Outcomes of acute coronary syndrome patients with concurrent extra-cardiac vascular disease in the era of transradial coronary intervention: A retrospective multicenter cohort study

Masaki Kodaira; Mitsuaki Sawano; Toshiki Kuno; Yohei Numasawa; Shigetaka Noma; Masahiro Suzuki; Shohei Imaeda; Ikuko Ueda; Keiichi Fukuda; Shun Kohsaka

doi:10.1371/journal.pone.0223215

. 2019 Oct 16;14(10):e0223215. doi: 10.1371/journal.pone.0223215

Outcomes of acute coronary syndrome patients with concurrent extra-cardiac vascular disease in the era of transradial coronary intervention: A retrospective multicenter cohort study

Masaki Kodaira ^1,^*, Mitsuaki Sawano ², Toshiki Kuno ^1,³, Yohei Numasawa ¹, Shigetaka Noma ⁴, Masahiro Suzuki ⁵, Shohei Imaeda ², Ikuko Ueda ², Keiichi Fukuda ², Shun Kohsaka ²

Editor: Corstiaan den Uil⁶

PMCID: PMC6795465 PMID: 31618228

Abstract

Background

Extra-cardiac vascular diseases (ECVDs), such as cerebrovascular disease (CVD) or peripheral arterial disease (PAD), are frequently observed among patients with acute coronary syndrome (ACS). However, it is not clear how these conditions affect patient outcomes in the era of transradial coronary intervention (TRI).

Methods and results

Among 7,980 patients with ACS whose data were extracted from the multicenter Japanese percutaneous coronary intervention (PCI) registry between August 2008 and March 2017, 888 (11.1%) had one concurrent ECVD (either PAD [345 patients: 4.3%] or CVD [543 patients; 6.8%]), while 87 patients (1.1%) had both PAD and CVD. Overall, the presence of ECVD was associated with a higher risk of mortality (odds ratio [OR]: 1.728; 95% confidence interval [CI]: 1.183–2.524) and bleeding complications (OR: 1.430; 95% CI: 1.028–2.004). There was evidence of interaction between ECVD severity and procedural access site on bleeding complication on the additive scale (relative excess risk due to interaction: 0.669, 95% CI: -0.563–1.900) and on the multiplicative scale (OR: 2.105; 95% CI: 1.075–4.122). While the incidence of death among patients with ECVD remained constant during the study period, bleeding complications among patients with ECVD rapidly decreased from 2015 to 2017, in association with the increasing number of TRI.

Conclusions

Overall, the presence of ECVD was a risk factor for adverse outcomes after PCI for ACS, both mortality and bleeding complications. In the most recent years, the incidence of bleeding complications among patients with ECVD decreased significantly coinciding with the rapid increase of TRI.

Introduction

Recent advancements in percutaneous coronary intervention (PCI) devices and techniques, such as the use of drug-eluting stents with improved safety and efficacy, has enabled interventionists to perform PCI in high-risk patients, including those with concurrent extra-cardiac vascular disease (ECVD).[1] This condition has been referred to as the presence of cerebrovascular disease (CVD) or peripheral artery disease (PAD) in addition to established coronary artery disease.[2–4] Indeed, performing PCI in patients with concurrent ECVD has been reported to be associated with lower procedural success rates and higher complication rates,[1] as demonstrated by the Global Registry of Acute Coronary Events (GRACE)[5] and the Reduction of Atherothrombosis for Continued Health Registry.[6] Previous studies from Europe and the United States have shown the negative prognostic value of ECVD for both short- and long-term outcomes of patients receiving PCI.[7–10] In addition, a recent study of patients with acute coronary syndrome (ACS) from Italy reported that the risk of mortality at 5 years post-PCI doubled for patients with one ECVD (62% among patients with CVD and 63% among patients with PAD) and increased by a further 80% in patients with both CVD and PAD, compared with a 33% mortality rate for ACS patients without ECVD.[8] Hence, there is a considerable need to establish an effective therapeutic strategy to improve outcomes of high-risk patients after PCI.

