as ischemic pain at rest, an ulcer, or gangrene in one or both legs attributed to objectively proven arterial occlusive disease. The main epicardial coronary arteries were defined as having a reference vessel diameter of >2.5 mm at left main-, left anterior descending-, left circumflex-, right coronary-, and the ramus artery. Major adverse cardiovascular and cerebrovascular events (MACCE) were defined as the composite of total death, myocardial infarction (MI), stroke, and revascularization including PCI and coronary artery bypass graft (CABG). Target lesion revascularization (TLR) was defined as ischemia-induced PTA of the target lesion due to restenosis or re-occlusion within the balloon angioplasty site, stent, or in the adjacent 5 mm of the distal or proximal segment. Target extremity revascularization (TER) was defined as clinically-driven PTA of the target lesion or any segment of the same limb containing the target lesion. Major adverse limb events (MALE) were defined as the composite of TER and target extremity surgery.

Statistical analysis

Differences in continuous variables, among the three groups, were evaluated by ANOVA or Kruskal-Wallis, and post-hoc analysis between the two groups were evaluated by Hochberg or Dunnett-T3 test. Differences in continuous variables between the two groups were evaluated using the unpaired t-test or Mann-Whitney rank test. Data are expressed as means ± standard deviations. For discrete variables, differences are expressed as counts and percentages and were analyzed with the χ2 test or Fisher’s exact test. Multivariable Cox-proportional hazards regression, which includes baseline-confounding factors, was used for assessing independent impact factors. To adjust for any potential confounders, propensity score matching (PSM) analysis was performed using a logistic regression model. Matching was performed with a 1:1 matching protocol using the nearest neighbor matching algorithm with a caliper width less than 0.01 the standard deviation of the propensity score. Clinical outcomes that occurred over a period of 5-year were analyzed by Kaplan-Meier analysis, and differences between groups were compared with the log-rank test before and after PSM. For all analyses, a two-sided p < 0.05 was considered statistically significant. All data were analyzed using SPSS (version 20.0, SPSS-PC, Inc. Chicago, Illinois).

Study endpoints

Primary endpoints were MACCE as the composite of total death, MI, stroke, revascularization such as PCI and CABG at 5-year follow-up. Secondary endpoints were TLR, TER, and target extremity surgery after PTA at 5-year clinical follow-up. Patients were followed up at one month and then every 6 months after the PTA procedure as well as whenever cardiovascular ischemic symptoms occurred. Follow-up was performed with face-to-face interviews at the regular outpatient clinic, medical chart reviews, and/or telephone contact.

Results

A total of 765 consecutive PAD patients underwent successful PTA and 674 patients subsequently underwent a routine CAG. The baselines clinical characteristics were similar between the CAG group (the CAD group and the no CAD group) and the no CAG group. In the CAG group, a total of 61.2% patients (413/674) were diagnosed with severe CAD in the main epicardial coronary arteries. Among the patients with CAD, 15.0% (62/413) and 59.0% (244/413) had left main disease and multi-vessel disease, respectively. Among the CAD patients, 71.6% (296/413) treated CAD lesions by PCI and/or CABG, during or after the PTA admission period based upon the physician’s discretion. The CAD group had more elderly patients, diabetics, and higher levels of creatinine than patients in the no CAD group (Table 1). The no CAD group had a higher prevalence of Buerger’s disease and were more likely to be current smokers and alcohol drinkers than the CAD group. The CAD group had a higher prevalence of femoral lesions (49.9% vs. 40.8%, p = 0.011) (Table 2).

Table 1. Baseline characteristics of the entire cohort and propensity-matched groups.

	All patients				Matched patients
	CAG		No CAG		CAG
Variable, N (%)	CAD (n = 413 Pts)	No CAD (n = 261 Pts)	(n = 91 Pts)	P value	CAD (n = 160 Pts)	Non-CAD (n = 160 Pts)	P value	S.diff
Sex, male	314 (76.0)	204 (78.1)	78 (85.7)	0.130	125 (78.1)	123 (76.8)	0.789	-0.14
Age, years	69.1 ± 9.1	66.3 ± 12.5	67.5 ± 10.1	0.003	67.9 ± 9.6	68.8 ± 11.1	0.210	-0.08
Body mass index, kg/m²	23.1 ± 3.3	23.3 ± 3.2	22.9 ± 3.2	0.497	23.4 ± 3.2	23.4 ± 3.1	0.483	0.02
Final diagnosis
Diabetic foot ulcer	239 (57.8)	139 (53.2)	59 (64.8)	0.143	96 (60.0)	94 (58.7)	0.820	-0.16
Wound	258 (62.4)	166 (63.6)	62 (68.1)	0.597	105 (65.6)	103 (64.3)	0.815	-0.16
Gangrene	138 (33.4)	88 (33.7)	30 (32.9)	0.991	57 (35.6)	47 (29.3)	0.233	-1.10
Claudication	73 (17.6)	56 (21.4)	21 (23.0)	0.327	31 (19.3)	32 (20.0)	0.888	0.14
Resting pain	44 (10.6)	34 (13.0)	11 (12.0)	0.639	21 (13.1)	19 (11.8)	0.735	-0.35
Buerger’s disease	6 (1.4)	15 (5.7)	4 (4.3)	0.008	3 (1.8)	2 (1.2)	> 0.99	-0.50
Other	37 (8.9)	7 (2.6)	0 (0.0)	<0.001	5 (3.1)	6 (3.7)	0.759	0.34
Risk Factors
Hypertension	302 (73.1)	178 (68.1)	61 (67.0)	0.279	113 (70.6)	117 (73.1)	0.619	0.30
Diabetes mellitus	317 (76.7)	169 (64.7)	74 (81.3)	<0.001	122 (76.2)	115 (71.8)	0.372	-0.51
Insulin	134 (32.4)	75 (28.7)	34 (37.3)	0.285	62 (38.7)	51 (31.8)	0.198	-1.16
Oral medication	127 (30.7)	70 (26.8)	35 (38.4)	0.111	36 (22.5)	49 (30.6)	0.100	1.58
Dyslipidemia	50 (12.1)	34 (13.0)	10 (10.9)	0.866	19 (11.8)	16 (10.0)	0.591	-0.57
Strokes	90 (21.7)	44 (16.8)	19 (20.8)	0.289	31 (19.3)	33 (20.6)	0.780	0.28
Hemorrhagic	9 (2.1)	8 (3.0)	4 (4.3)	0.467	0 (0.0)	4 (2.5)	0.123	2.24
Ischemic	81 (19.6)	36 (13.7)	16 (17.5)	0.152	31 (19.3)	29 (18.1)	0.775	-0.29
Chronic renal insufficiency	132 (31.9)	67 (25.6)	32 (35.1)	0.122	56 (35.0)	52 (32.5)	0.636	-0.43
Dialysis	82 (19.8)	40 (15.3)	19 (20.8)	0.273	32 (20.0)	30 (18.7)	0.777	-0.28
Congestive heart failure	29 (7.0)	14 (5.3)	3 (3.2)	0.345	11 (6.8)	12 (7.5)	0.829	0.23
History of smoking	213 (51.5)	148 (56.7)	52 (57.1)	0.348	81 (50.6)	83 (51.8)	0.823	0.18
Current of smoking	118 (28.5)	108 (41.3)	31 (34.0)	0.003	46 (28.7)	48 (30.0)	0.806	0.23
History of alcohol drinking	131 (31.7)	107 (40.9)	33 (36.2)	0.049	52 (32.5)	55 (34.3)	0.722	0.32
Currently alcohol drinking	80 (19.3)	76 (29.1)	18 (19.7)	0.010	29 (18.1)	32 (20.0)	0.669	0.43
Laboratory findings
Hemoglobin, mg/dL	11.3 ± 1.9	11.9 ± 2.1	11.3 ± 1.9	0.004	11.5 ± 2.0	11.6 ± 2.1	0.548	-0.07
Fasting glucose, mg/dL	151 ± 74	137 ± 77	145 ± 77	0.074	154 ± 70	144 ± 80	0.068	0.13
Hemoglobin A1c, %	7.2 ± 1.6	6.8 ± 1.5	7.1 ± 1.4	0.015	7.3 ± 1.7	7.0 ± 1.4	0.278	0.18
Total cholesterol, mg/dL	146 ± 42	147 ± 46	137 ± 34	0.235	146 ± 47	147 ± 47	0.645	-0.04
Triglycerides, mg/dL	126 ± 98	129 ± 89	117 ± 59	0.631	124 ± 70	135 ± 104	0.711	-0.13
HDL cholesterol, mg/dL	37 ± 12	38 ± 13	35 ± 11	0.108	36 ± 13	37 ± 13	0.412	-0.11
LDL cholesterol, mg/dL	88.6 ± 34.9	90.9 ± 36.9	79.8 ± 31.8	0.065	88 ± 37	89 ± 37	0.779	-0.03
hs-CRP, mg/L	23.1 ± 47.5	18.3 ± 37.3	22.6 ± 32.7	0.690	22.5 ± 45	20 ± 35.7	0.442	0.06
Creatinine, mg/dL	2.2 ± 2.8	1.7 ± 2.2	2.4 ± 2.9	0.029	2.3 ± 2.8	2.0 ± 2.5	0.200	0.11

Open in a new tab

Data are presented as N (%) or mean ± standard deviation. CAD, coronary artery disease; S.diff, standardized difference; HDL, high-density lipoprotein; LDL, low-density lipoprotein; hs-CRP, high-sensitive C-reactive protein.