During the last decade, the implementation of strategies to minimize PCI-related bleeding, including transradial intervention (TRI), has been proven to reduce the overall rate of PCI-related bleeding complications.[11, 12] The Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of Angiox (MATRIX) randomized trial reported that the use of TRI was related to reduced adverse clinical events in ACS patients compared to transfemoral intervention (TFI).[13] However, it is unclear whether the modern application of TRI could improve outcomes among patients with ACS and ECVD.[14] With TRI being less invasive than transfemoral intervention (TFI), we hypothesized that TRI may modify the negative effects of ECVD on ACS patients’ outcomes; thus, consideration of the interaction of procedural site and severity of ECVD on in-hospital outcomes may influence decision making for high-risk patients. In light of the increasing interest in early interventional strategies for high-risk patients with ACS, establishing and quantifying the contributions of TRI to the health of patients with ACS and concurrent ECVD is of utmost importance. In this study, our primary aim was to examine the impact effect of ECVD (CVD and/or PAD) on in-hospital outcomes among patients with ACS undergoing PCI. Our secondary aim was to assess temporal trends of ACS patients with ECVD and the incidence of in-hospital outcomes, in relation to the increased utilization of TRI in Japan.

Methods and materials

Study population and study design

Our study cohort was derived from the Japan Cardiovascular Database-Keio interhospital Cardiovascular Studies (JCD-KiCS) registry, which is an ongoing, prospective, multicenter cohort study designed to collect data on the demographics, procedural characteristics, and outcomes of patients undergoing PCI. Details of the registry have been previously published.[15–17] In brief, the JCD-KiCS registry collects data on more than 200 variables in accordance with the National Cardiovascular Data Registry CathPCI version 4, the largest registry of PCI in the United States.[18] The JCD-KiCS registry study protocol was approved by the Institutional Review Board of Keio University School of Medicine, as well as those of each participating hospital. The study was carried out in accordance with the approved guidelines and the Declaration of Helsinki. All participants provided informed consent.

To fulfill the purpose of our study and evaluate temporal trends, we selected four hospitals that continually registered patient data from August 2008 to March 2017. Within this selected cohort, a total of 9,209 patients underwent PCI for ACS. We excluded 778 patients who were admitted with cardiogenic shock and 110 patients in cardiopulmonary arrest. Furthermore, we excluded 351 patients due to missing data on patient age and sex, leaving a final cohort of 7,980 patients with ACS (Fig 1). Our primary hypothesis was that ECVD is associated with an increased incidence of adverse clinical outcomes in a cumulative manner, with higher risks observed among patients with ACS and more than two concurrent ECVDs. The secondary hypothesis was that the incidence of adverse in-hospital clinical outcomes has decreased among patients with ECVD in recent years, with a significant association between outcomes and higher utilization of TRI. Therefore, we compared the primary and secondary outcomes between TRI and TFI in the study cohort over the 9-year period, from 2008 to 2017. In addition, we assessed the joint association of ECVD severity and PCI procedural site with in-hospital outcomes, applying both multiplicative interaction and additive interaction analyses.

Fig 1 — Flow diagram showing the derivation of the final study cohort. JCD-KiCS, Japan Cardiovascular Database-Keio interhospital Cardiovascular Studies; PCI, percutaneous coronary intervention; ACS, acute coronary syndrome.

Study definitions and outcomes

We considered ECVD lesions to be present when either CVD or PAD was documented prior to or during hospitalization for PCI. Specifically, CVD was defined as a history of stroke or transient ischemic attack, detection of carotid artery stenosis (>79%) via a non-invasive or invasive carotid test, or previous history of carotid artery surgery/intervention for carotid artery stenosis. Peripheral arteries included the aortoiliac, femoral-popliteal, renal, mesenteric, and abdominal aortic arteries. The definition of PAD was taken as claudication; amputation or arterial vascular insufficiency; vascular construction, bypass surgery, or percutaneous intervention to the extremities; documented aortic aneurysm; a positive non-invasive test result (ankle brachial index (ABI) ≤ 0.9); and ultrasound, magnetic resonance imaging, computed tomography, or angiographic imaging indicating >50% stenosis in any peripheral artery. The primary outcome of interest in the present analysis was in-hospital death. The secondary outcome was the development of a type 3 bleeding complication, as defined by the Bleeding Academic Research Consortium criteria.[19]