Table 2. Coronary angiographic and clinical limb characteristics.

	All patients				Matched patients
	CAG		No CAG		CAG
Variable, N (%)	CAD (n = 413 Pts) (n = 545 Limb)	No CAD (n = 261 Pts) (n = 313 Limb)	(n = 91 Pts) (n = 110 Limb)	P value	CAD (n = 160 Pts) (n = 197 Limb)	Non-CAD (n = 160 Pts) (n = 201 Limb)	P value	S.diff
Coronary artery information (No. patients)
Treated coronary artery disease	296 (71.6)	0 (0.0)	22 (24.1)	<0.001	113 (70.6)	0 (0.0)	< 0.001	-11.93
CABG	25 (6.0)	0 (0.0)	7 (7.6)	<0.001	12 (7.5)	0 (0.0)	< 0.001	-3.87
PCI	283 (68.5)	0 (0.0)	17 (18.6)	<0.001	107 (66.8)	0 (0.0)	< 0.001	-11.60
PCI in PTA	214 (51.8)	0 (0.0)	0 (0.0)	<0.001	84 (52.5)	0 (0.0)	< 0.001	-10.27
Coronary artery	244 (59.0)	0 (0.0)		<0.001
Left main	62 (15.0)	0 (0.0)		<0.001	20 (12.5)	0 (0.0)	< 0.001	-5.00
Left anterior descending	251 (60.7)	0 (0.0)		<0.001	91 (56.8)	0 (0.0)	< 0.001	-10.70
Left circumflex	233 (56.4)	0 (0.0)		<0.001	93 (58.1)	0 (0.0)	< 0.001	-10.81
Right coronary artery	236 (57.1)	0 (0.0)		<0.001	91 (56.8)	0 (0.0)	< 0.001	-10.70
Disease artery, N	1.8 ± 0.8	0.0 ± 0.0		<0.001	1.8 ± 0.7	-	< 0.001	3.26
Peripheral artery information, limbs
Ankle brachial index	0.67 ± 0.37	0.72 ± 0.38	0.83 ± 0.30	0.011	0.67 ± 0.40	0.66 ± 0.42	0.863	0.03
Limb site							0.619	-0.36
Right	289 (53.0)	149 (47.6)	56 (50.9)	0.310	99 (50.2)	96 (47.7)
Left	256 (46.9)	164 (52.3)	54 (49.0)	0.310	98 (49.7)	105 (52.2)
Rutherford grade, limbs							0.74	1.00
Grade 0 (Category 0)	51 (9.3)	16 (5.1)	3 (2.7)	<0.001	9 (4.5)	14 (6.9)
Grade 1	147 (26.9)	98 (31.3)	25 (22.7)		56 (28.4)	56 (27.8)
Category 1	29 (5.3)	17 (5.4)	2 (1.8)		11 (5.5)	11 (5.4)
Category 2	42 (7.7)	23 (7.3)	7 (6.3)		19 (9.6)	14 (6.9)
Category 3	76 (13.9)	58 (18.5)	16 (14.5)		26 (13.1)	31 (15.4)
Grade 2	180 (33)	114 (36.4)	57 (51.8)		77 (39.0)	80 (39.8)
Category 4	46 (8.4)	38 (12.1)	14 (12.7)		14 (7.1)	25 (12.4)
Category 5	134 (24.5)	76 (24.2)	43 (39)		63 (31.9)	55 (27.3)
Grade 3 (Category 6)	167 (30.6)	85 (27.1)	25 (22.7)		55 (27.9)	51 (25.3)
Location, limbs
Distal aorta	16 (2.9)	14 (4.4)	4 (3.6)	0.499	11 (5.5)	9 (4.4)	0.614	-0.49
Iliac artery	164 (30.0)	81 (25.8)	21 (19.0)	0.046	59 (29.9)	52 (25.8)	0.364	-0.77
Femoral artery	272 (49.9)	128 (40.8)	44 (40.0)	0.016	96 (48.7)	87 (43.2)	0.276	-0.80
Popliteal artery	43 (7.8)	35 (11.1)	19 (17.2)	0.008	22 (11.1)	14 (6.9)	0.144	-1.40
Anterior tibia artery	254 (46.6)	156 (49.8)	65 (59.0)	0.055	98 (49.7)	106 (52.7)	0.551	0.42
Posterior tibia artery	210 (38.5)	111 (35.4)	45 (40.9)	0.521	69 (35.0)	72 (35.8)	0.868	0.13
Peroneal artery	105 (19.2)	56 (17.8)	26 (23.6)	0.422	40 (20.3)	41 (20.3)	0.982	0.02

Open in a new tab

Data are presented as N (%) or mean ± standard deviation. CAD, coronary artery disease; S.diff, standardized difference; CABG, coronary artery bypass graft surgery; PCI, percutaneous coronary intervention; PTA, percutaneous transluminal angioplasty.

Procedural and in-hospital complications after PTA were similar among the three groups (Table 3). The CAD group received more clopidogrel, sarpogrelate, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers (ARB), β-blocker than the non-CAD, and no-CAG group (Table 3).

Table 3. Post-procedural complications and medications.

	All patients				Matched patients
	CAG		No CAG		CAG
Variable, N (%)	CAD (n = 413 Pts)	No CAD (n = 261 Pts)	(n = 91 Pts)	P value	CAD (n = 160 Pts)	Non-CAD (n = 160 Pts)	P value
Complications at access site	51 (12.3)	24 (9.1)	6 (6.5)	0.181	10 (6.2)	16 (10.0)	0.22
Arteriovenous fistula	3 (0.7)	2 (0.7)	1 (1.0)	0.851	1 (0.6)	2 (1.2)	> 0.99
Pseudo-aneurysm	4 (0.9)	4 (1.5)	1 (1.0)	0.890	0 (0.0)	3 (1.8)	0.248
Hematoma	48 (11.6)	20 (7.6)	5 (5.4)	0.088	10 (6.2)	12 (7.5)	0.659
minor, < 4 cm	28 (6.7)	13 (4.9)	3 (3.2)	0.349	6 (3.7)	7 (4.3)	0.777
Major, > 4 cm	20 (4.8)	7 (2.6)	2 (2.1)	0.251	4 (2.5)	5 (3.1)	> 0.99
Bleeding complications	98 (23.7)	42 (16.0)	19 (20.8)	0.059
Major bleeding	9 (2.1)	4 (1.5)	2 (2.1)	0.828	3 (1.8)	2 (1.2)	> 0.99
Gastrointestinal bleeding	5 (1.2)	2 (0.7)	2 (2.1)	0.494	1 (0.6)	0 (0.0)	> 0.99
Retroperitoneal bleeding	4 (0.9)	2 (0.7)	0 (0.0)	>0.999	2 (1.2)	2 (1.2)	> 0.99
Transfusion	172 (41.6)	72 (27.5)	31 (34.0)	0.001	62 (38.7)	58 (36.2)	0.605
Transfusion, pints	3.1 ± 7.3	2.2 ± 6.8	2.0 ± 3.9	0.165	2.6 ± 6.1	2.9 ± 7.8	0.746
In-hospital complications
Acute limb ischemia	5 (1.2)	7 (2.6)	0 (0.0)	0.178	1 (0.6)	3 (1.8)	0.623
Acute renal failure	9 (2.1)	3 (1.1)	3 (3.2)	0.398	3 (1.8)	3 (1.8)	> 0.99
Congestive heart failure	3 (0.7)	0 (0.0)	1 (1.0)	0.179	-	-	-
Strokes	1 (0.2)	3 (1.1)	0 (0.0)	0.348	0 (0.0)	2 (1.2)	0.498
Hemorrhagic	0 (0.0)	1 (0.3)	0 (0.0)	0.460	0 (0.0)	1 (0.6)	> 0.99
Ischemic	1 (0.2)	2 (0.7)	0 (0.0)	0.701	0 (0.0)	1 (0.6)	> 0.99
Post-procedural medications
Aspirin	405 (98.0)	254 (97.3)	88 (96.7)	0.675	155 (96.8)	155 (96.8)	> 0.99
Clopidogrel	379 (91.7)	224 (85.8)	80 (87.9)	0.047	142 (88.7)	142 (88.7)	> 0.99
Cilostazol	179 (43.3)	118 (45.2)	33 (36.2)	0.330	62 (38.7)	69 (43.1)	0.426
Anplag	100 (24.2)	51 (19.5)	11 (12.0)	0.027	25 (15.6)	33 (20.6)	0.246
ARBs	176 (42.6)	106 (40.6)	32 (35.1)	0.419	72 (45.0)	65 (40.6)	0.429
ACEIs	86 (20.8)	19 (7.2)	10 (10.9)	<0.001	15 (9.3)	16 (10.0)	0.85
Calcium channel blocker	182 (44.0)	106 (40.6)	35 (38.4)	0.501	60 (37.5)	69 (43.1)	0.305
β-blocker	143 (34.6)	54 (20.6)	16 (17.5)	<0.001	38 (23.7)	41 (25.6)	0.697
Diuretic	116 (28.0)	58 (22.2)	22 (24.1)	0.223	39 (24.3)	39 (24.3)	> 0.99
Statin	341 (82.5)	223 (85.4)	73 (80.2)	0.441	134 (83.7)	134 (83.7)	> 0.99

Open in a new tab

Data are presented as N (%) or mean ± standard deviation. CAD, coronary artery disease; S.diff, standardized difference; ARBs: Angiotensin II receptor blockers; ACEIs, angiotensin-converting enzyme inhibitors.

In this study, the 5-year survival rate of patients with PAD who underwent PTA was 88.5%. Survival rates were similar among the CAD group, the no CAD group and the no CAG group up to 5-year of clinical follow-up, respectively (87.7% vs. 90.4% vs. 86.8% P = 0.241) (Table 4, Fig 1). There was a trend toward a higher incidence of cardiac death in the no CAG group (3.0% vs. 0.8% vs. 3.6%, P = 0.066) than the CAD group and the no CAD group. Coronary revascularization was higher in the CAD group (9.4% vs. 0.8% vs. 4.9% P = 0.005). There was no difference between the two groups in PTA-related events such as peripheral revascularization or target extremity surgery (Table 4).

Table 4. Kaplan–Meier curve analysis of clinical outcomes and log-rank test results.

	All patients				Matched patients
	CAG		No CAG		CAG
Variables, N (%)	CAD (n = 413 Pts)	No CAD (n = 261 Pts)	(n = 91 Pts)	P value	CAD (n = 160 Pts)	Non-CAD (n = 160 Pts)	P value
Five-year clinical outcomes
Total death	51 (12.3)	25 (9.6)	12 (13.2)	0.241	13 (8.1)	21 (13.1)	0.153
Cardiac death	12 (3.0)	2 (0.8)	3 (3.6)	0.066	5 (3.1)	2 (1.3)	0.263
Non-Cardiac death	39 (9.6)	23 (8.9)	9 (10.0)	0.685	8 (5.1)	19 (11.9)	0.030
Myocardial infarction	12 (3.1)	3 (1.2)	5 (6.0)	0.022	2 (1.2)	2 (0.6)	0.989
STEMI	5 (1.3)	1 (0.4)	3 (3.6)	0.035	1 (0.6)	1 (0.6)	0.998
Coronary revascularization	36 (9.4)	2 (0.8)	4 (4.9)	0.005	13 (8.5)	0 (0.0)	< 0.001
Strokes	17 (4.4)	15 (6.0)	2 (2.3)	0.150	8 (5.2)	10 (6.5)	0.587
MACCE	88 (21.3)	39 (14.9)	17 (18.7)	0.153	28 (17.5)	29 (18.1)	0.874
Variables, N (%)	CAD (n = 545 Limb)	Non-CAD (n = 313 Limb)	Not CAG (n = 110 Limb)	P value	CAD (n = 197 Limb)	Non-CAD (n = 201 Limb)	P value
Peripheral revascularization
Target lesion revascularization	80 (15.6)	57 (19.3)	21 (20.9)	0.781	33 (17.3)	37 (19.7)	0.593
Target extremity revascularization	86 (16.8)	62 (21.0)	22 (21.9)	0.627	36 (18.9)	41 (21.7)	0.491
Target extremity surgery
Above the knee amputations	1 (0.1)	3 (1.0)	3 (2.8)	0.366	0 (0.0)	2 (1.0)	0.157
Above the ankle amputations	23 (4.4)	15 (4.9)	9 (8.4)	0.332	5 (2.6)	10 (5.1)	0.187
Below the ankle amputations	102 (19.2)	47 (15.4)	26 (24.4)	0.029	44 (22.5)	32 (16.4)	0.121
Major adverse limb events	161 (30.6)	93 (30.6)	40 (38.2)	0.226	65 (33.3)	62 (32)	0.705

Open in a new tab

Data are presented as incidence (%). CAD, coronary artery disease; STEMI; ST-segment elevation myocardial infarction; MACCE, major adverse cerebrovascular and cardiac events.

Fig 1 — Figure A,C,E, and G show an Un-adjusted hazard ratio by Cox-proportional hazards regression analysis. Figure B,D,F, and H show an adjusted hazard ratio by Cox-proportional hazards regression analysis. Adjusted confounders are Wound, Sex, Age, Hypertension, Diabetes mellitus, Chronic Renal Insufficiency, Current of smoking, treated limb side, and treated lesion (femoral, Popliteal, and Below the knee artery). MACCE, major adverse cerebrovascular and cardiac events; CI, confidence interval; CAD, coronary artery disease; CAG, coronary angiogram.

PSM analysis between the CAD group and the non-CAD group yielded two matched groups (160 pairs, n = 320) with balanced baseline characteristics (Tables 1–3). There were no differences in MI, strokes, peripheral revascularization, or target extremity surgeries between the two groups over the 5-year clinical follow-up period except for non-cardiac death and coronary revascularization. The non-cardiac death was higher in the non-CAD group (5.1% vs. 12.0%, P<0.001) but the coronary revascularization was higher in the CAD group (8.5% vs. 0.0%, P<0.001) (Table 4).

Discussion

The main finding of this study is that routine CAG and subsequent PCI for significant CAD in symptomatic PAD patients undergoing PTA is safe and resulted in similar long-term survival as compared with the symptomatic PAD patients who undergoing PTA and who did not have CAD. Not surprisingly, repeat PCI was performed more frequently in PAD patients with CAD at long-term follow-up.

The summarize of this study is that PAD patients with CAD were expected to have very poor long-term survival, but they are shown no different long-term prognosis such as mortality compared to PAD patients without CAD. These PAD patients with CAD had received PCI and/or optimal medication treatment after the CAG. Considering the high mortality rate of patients with PAD [15], the imaging evaluation of the coronary arteries such as the CAG in PAD patients is important for improving their long-term survival.

PTA is commonly performed to treat PAD patients such as critical limb ischemia (CLI). Both PAD and CAD are known to be associated with a poor quality of life and a poor prognosis [1,2,5,7]. These diseases share most risk factors, and are often comorbid. The best treatment option for these patients may be lifestyle modification and early prevention through global risk reduction [4,14,16,17]. In addition, evaluation of coronary arteries along with subsequent optimal treatment of PAD patients undergoing PTA may improve survival [6,8,11,13,18]. However, an effects on a routine evaluation of the coronary artery such as routine CAG and echocardiography has been controversial in patients undergoing PTA in terms of cost effectiveness. The majority of CAD patients who received PCI in our study received elective PCI. The COURAGE Trial shown that PCI may not have the advantage in stable CAD patients [23]. Also, some clinician can think of it, regardless of symptoms, doing PCI based on CAG results can be an excessive treatment. However, a large number of patients receiving PTA are CLI patients such as wounds and diabetic foot ulcer. Two-thirds of our study population is CLI. Most CLI patients may have limited activity, making it difficult to clearly assess coronary function and associated with less ischemic symptoms. Higher prevalence of advanced PAD patients also associated with higher incidence of silent myocardial ischemia. Our research results provide insight into the long-term clinical effects of active PCI for CAD patients according to routine evaluation of coronary artery and treatment decisions by clinician in PAD patients undergoing PTA. In real world clinical practice, physicians who are performing endovascular intervention commonly only focusing on the extremity target lesion intervention without concerning of CAD evaluation and management [15]. Also, the use of cardio-protective drugs such as antiplatelet therapy, statin, and ACE inhibitors in PAD helps to improve survival, but the introduction of these guidelines is more than a decade behind CAD [15]. Thus, main intention of this report is to provoke all the endovascular intervention specialties should check patient’s co-existing significant CAD and to have an idea to safely manage the CAD together to prevent future cardiovascular events. Routine CAD checkup is not commonly widely accepted in daily clinical practice, especially in terms of cost-effectiveness but this should be changed according to our novel data.

Generally, severe CAD is reported in 54% to 69% of patients with CLI [7–10]. In the present study, 61.2% of patients with PAD were diagnosed with severe CAD. Left main disease and multi-vessel disease were observed at frequencies of 15% and 59%, respectively, in the CAD patients, which portend poor prognosis if left undiagnosed and untreated. Therefore, prompt diagnosis of life-threatening CAD and appropriate revascularization may improve clinical outcomes. Similary, Faglia et al., reported that attention to CAD at the time of admission for treatment of CLI improves the survival of patients with diabetes [11].