Statistical analysis

For descriptive analysis, we used Pearson chi-square tests to compare categorical values and Student’s t test to compare continuous variables between the groups. All continuous variables are presented as number (percentage) or mean ± standard deviation. First, baseline characteristics and outcomes were stratified and compared according to the number of extra-cardiac atherosclerotic sites. Second, multivariate logistic regression analysis was performed to assess the effect of ECVD after adjusting for potential confounders, including mortality and bleeding events. The multivariate logistic regression models included variables incorporated in the National Cardiovascular Data Registry risk models for in-hospital mortality[20] and bleeding risk,[21] comprising the following: age, ECVD, chronic kidney disease (CKD), ST-elevation myocardial infarction (STEMI), chronic lung disease, heart failure upon admission, and history of heart failure comprising in-hospital mortality and age, sex, body mass index (BMI), ECVD, CKD, STEMI, history of PCI, and hemoglobin for bleeding risk. Third, we evaluated whether the association between ECVD severity and in-hospital outcomes among ACS patients differed according to procedure site using multiplicative and additive interaction analyses. Results of interaction were reported according to the recommendations from the International Epidemiological Association.[22] Relative excess risk of interaction (RERI) was used to describe the magnitude of risk due to additive interaction, with a score of >0 taken as evidence of positive additive interaction.[23] Multiplicative interaction was described as an adjusted odds ratio for the interaction term in the logistic regression model, with the variables shown above. Finally, we examined temporal trends in patient characteristics and clinical outcomes over time. We evaluated three consecutive periods, namely, 2008–2010, 2011–2014, and 2015–2017, and included these categories in addition to the above variables to adjust for the registration year in multivariate logistic regression models. Then, we calculated the unadjusted in-hospital mortality and bleeding complications for each period and examined whether trends differed based on the presence of ECVD. In addition, comparison of the primary and secondary endpoints between the two different access sites, TRI and TFI, was performed using similar multivariable regression analyses and covariates. We then calculated the expected outcomes using the previously published regression model. The observed rates of death and bleeding events among patients with ECVD were divided according to their expected rates to obtain the observed/expected (O/E) outcome ratios.[20, 24, 25]

Records with missing data on sex or age (351 patients) were excluded as part of our sampling plan (Fig 1). Consequently, our study population had <0.5% missing data for the covariates used in the death or bleeding complications model, except for estimated glomerular filtration rate (2.6%), pre-procedure hemoglobin level (0.7%), and BMI (6.7%). A single imputation approach was used to handle these missing data. Specifically, missing categorical covariates were set to their lowest risk value, while continuous covariates were replaced with sex-specific medians.

Pre-specified subgroup analyses were conducted for sex (female/male), age groups (age ≥80/age <80), clinical presentation (STEMI/unstable angina or non-STEMI), and access site (TRI/TFI). Statistical analyses were conducted using SPSS version 24.0 (IBM Corp. Armonk, NY, USA) and STATA version 15.1 (StataCorp, College Station, Texas) for performance of RERI. Statistical significance was set at p < 0.05.

Results

Sample characteristics

The current analysis included 7,980 patients who underwent PCI for ACS. Of these, 888 patients (11.1%) had one additional vascular disease (CAD +PAD: 345 patients [4.3%], CAD + CVD: 543 patients [6.8%]), whereas 87 patients (1.1%) had all three types (CAD + PAD + CVD) of vascular disease (Fig 2). The baseline characteristics are presented in Table 1. Patients with ECVDs were significantly older with lower BMIs and were more likely to have undergone PCI or coronary artery bypass grafting in the past. In addition, the prevalence of patients with diabetes, chronic kidney failure, on dialysis, and with heart failure upon admission increased as the number of ECVDs increased. Conversely, patients without ECVDs were more likely to be current smokers. Angiographic and procedural data are shown in Table 2. Patients with ECVDs were more likely to have chronic total occlusion, three-vessel disease, or American Heart Association/American College of Cardiology type C lesions. There were no differences among the three groups in terms of the rate of TRI or intra-aortic balloon pump use.

Fig 2 — CAD, coronary artery disease; CVD, cerebrovascular disease; PAD, peripheral artery disease.

Table 1. Baseline clinical characteristics in relation with the number of extra-cardiac lesions.