Aforementioned in introduction part, patients with PAD have particularly a high mortality rate from cardiovascular events [6,15]. Mortality rates of up to 20% within 6 months from diagnosis and in excess of 50% at 5 years have been reported for CLI [15]. On the other hand, in our study, the mortality rates of PTA patients were significantly lower than the previous studies. The present observation of long-term clinical results of 5-years in patients undergoing PTA, mortality rates were similar among the CAD group, the non-CAD group and the no-CAG group, respectively (12.3% vs. 9.6 vs. 13.2%). This means that the imaging evaluation of the coronary arteries in PAD patients is important for improving their long-term survival and prevent of MI.

After PSM analysis, coronary revascularization remained higher in the CAD group than the non-CAD group, highlighting the fact that repeat coronary revascularization remains a problem in CAD patients. Also, regardless of the baseline risk adjustment, there was no difference between the two groups in PTA-related events such as peripheral revascularization or target extremity surgery. The strategy for CAD evaluation and treatment in PTA patients seems to be a safe and effective strategy not only for better short-term outcomes but also durable long-term outcomes. Similar to our research, Chen and colleagues have registered the multi-center randomized controlled trial (NCT02169258) “Routine Coronary Catheterization in Low Extremity Artery Disease Undergoing Percutaneous Transluminal Angioplasty (PIROUETTE-PTA)” at ClinicalTrials.gov [18]. Estimated enrollment is 700 participants and the primary endpoint of the study was composite major adverse cardiac events at the 1-year follow-up.

There are some limitations to our study. First, the results of our study were derived indirectly by comparison with the survival rates of other studies. In general, the 5-year survival rate of PAD patients is around 50% [15], and the survival rate of our study subjects, 88.5%, was very high. The no CAG group without cardiac function evaluation should be allocated to verify the effectiveness of routine CAG in PAD patients, but this is a problem that may be against research ethics. In this study, PTA was performed by an interventionist based on cardiology, the cardiac function of all subjects was evaluated non-invasively and/or invasively by the cardiologist. Therefore, the no CAG group in this study should not be confused with the patients that did not perform cardiac function evaluation. Second, we analyzed data retrospectively, and PSM analysis was performed to minimize confounding factors, which could have affected our results. The registry was designed as an all-comers prospective registry from 2006. However, we could not adjust for all limiting factors not shown in medical records or collected through telephone contact. Third, in the PSM analysis, a total of 320 patients from 160 pairs in both groups were analyzed. This sample size may be insufficient to produce results. Our study is a registered observational study and may be a limitation of analysis. As Chen and colleagues’ research results come out, the results will be updated a bit (18).

In conclusion, a strategy of routine CAG and subsequent PCI, if required, appears to be a reasonable strategy for significant PAD patients undergoing PTA. Our results highlight the importance of CAD evaluation in patients with PAD. A result of randomized trial is needed to assess the efficacy and safety of this treatment strategy for PAD patients finally [18].

Data Availability

All relevant data are within the paper.

Funding Statement

This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: 9991006707, KMDF_PR_20200901_0034).

References

1.Ouriel K (2001) Detection of peripheral arterial disease in primary care. JAMA 286: 1380–1381. 10.1001/jama.286.11.1380 [DOI] [PubMed] [Google Scholar]
2.Regensteiner JG, Hiatt WR, Coll JR, Criqui MH, Treat-Jacobson D, et al. (2008) The impact of peripheral arterial disease on health-related quality of life in the Peripheral Arterial Disease Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) Program. Vasc Med 13: 15–24. 10.1177/1358863X07084911 [DOI] [PubMed] [Google Scholar]
3.Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, et al. (2017) Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol 70: 1–25. 10.1016/j.jacc.2017.04.052 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Selvin E, Erlinger TP (2004) Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation 110: 738–743. 10.1161/01.CIR.0000137913.26087.F0 [DOI] [PubMed] [Google Scholar]
5.Hussein AA, Uno K, Wolski K, Kapadia S, Schoenhagen P, et al. (2011) Peripheral arterial disease and progression of coronary atherosclerosis. J Am Coll Cardiol 57: 1220–1225. 10.1016/j.jacc.2010.10.034 [DOI] [PubMed] [Google Scholar]
6.Jeremias A, Gruberg L, Patel J, Connors G, Brown DL (2010) Effect of peripheral arterial disease on in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol 105: 1268–1271. 10.1016/j.amjcard.2009.12.043 [DOI] [PubMed] [Google Scholar]
7.Faglia E, Dalla Paola L, Clerici G, Clerissi J, Graziani L, et al. (2005) Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003. Eur J Vasc Endovasc Surg 29: 620–627. 10.1016/j.ejvs.2005.02.035 [DOI] [PubMed] [Google Scholar]
8.Lee MS, Rha SW, Han SK, Choi BG, Choi SY, et al. (2015) Clinical outcomes of patients with critical limb ischemia who undergo routine coronary angiography and subsequent percutaneous coronary intervention. J Invasive Cardiol 27: 213–217. [PubMed] [Google Scholar]
9.Nishijima A, Yamamoto N, Yoshida R, Hozawa K, Yanagibayashi S, et al. (2017) Coronary Artery Disease in Patients with Critical Limb Ischemia Undergoing Major Amputation or Not. Plast Reconstr Surg Glob Open 5: e1377. 10.1097/GOX.0000000000001377 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Ryu HM, Kim JS, Ko YG, Hong MK, Jang Y, et al. (2012) Clinical outcomes of infrapopliteal angioplasty in patients with critical limb ischemia. Korean Circ J 42: 259–265. 10.4070/kcj.2012.42.4.259 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Faglia E, Clerici G, Caminiti M, Quarantiello A, Curci V, et al. (2008) Advantages of myocardial revascularization after admission for critical limb ischemia in diabetic patients with coronary artery disease: data of a cohort of 564 consecutive patients. J Cardiovasc Med (Hagerstown) 9: 1030–1036. 10.2459/JCM.0b013e328306f2da [DOI] [PubMed] [Google Scholar]
12.Parikh SV, Saya S, Divanji P, Banerjee S, Selzer F, et al. (2011) Risk of death and myocardial infarction in patients with peripheral arterial disease undergoing percutaneous coronary intervention (from the National Heart, Lung and Blood Institute Dynamic Registry). Am J Cardiol 107: 959–964. 10.1016/j.amjcard.2010.11.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
13.O’Rourke DJ, Quinton HB, Piper W, Hernandez F, Morton J, et al. (2004) Survival in patients with peripheral vascular disease after percutaneous coronary intervention and coronary artery bypass graft surgery. Ann Thorac Surg 78: 466–470; discussion 470. 10.1016/j.athoracsur.2004.01.044 [DOI] [PubMed] [Google Scholar]
14.Pentecost MJ, Criqui MH, Dorros G, Goldstone J, Johnston KW, et al. (1994) Guidelines for peripheral percutaneous transluminal angioplasty of the abdominal aorta and lower extremity vessels. A statement for health professionals from a special writing group of the Councils on Cardiovascular Radiology, Arteriosclerosis, Cardio-Thoracic and Vascular Surgery, Clinical Cardiology, and Epidemiology and Prevention, the American Heart Association. Circulation 89: 511–531. 10.1161/01.cir.89.1.511 [DOI] [PubMed] [Google Scholar]
15.Teraa M, Conte MS, Moll FL, Verhaar MC (2016) Critical Limb Ischemia: Current Trends and Future Directions. J Am Heart Assoc 5. 10.1161/JAHA.115.002938 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Iqbal J, Zhang YJ, Holmes DR, Morice MC, Mack MJ, et al. (2015) Optimal medical therapy improves clinical outcomes in patients undergoing revascularization with percutaneous coronary intervention or coronary artery bypass grafting: insights from the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial at the 5-year follow-up. Circulation 131: 1269–1277. 10.1161/CIRCULATIONAHA.114.013042 [DOI] [PubMed] [Google Scholar]
17.Stone KE, Chiquette E, Chilton RJ (2007) Diabetic endovascular disease: role of coronary artery revascularization. Am J Cardiol 99: 105B–112B. 10.1016/j.amjcard.2006.11.024 [DOI] [PubMed] [Google Scholar]
18.Chen IC, Lee CH, Chao TH, Tseng WK, Lin TH, et al. (2016) Impact of routine coronary catheterization in low extremity artery disease undergoing percutaneous transluminal angioplasty: study protocol for a multi-center randomized controlled trial. Trials 17. 10.1186/s13063-016-1237-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Lee MS, Rha S-W, Han SK, Choi BG, Choi SY, et al. (2015) Gender Differences in Endovascular Revascularization for Peripheral Arterial Disease. Vascular Disease Management 12: 117–125. [Google Scholar]
20.Lee MS, Rha SW, Han SK, Choi BG, Choi SY, et al. (2015) Comparison of diabetic and non-diabetic patients undergoing endovascular revascularization for peripheral arterial disease. J Invasive Cardiol 27: 167–171. [PubMed] [Google Scholar]
21.Diehm N, Baumgartner I, Jaff M, Do DD, Minar E, et al. (2007) A call for uniform reporting standards in studies assessing endovascular treatment for chronic ischaemia of lower limb arteries. Eur Heart J 28: 798–805. 10.1093/eurheartj/ehl545 [DOI] [PubMed] [Google Scholar]
22.Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, et al. (2007) Clinical end points in coronary stent trials. Circulation 115: 2344–2351. 10.1161/CIRCULATIONAHA.106.685313 [DOI] [PubMed] [Google Scholar]
23.Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, et al. (2007) Optimal medical therapy with or without PCI for stable coronary disease. New England Journal of Medicine 356: 1503–1516. 10.1056/NEJMoa070829 [DOI] [PubMed] [Google Scholar]

PLoS One. doi: 10.1371/journal.pone.0251542.r001

Decision Letter 0

Xianwu Cheng

15 Oct 2019

PONE-D-19-21312

Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease underwent Percutaneous Coronary Intervention

PLOS ONE

Dear Prof. Rha

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

We would appreciate receiving your revised manuscript by December 10, 2019. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Xianwu Cheng, M.D., Ph.D., FAHA

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2) During your revisions, please note that a simple title correction is required: "Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease *undergoing* Percutaneous Coronary Intervention". Please ensure this is updated in the manuscript file and the online submission information.

3) Thank you for stating the following financial disclosure:

[The authors have no financial conflicts of interest relevant to the manuscript to

disclose.].

Please provide an amended Funding Statement that declares *all* the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.
Please state what role the funders took in the study. If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4) In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The main finding of this study is that routine coronary angiography and subsequent percutaneous intervention for significant coronary artery disease in patients with symptomatic peripheral arterial disease is safe and resulted in similar long-term survival to those who did not have coronary artery disease.

1 The correlation of coronary and peripheral arterial disease is well known and treatment strategies have been discussed and examined. What therefore is the novelty in this study of its conclusions

2 How does a single center study that performed angiography on each patients help

a. Would it not have been more meaningful to compare those with symptoms who did and did not undergo angiography

3 What new conclusions were learned not seen in ref, 8 the authors 1 year experience with this group

4 Was a power calculation performed to determine if 160 matched patients could indeed detect a meaningful difference

Reviewer #2: Comments to Authors:

The authors provide an interesting and potential important manuscript describing"Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease underwent Percutaneous Coronary Intervention" The main issues concerning this paper are those concerning the relationship between PAD and CAD. The previous study had figured out that 54%-69% of CAD patients with PAD, but a limited paper had researched that the percent of CAD in PAD patients.This study was designed to observe CAD in patients with PAD, and conclude that patients with PAD often have CAD disease.

There are some weak points that need to be addressed by the authors.

Major

1. In all patient analysis, the CAD patients showed a significantly higher prevalence of DM as compared with non-CAD subjects (P < 0.01). However, in age-matched analysis, there was no significant difference between two groups. The authors explain it.

2. As shown in Table 4, in all patients, total death (five-year outcomes) was higher in CAD group than in non-CAD group without significant difference. In contrast, in age matched analysis, it was higher non-CAD group than that of CDA patients. Why?

3. Discussion sections were disorganized, the authors did not clearly figured out their own findings and did not derive clinical implication in each section based on your own and previous observations..

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Hailong Wang

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: Comments to Authors(Dr wang).doc

Click here for additional data file.^{(26.5KB, doc)}

PLoS One. 2021 May 19;16(5):e0251542. doi: 10.1371/journal.pone.0251542.r002

Author response to Decision Letter 0

23 Mar 2020

PONE-D-19-21312

Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease undergoing Percutaneous Coronary Intervention

Dear editor:

Thank you so much for your e-mail sent to us on November 29 2019. We really appreciate the great opportunity you have kindly given to us to resubmit our work!! We really appreciate your excellent advice which has helped us a lot to improve the quality of our manuscript. According to your comments, we have amended the relevant parts in the manuscript. All of your questions were answered below. In the process of revising the manuscript, Jin-Seok Kim was added as an author, and he was fully involved in the revision of the study. All authors have approved Dr. Kim's inclusion as an author.

Yours sincerely,

*Correspondence to:

Seung-Woon Rha, MD, PhD, E‐mail: swrha617@yahoo.co.kr (S-WR)

Byoung Geol Choi, PhD, E‐mail: trv940@korea.ac.kr (BGC)

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

Response: Thank you so much for your careful review. We reflected this in the revised manuscript.

Response: Thank you so much for your careful review and comment. We reflected this in the title of the revised manuscript as following as “Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease undergoing Percutaneous Coronary Intervention”

3) Thank you for stating the following financial disclosure:

[The authors have no financial conflicts of interest relevant to the manuscript to

disclose.].

Please provide an amended Funding Statement that declares *all* the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.

Please state what role the funders took in the study. If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Response: Thank you so much for your careful review and comment. We reflected this in the revised manuscript (line 18 on page 1 to line 22) and the cover letter.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

Response: Thank you so much for your careful review and comment. We reflected this in the revised manuscript (line 21 on page 1).

Dear reviewer:

Thank you so much for your very insightful and serious comments for our manuscript! We really appreciate your excellent advice which has helped us a lot in improving our manuscript. According to your comments, we have amended the relevant parts in the manuscript. Some of your questions were answered below.

Yours sincerely,

*Correspondence to:

Seung-Woon Rha, MD, PhD, E‐mail: swrha617@yahoo.co.kr (S-WR)

Byoung Geol Choi, PhD, E‐mail: trv940@korea.ac.kr (BGC)

1 The correlation of coronary and peripheral arterial disease is well known and treatment strategies have been discussed and examined. What therefore is the novelty in this study of its conclusions

Response: Thank you so much for your careful review and important comment. As you understand, the treatment of PAD and CAD is very important for improving patient’s survival and quality of life. However, in patients undergoing PTA, routine evaluation of the presence of significant coronary artery disease may be controversial. In real world clinical practice, physicians who are performing endovascular intervention commonly only focusing on the extremity target lesion intervention without concerning of coronary artery disease evaluation and management, especially in particular specialties such as vascular surgeon or interventional radiologists. Thus, main intention of this report is to provoke all the endovascular intervention specialties should check patient’s co-existing significant CAD and to have an idea to safely manage the CAD together to prevent future cardiovascular events. Routine CAD checkup is not commonly widely accepted in daily clinical practice, especially in terms of cost-effectiveness but this should be changed according to our novel data.

Therefore, we added the following in the second paragraph with a conclusion in the last paragraph of the discussion part (line 1 on page 10 to line 4)

2 How does a single center study that performed angiography on each patients help

a. Would it not have been more meaningful to compare those with symptoms who did and did not undergo angiography

Response: Thank you so much for your careful review and important comment. Korea University Guro Hospital (KUGH), which conducted this study, is a university hospital for training, and is a large-scale center that performs many CAG, PCI, and PTAs every year. Data are collected by a trained research coordinator using a standardized case report form. And professional researchers analyze it consistently. It may be smaller than a multicenter study, but it can collect and analyze data more efficiently and accurately. Our study is a comparative study of the CAD group and the non-CAD group who received appropriate treatment through coronary artery evaluation in patients undergoing PTA. Therefore, the group without CAG was excluded. Main purpose of this study is to show whether the concomitant optimal revascularization of significant CAD regardless of patient’s symptom in PAD patients undergoing PTA could reduce the cardiovascular event risk compared with PAD patients without significant CAD. Selective CAD evaluation according to ischemic symptoms in PAD patients undergoing PTA is not a suitable and safe strategy because many of them are elderly, diabetics and limited ambulation to provoke ischemic chest pain or dyspnea due to diabetic foot wound. Thus, selective symptom driven CAD evaluation cannot be ideally accepted in context of ‘pan-atherosclerosis’ of PAD patients. We will consider a comparative study in symptomatic PAD patients between CAG and non-CAG groups in future studies.

3 What new conclusions were learned not seen in ref, 8 the authors 1-year experience with this group

Response: Thank you so much for your careful review and important comment. The results of our previous study, which observed the results for one year, the CAD group that received optimal treatment through routine coronary artery evaluation showed similar clinical results than the non-CAD group in CLI patients received PTA [8]. Similarly, in the present observation of long-term clinical results of 5-year in patients undergoing PTA, the clinical results of the CAD and non-CAD groups were similar. The strategy for CAD evaluation and treatment in PTA patients seems to be a safe and effective strategy not only for better short-term outcomes but also durable long-term outcomes. We wanted to show the durable long-term results from this routine CAD work up and management strategy in PAD patients undergoing PTA. We added this to the discussion part (line 20 on page 9 to line 14 on page 10).

4 Was a power calculation performed to determine if 160 matched patients could indeed detect a meaningful difference

Response: Thank you so much for your careful review and important comment. This study was designed as a prospective registration study and retrospective analysis was performed. Therefore, the sample size after PSM may not be sufficient, which may be a limitation of the study. We added this to the limitations of the discussion part (line 17 on page 10 to line 19) as following as “Second, In the PSM analysis, a total of 320 patients from 160 pairs in both groups were analyzed. This sample size may be insufficient to produce results. Our study is a registered observational study and may be a limitation of analysis.”