	CAD only n = 7005	CAD and 1 site n = 888	CAD and 2 sites n = 87	p Value
Female (%)	1620 (22.9%)	198 (21.6%)	22 (25.3%)	0.555
Age	66.8 ± 12.1	72.7 ± 10.1	74 ± 9.3	<0.001
BMI	24.1 ± 3.7	23.0 ± 3.6	22.7 ± 3.6	<0.001
History of MI (%)	1016 (13.9%)	173 (18.8%)	16 (18.4%)	<0.001
History of heart failure (%)	370 (5.1%)	107 (11.7%)	16 (18.4%)	<0.001
Diabetes (%)	2542 (34.7%)	394 (42.9%)	46 (52.9%)	<0.001
Dialysis (%)	203 (2.8%)	90 (9.8%)	16 (18.4%)	<0.001
Chronic kidney disease (%)	2586 (35.3%)	501 (54.6%)	62 (71.3%)	<0.001
Chronic lung disease (%)	188 (2.6%)	56 (6.1%)	3 (3.4%)	<0.001
Hypertension (%)	4925 (67.3%)	757 (82.5%)	71 (81.6%)	<0.001
Current smoker (%)	2741 (37.5%)	280 (30.5%)	32 (36.8%)	<0.001
Dyslipidemia (%)	4393 (60.0%)	568 (61.9%)	50 (57.5%)	0.493
Family history of CAD (%)	775 (10.6%)	91 (9.9%)	8 (9.2%)	0.218
Atrial fibrillation (%)	263 (3.6%)	74 (8.1%)	10 (11.5%)	<0.001
History of PCI (%)	1416 (19.4%)	250 (27.2%)	26 (29.9%)	<0.001
History of CABG (%)	199 (2.7%)	60 (6.5%)	10 (11.5%)	<0.001
Intervention indication, STEMI (%)	3194 (45.6%)	319 (35.9%)	23 (26.4%)	<0.001
Intervention indication, NSTEMI (%)	1209 (17.3%)	180 (20.3%)	21 (24.1%)	0.024
Heart failure at admission (%)	876 (12.0%)	175 (19.1%)	22 (25.3%)	<0.001

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BMI, body mass index; CABG, coronary artery bypass grafting; CAD, coronary artery disease; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI,ST-elevation myocardial infarction

Table 2. Procedural characteristics according to the number of extra-cardiac lesions.

	CAD only n = 7005	CAD and 1 site n = 888	CAD and 2 sites n = 87	p Value
Procedural characteristics
Transradial (%)	2898 (39.6%)	358 (39.0%)	26 (29.9%)	0.175
Transfemoral (%)	4155 (59.3%)	500 (56.3%)	51 (58.6%)	0.228
IABP (%)	562 (7.7%)	82 (8.9%)	4 (4.6%)	0.221
Bifurcation (%)	1877 (27.3%)	208 (24.1%)	23 (28.0%)	0.136
CTO (%)	152 (6.4%)	28 (12.2%)	2 (10.0%)	0.004
Type C lesion (%)	1916 (28.3%)	260 (30.7%)	34 (42.5%)	0.008
Three-vessel disease (%)	1583 (22.6%)	273 (30.7%)	41 (47.1%)	<0.001
Target LMT (%)	195 (2.8%)	37 (4.2%)	4 (4.9%)	0.042
Target LAD (%)	3415 (49.1%)	367 (41.7%)	35 (42.7%)	<0.001
Cardio-protective medications
DAPT at arrival (%)	5587 (79.8%)	772 (81.3%)	73 (83.9%)	0.362
DAPT at discharge (%)	6742 (96.2%)	840 (94.6%)	83 (95.4%)	0.056
Beta-blocker at discharge (%)	4976 (75.3%)	613 (71.9%)	54 (68.4%)	0.038
Statin at discharge (%)	5936 (89.8%)	706 (82.8%)	58 (72.5%)	<0.001

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CAD, coronary artery disease; CTO, chronic total occlusion; DAPT, dual antiplatelet therapy; IABP, intra-aortic balloon pump; LMT, left main trunk; LAD, left arterial descending.

Outcomes according to the number of extra-cardiac vascular diseases

The incidence of in-hospital deaths and bleeding complications according to the number of ECVDs is presented in S1 Fig. The risk of in-hospital mortality