Dear reviewer:

Yours sincerely,

*Correspondence to:

Seung-Woon Rha, MD, PhD, E‐mail: swrha617@yahoo.co.kr (S-WR)

Byoung Geol Choi, PhD, E‐mail: trv940@korea.ac.kr (BGC)

Reviewer #2: Comments to Authors:

The authors provide an interesting and potential important manuscript describing "Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease underwent Percutaneous Coronary Intervention" The main issues concerning this paper are those concerning the relationship between PAD and CAD. The previous study had figured out that 54%-69% of CAD patients with PAD, but a limited paper had researched that the percent of CAD in PAD patients. This study was designed to observe CAD in patients with PAD, and conclude that patients with PAD often have CAD disease.

There are some weak points that need to be addressed by the authors.

Major

Response: Thank you so much for your careful review and important comment. In this study, the CAD group had a higher prevalence of DM than the non-CAD. DM, like CAD, is an important and independent factor affecting the survival of PAD patients. The propensity score matching used in this study is a method of adjusting all the possible baseline confounding variables such as DM, hypertension, smoking, alcohol drinking, laboratory findings, and others that can affect not only the age but also the endpoints of this study.

Response: Thank you so much for your careful review and important comment. In all patient analysis of this study, the CAD group had more elderly, diabetic, and higher creatinine levels than patients in the non-CAD group (Table 1). Although not statistically significant, this baseline difference can explain the higher mortality rate in the CAD group. After PSM analysis (This is not an age matching method), although there was no statistical significance, in contrast, the non-CAD group had a high mortality rate. This is because non-cardiac death was higher in the non-CAD group than in the CAD group. As in "Matched patients" in Tables 1 to 3, the baseline characteristics of the two groups were well balanced by the PSM method, but the variables that could not be evaluated may have affected non-cardiac death. This is described in the limitations of the discussion part (line 7 on page 10 to line 9) as follows as “we could not adjust for all limiting factors not shown in medical records or collected through telephone contact.”

Response: Thank you so much for your careful review and important comment. We actively revised the discussion to reflect your opinion. We attach a revised manuscript.

Attachment

Submitted filename: Pone-PTA-CAD-Rebuttal-Rha.doc

Click here for additional data file.^{(50KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0251542.r003

Decision Letter 1

Xianwu Cheng

13 May 2020

PONE-D-19-21312R1

Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease undergoing Percutaneous Coronary Intervention

PLOS ONE

Dear Prof. Rha

We would appreciate receiving your revised manuscript by Jun 27 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Xianwu Cheng, M.D., Ph.D., FAHA

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Reviewer#1 has still pointed out the original concerns was not addressed satisfactory by the authors. Thus, the authors may resubmit a revised version one more time, but it will be re-reviewed and there exists no guarantee that even with revision it will necessarily be accepted.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: I will restrict my comments to responses on my previous critique

1 The correlation of coronary and peripheral arterial disease is well known and treatment strategies have been discussed and examined. What therefore is the novelty in this study of its conclusions

ARE THERE ANY DATA TO SUPPORT THIS STATEMENT. WE ARE IN FACT CONCERNED ABOUT THE PRESENCE OF CAD IN PAD PATIENTS IN OUR INSTITUTION AND ELSEWHERE.

Thus, main intention of this report is to provoke all the endovascular intervention specialties should check patient’s co-existing significant CAD and to have an idea to safely manage the CAD together to prevent future cardiovascular events. Routine CAD checkup is not commonly widely accepted in daily clinical practice, especially in terms of cost-effectiveness but this should be changed according to our novel data.

Therefore, we added the following in the second paragraph with a conclusion in the last paragraph of the discussion part (line 1 on page 10 to line 4)

2 How does a single center study that performed angiography on each patients help

a. Would it not have been more meaningful to compare those with symptoms who did and did not undergo angiography

THE FAILURE TO COMPARE THOSE WHO DID WITH THOSE WHO DID NOT UNDERGO ANGIOGRAPHY LEAVES NO DEFINITIVE CONCLUSION

3 What new conclusions were learned not seen in ref, 8 the authors 1-year experience with this group

WHY WOULD ONE EXPECT THAT LONG-TERM OUTCOMES WOULD BE SIGNIFICANTLY WORSE THAN SHORT TERM. THIS IS WHY THERE NEEDS TO BE A NON-ANGIOGRAM GROUP TO SEE NOT ONLY OUTCOME BUT CROSSOVER

4 Was a power calculation performed to determine if 160 matched patients could indeed detect a meaningful difference

PERHAPS THE AUTHORS COULD ADD A STATEMENT AS TO HOW MANY PATIENTS WOULD HAVE NEEDED TO BE STUDIED TO SHOW A DIFFERENCE RATHER THAN SAY MAY BE INSUFFICIENT.

Reviewer #2: Thank you very much for your reasonable explanation. I believe this paper will give readers a new perspective on CVD and PAD

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

PLoS One. 2021 May 19;16(5):e0251542. doi: 10.1371/journal.pone.0251542.r004

Author response to Decision Letter 1

25 Oct 2020

Dear reviewer:

Yours sincerely,

*Correspondence to:

Seung-Woon Rha, MD, PhD, E‐mail: swrha617@yahoo.co.kr

1 The correlation of coronary and peripheral arterial disease is well known and treatment strategies have been discussed and examined. What therefore is the novelty in this study of its conclusions

ARE THERE ANY DATA TO SUPPORT THIS STATEMENT. WE ARE IN FACT CONCERNED ABOUT THE PRESENCE OF CAD IN PAD PATIENTS IN OUR INSTITUTION AND ELSEWHERE.

Response: Thank you so much for your careful review and important comment. As you know that the patients with PAD have particularly a high mortality rate from cardiovascular events. The severe CAD has been reported in 54% to 69% of patients with PAD [1-4]. So, the use of cardio-protective drugs as antiplatelet therapy, statin, and ACE inhibitors in PAD helps improve survival, but the introduction of these guidelines is more than a decade behind CAD. Also, the underuse of cardio-protective medication in the PAD population in comparison to patients with CAD has been published previously. These are well explained in Teraa's review. We cited his review in the revised manuscript [5].

Therefore, we changed the following in the second paragraph of the discussion part (line 4 to line 8 on page 11) as follows as “ In real world clinical practice, physicians who are performing endovascular intervention commonly only focusing on the extremity target lesion intervention without concerning of CAD evaluation and management. Also, the use of cardio-protective drugs such as antiplatelet therapy, statin, and ACE inhibitors in PAD helps to improve survival, but the introduction of these guidelines is more than a decade behind CAD.”

[References]

1. Faglia E, Dalla Paola L, Clerici G, Clerissi J, Graziani L, et al. (2005) Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003. Eur J Vasc Endovasc Surg 29: 620-627.

2. Lee MS, Rha SW, Han SK, Choi BG, Choi SY, et al. (2015) Clinical outcomes of patients with critical limb ischemia who undergo routine coronary angiography and subsequent percutaneous coronary intervention. J Invasive Cardiol 27: 213-217.

3. Nishijima A, Yamamoto N, Yoshida R, Hozawa K, Yanagibayashi S, et al. (2017) Coronary Artery Disease in Patients with Critical Limb Ischemia Undergoing Major Amputation or Not. Plast Reconstr Surg Glob Open 5: e1377.

4. Ryu HM, Kim JS, Ko YG, Hong MK, Jang Y, et al. (2012) Clinical outcomes of infrapopliteal angioplasty in patients with critical limb ischemia. Korean Circ J 42: 259-265.

5. Teraa M, Conte MS, Moll FL, Verhaar MC (2016) Critical Limb Ischemia: Current Trends and Future Directions. J Am Heart Assoc 5.

2 How does a single center study that performed angiography on each patients help

a. Would it not have been more meaningful to compare those with symptoms who did and did not undergo angiography

THE FAILURE TO COMPARE THOSE WHO DID WITH THOSE WHO DID NOT UNDERGO ANGIOGRAPHY LEAVES NO DEFINITIVE CONCLUSION

Response: Thank you so much for your important comment. We fully agree with your opinion. In the revised manuscript, we analyzed by adding 91 cases (as defined as the no-CAG group) who did not perform routine coronary angiography. Patients were divided into three groups; 1) routine CAG and a presence of CAD (CAD group: 413 patients), 2) routine CAG without CAD (non-CAD group: 261 patients), and 3) no-CAG group (91 patients). During the 5-year clinical follow-up, the routine CAG group was associated with reduced risk of myocardial infarction by 65.3% as compared to the no-CAG group. Also, there were no differences in the incidence of any clinical events between the CAD group and the non-CAD group except for the incidence of repeat percutaneous coronary intervention (PCI), which was higher in the CAD group than the non-CAD group. These are the results section of the revised manuscript (lines 19 to 19 lines on 8 pages, 15 to 20 lines on 9 pages), the discussion section (lines 22 to 24 lines on 11 pages) and the statistical analysis part (lines 19 to 21 on 7 page) in the method section.

3 What new conclusions were learned not seen in ref, 8 the authors 1-year experience with this group

WHY WOULD ONE EXPECT THAT LONG-TERM OUTCOMES WOULD BE SIGNIFICANTLY WORSE THAN SHORT TERM. THIS IS WHY THERE NEEDS TO BE A NON-ANGIOGRAM GROUP TO SEE NOT ONLY OUTCOME BUT CROSSOVER

Response: Thank you so much for your important comment. We fully agree with your opinion. As mentioned earlier, we analyzed by adding A NON-ANGIOGRAM GROUP (the no-CAG group) and reflected it in the revised manuscript.

4 Was a power calculation performed to determine if 160 matched patients could indeed detect a meaningful difference

PERHAPS THE AUTHORS COULD ADD A STATEMENT AS TO HOW MANY PATIENTS WOULD HAVE NEEDED TO BE STUDIED TO SHOW A DIFFERENCE RATHER THAN SAY MAY BE INSUFFICIENT.

Response: Thank you so much for your careful review and important comment. Already, a randomized clinical trial similar to ours is in progress, and relevant information is described in the discussion part (lines 12 to 17 lines on 12 pages) as follows as “Similar to our research, Chen and colleagues have registered the multi-center randomized controlled trial (NCT02169258) “Routine Coronary Catheterization in Low Extremity Artery Disease Undergoing Percutaneous Transluminal Angioplasty (PIROUETTE-PTA)” at ClinicalTrials.gov [18]. Estimated enrollment is 700 participants and the primary endpoint of the study was composite major adverse cardiac events at the 1-year follow-up.”

Also, we change this to the limitations part of the discussion section (line 17 to line 20 on page 12) as follows as “Second, In the PSM analysis, a total of 320 patients from 160 pairs in both groups were analyzed. This sample size may be insufficient to produce results. Our study is a registered observational study and may be a limitation of analysis. As Chen and colleagues' research results come out, the results will be updated a bit.”

Attachment

Submitted filename: Pone-PTA-CAD-Rebuttal_R2.doc

Click here for additional data file.^{(293.5KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0251542.r005

Decision Letter 2

Xianwu Cheng

4 Nov 2020

PONE-D-19-21312R2

Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease undergoing Percutaneous Coronary Intervention

PLOS ONE

Dear Dr. Rha

Please submit your revised manuscript by December 20, 2020. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Xianwu Cheng, M.D., Ph.D., FAHA

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The original reviewer #1 has still pointed out that the authors did not satisfactory address the original comments. He/She has concerned the statistical anapysis and data. As known, it is third peer-reviewer processes. Thus, it is final chance to revise manuscript with additional analysis and respond satisfactory to all of his/her comments.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: No

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: I find this paper somewhat confusing still. The authors have tried to respond to my inquiries but as best as I can tell there is a barely statistically significant difference in groups that did and did not undergo angiography in the setting of symptomatic peripheral arterial disease.

This remains in my mind a not compelling and in fact a confusing story

I this remains confusing – there are three groups – two that had routine angiography one with and one without coronary artery disease and a third who did not undergo angiography. And the five year clinical follow up is that both groups who underwent coronary angiography were equivalent but had minor HR 0.347 p=0.049 reduction compared to those who did not. In other words regardless as to whether coronary artery disease was discovered and regardless as to whether an intervention was performed.

Is this correct?

If this is correct – what is the message that angiography is to be performed

Is it the case that there is benefit on the crossover group only or the entire group?

II Moreover, the text is till confusing – take for example the next to last paragraph which reads

Third, all subjects in this study underwent CAG, and therefore our results are not generalizable to patients who do not receive CAG. Finally, all the PAD patients with significant CAD patients did not undergone PCI due to some reasons including clinical judgment based upon the discretion of the clinician and patient preference. Only 71.6% of all CAD patients underwent PCI or CABG before, after or at the same time as admission for PTA. This registry reflects the real-world practice of PAD patients.

1 the text is unclear – there are some extra words

2 was the benefit referred to in all patients who had CAG irrespective of whether they

a. had CAD

b. had an intervention

or were only the 71.6% of all CAD patients who underwent PCI or CABG considered?

This latter issue is further confusing by the note on page “In the present study, the CAG group had reduced significantly the risk of myocardial infarction by 65.3% than the no-CAG group during 5 years of clinical follow-up.”

III the idea that this paper is a follow up to reference 8 is confusing given that the numbers are so different

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 May 19;16(5):e0251542. doi: 10.1371/journal.pone.0251542.r006

Author response to Decision Letter 2

14 Apr 2021

This remains in my mind a not compelling and in fact a confusing story

Is this correct?

If this is correct – what is the message that angiography is to be performed

Is it the case that there is benefit on the crossover group only or the entire group?

>>> We sincerely appreciate your comments. Your point is correct. Although the risk of MI in the CAG group (HR: 0.347, 95% CI: 0.121 to 0.998, p=0.049, Figure 1, F) was lower compared to the no CAG group, this is due to the no CAD group (HR: 0.204, 95% CI: 0.049 to 0.852). The risk of MI in the CAD group (HR: 0.523, 95% CI: 0.184 to 1.485) was lower than that of the group without CAG, but there was no statistical significance (This statistical values were not shwon on the table and figure). Therefore, this might be confusing to readers and reviewers. In the revised manuscript, all statements that the MI risk reduction due to the CAG test has been deleted and changed. Comparing 3 groups appears to be clinically important and relevant due to it is practically reflecting real world clinical practice. Some proportion of patients definitely refuse to undergo coronary angiography due to absence of symptoms, cost issues and other personal preferences. Thus we need to know the long term impact of the active coronary surveillance in advanced PAD patients undergoing PTA.

II Moreover, the text is till confusing – take for example the next to last paragraph which reads

1 the text is unclear – there are some extra words

2 was the benefit referred to in all patients who had CAG irrespective of whether they

a. had CAD

b. had an intervention

or were only the 71.6% of all CAD patients who underwent PCI or CABG considered?

>>> We sincerely appreciate your comments. We have made some changes to this statement in the limitation section as follows as “The results of our study were derived indirectly by comparison with the survival rates of other studies. In general, the 5-year survival rate of PAD patients is around 50% [15], and the survival rate of our study subjects, 88.5%, was very high. The no CAG group without cardiac function evaluation should be allocated to verify the effectiveness of routine CAG in PAD patients, but this is a problem that may be against research ethics. In this study, PTA was performed by an interventionist based on cardiology, the cardiac function of all subjects was evaluated non-invasively and/or invasively by the cardiologist. Therefore, the no CAG group in this study should not be confused with the patients that did not perform cardiac function evaluation.” Also, we have some changes in the method section as follows as "A total of 765 consecutive PAD patients underwent successful PTA and 674 patients underwent routine CAG. For the remaining 91 patients who did not receive the CAG, but the cardiac function was evaluated non-invasively by the cardiologist. "

>>>This latter issue is further confusing by the note on page “In the present study, the CAG group had reduced significantly the risk of myocardial infarction by 65.3% than the no-CAG group during 5 years of clinical follow-up.”

We sincerely appreciate your comments. Your point is correct. Although the risk of MI in the CAG group (HR: 0.347, 95% CI: 0.121 to 0.998) is lower compared to the no CAG group, this is due to the no CAD group (HR: 0.204, 95% CI: 0.049 to 0.852). The risk of MI in the CAD group (HR: 0.523, 95% CI: 0.184 to 0.1.485) was lower than that of the group without CAG, but there was no statistical significance. Therefore, in the revised manuscript, all statements that the MI risk reduction due to the CAG test has been deleted and changed. The main finding of this study is that routine CAG and subsequent PCI for significant CAD in symptomatic PAD patients undergoing PTA is safe and resulted in similar long-term survival as compared with the symptomatic PAD patients who undergoing PTA and who did not have CAD. Not surprisingly, repeat PCI was performed more frequently in PAD patients with CAD at long-term follow-up. We wanted to demonstrate the risk reduction of advanced PAD patients with significant CAD patients by providing long-term clinical benefit from active coronary revascularization as compared to those of PAD patients without significant CAD. Thus, wanted to show the clinical benefit of active concomitant coronary surveillance in advanced PAD patients undergoing PTA to improve their prognosis.

III the idea that this paper is a follow up to reference 8 is confusing given that the numbers are so different

>>> We sincerely appreciate your comments. We agree with your comments. This study differs from the study in Reference 8 in its study subjects and study duration. Therefore, the statement of reference 8 has been deleted and changed in the revised manuscript.

Attachment

Submitted filename: R3 PTA-CAD-MS rebuttal.doc

Click here for additional data file.^{(36.5KB, doc)}

PLoS One. doi: 10.1371/journal.pone.0251542.r007

Decision Letter 3

Xianwu Cheng

29 Apr 2021

Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease undergoing Percutaneous Coronary Intervention

PONE-D-19-21312R3

Dear Dr Rha

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Xianwu Cheng, M.D., Ph.D., FAHA

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Although the original reviewer#1 has still rejected, following third peer-review processes, the authors satisfactory addressed all of original coments.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

PLoS One. doi: 10.1371/journal.pone.0251542.r008

Acceptance letter

Xianwu Cheng

7 May 2021

PONE-D-19-21312R3

Long-term Outcomes of Peripheral Arterial Disease Patients with Significant Coronary Artery Disease undergoing Percutaneous Coronary Intervention

Dear Dr. Rha:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Associate Prof. Xianwu Cheng

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Attachment

Submitted filename: Comments to Authors(Dr wang).doc

Click here for additional data file.^{(26.5KB, doc)}

Attachment

Submitted filename: Pone-PTA-CAD-Rebuttal-Rha.doc

Click here for additional data file.^{(50KB, doc)}

Attachment

Submitted filename: Pone-PTA-CAD-Rebuttal_R2.doc

Click here for additional data file.^{(293.5KB, doc)}

Attachment

Submitted filename: R3 PTA-CAD-MS rebuttal.doc

Click here for additional data file.^{(36.5KB, doc)}

Data Availability Statement

All relevant data are within the paper.

[pone.0251542.ref001] 1.Ouriel K (2001) Detection of peripheral arterial disease in primary care. JAMA 286: 1380–1381. 10.1001/jama.286.11.1380 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref002] 2.Regensteiner JG, Hiatt WR, Coll JR, Criqui MH, Treat-Jacobson D, et al. (2008) The impact of peripheral arterial disease on health-related quality of life in the Peripheral Arterial Disease Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) Program. Vasc Med 13: 15–24. 10.1177/1358863X07084911 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref003] 3.Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, et al. (2017) Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015. J Am Coll Cardiol 70: 1–25. 10.1016/j.jacc.2017.04.052 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0251542.ref004] 4.Selvin E, Erlinger TP (2004) Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation 110: 738–743. 10.1161/01.CIR.0000137913.26087.F0 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref005] 5.Hussein AA, Uno K, Wolski K, Kapadia S, Schoenhagen P, et al. (2011) Peripheral arterial disease and progression of coronary atherosclerosis. J Am Coll Cardiol 57: 1220–1225. 10.1016/j.jacc.2010.10.034 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref006] 6.Jeremias A, Gruberg L, Patel J, Connors G, Brown DL (2010) Effect of peripheral arterial disease on in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol 105: 1268–1271. 10.1016/j.amjcard.2009.12.043 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref007] 7.Faglia E, Dalla Paola L, Clerici G, Clerissi J, Graziani L, et al. (2005) Peripheral angioplasty as the first-choice revascularization procedure in diabetic patients with critical limb ischemia: prospective study of 993 consecutive patients hospitalized and followed between 1999 and 2003. Eur J Vasc Endovasc Surg 29: 620–627. 10.1016/j.ejvs.2005.02.035 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref008] 8.Lee MS, Rha SW, Han SK, Choi BG, Choi SY, et al. (2015) Clinical outcomes of patients with critical limb ischemia who undergo routine coronary angiography and subsequent percutaneous coronary intervention. J Invasive Cardiol 27: 213–217. [PubMed] [Google Scholar]

[pone.0251542.ref009] 9.Nishijima A, Yamamoto N, Yoshida R, Hozawa K, Yanagibayashi S, et al. (2017) Coronary Artery Disease in Patients with Critical Limb Ischemia Undergoing Major Amputation or Not. Plast Reconstr Surg Glob Open 5: e1377. 10.1097/GOX.0000000000001377 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0251542.ref010] 10.Ryu HM, Kim JS, Ko YG, Hong MK, Jang Y, et al. (2012) Clinical outcomes of infrapopliteal angioplasty in patients with critical limb ischemia. Korean Circ J 42: 259–265. 10.4070/kcj.2012.42.4.259 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0251542.ref011] 11.Faglia E, Clerici G, Caminiti M, Quarantiello A, Curci V, et al. (2008) Advantages of myocardial revascularization after admission for critical limb ischemia in diabetic patients with coronary artery disease: data of a cohort of 564 consecutive patients. J Cardiovasc Med (Hagerstown) 9: 1030–1036. 10.2459/JCM.0b013e328306f2da [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref012] 12.Parikh SV, Saya S, Divanji P, Banerjee S, Selzer F, et al. (2011) Risk of death and myocardial infarction in patients with peripheral arterial disease undergoing percutaneous coronary intervention (from the National Heart, Lung and Blood Institute Dynamic Registry). Am J Cardiol 107: 959–964. 10.1016/j.amjcard.2010.11.019 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0251542.ref013] 13.O’Rourke DJ, Quinton HB, Piper W, Hernandez F, Morton J, et al. (2004) Survival in patients with peripheral vascular disease after percutaneous coronary intervention and coronary artery bypass graft surgery. Ann Thorac Surg 78: 466–470; discussion 470. 10.1016/j.athoracsur.2004.01.044 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref014] 14.Pentecost MJ, Criqui MH, Dorros G, Goldstone J, Johnston KW, et al. (1994) Guidelines for peripheral percutaneous transluminal angioplasty of the abdominal aorta and lower extremity vessels. A statement for health professionals from a special writing group of the Councils on Cardiovascular Radiology, Arteriosclerosis, Cardio-Thoracic and Vascular Surgery, Clinical Cardiology, and Epidemiology and Prevention, the American Heart Association. Circulation 89: 511–531. 10.1161/01.cir.89.1.511 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref015] 15.Teraa M, Conte MS, Moll FL, Verhaar MC (2016) Critical Limb Ischemia: Current Trends and Future Directions. J Am Heart Assoc 5. 10.1161/JAHA.115.002938 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0251542.ref016] 16.Iqbal J, Zhang YJ, Holmes DR, Morice MC, Mack MJ, et al. (2015) Optimal medical therapy improves clinical outcomes in patients undergoing revascularization with percutaneous coronary intervention or coronary artery bypass grafting: insights from the Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) trial at the 5-year follow-up. Circulation 131: 1269–1277. 10.1161/CIRCULATIONAHA.114.013042 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref017] 17.Stone KE, Chiquette E, Chilton RJ (2007) Diabetic endovascular disease: role of coronary artery revascularization. Am J Cardiol 99: 105B–112B. 10.1016/j.amjcard.2006.11.024 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref018] 18.Chen IC, Lee CH, Chao TH, Tseng WK, Lin TH, et al. (2016) Impact of routine coronary catheterization in low extremity artery disease undergoing percutaneous transluminal angioplasty: study protocol for a multi-center randomized controlled trial. Trials 17. 10.1186/s13063-016-1237-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pone.0251542.ref019] 19.Lee MS, Rha S-W, Han SK, Choi BG, Choi SY, et al. (2015) Gender Differences in Endovascular Revascularization for Peripheral Arterial Disease. Vascular Disease Management 12: 117–125. [Google Scholar]

[pone.0251542.ref020] 20.Lee MS, Rha SW, Han SK, Choi BG, Choi SY, et al. (2015) Comparison of diabetic and non-diabetic patients undergoing endovascular revascularization for peripheral arterial disease. J Invasive Cardiol 27: 167–171. [PubMed] [Google Scholar]

[pone.0251542.ref021] 21.Diehm N, Baumgartner I, Jaff M, Do DD, Minar E, et al. (2007) A call for uniform reporting standards in studies assessing endovascular treatment for chronic ischaemia of lower limb arteries. Eur Heart J 28: 798–805. 10.1093/eurheartj/ehl545 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref022] 22.Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, et al. (2007) Clinical end points in coronary stent trials. Circulation 115: 2344–2351. 10.1161/CIRCULATIONAHA.106.685313 [DOI] [PubMed] [Google Scholar]

[pone.0251542.ref023] 23.Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, et al. (2007) Optimal medical therapy with or without PCI for stable coronary disease. New England Journal of Medicine 356: 1503–1516. 10.1056/NEJMoa070829 [DOI] [PubMed] [Google Scholar]

PERMALINK

Long-term outcomes of peripheral arterial disease patients with significant coronary artery disease undergoing percutaneous coronary intervention

Byoung Geol Choi

Ji-Yeon Hong

Seung-Woon Rha

Cheol Ung Choi

Michael S Lee

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Methods

Ethical approval

Data source and population

Percutaneous transluminal angioplasty

Study definitions [21,22]

Statistical analysis

Study endpoints

Results

Table 1. Baseline characteristics of the entire cohort and propensity-matched groups.

Table 2. Coronary angiographic and clinical limb characteristics.

Table 3. Post-procedural complications and medications.

Table 4. Kaplan–Meier curve analysis of clinical outcomes and log-rank test results.

Fig 1. Survival analysis of 5-year clinical outcomes by Kaplan–Meier curve and Cox-proportional hazards regression analysis.

Discussion

Data Availability

Funding Statement

References

Decision Letter 0

Xianwu Cheng

Roles

Author response to Decision Letter 0

Decision Letter 1

Xianwu Cheng

Roles

Author response to Decision Letter 1

Decision Letter 2

Xianwu Cheng

Roles

Author response to Decision Letter 2

Decision Letter 3

Xianwu Cheng

Roles

Acceptance letter

Xianwu Cheng

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases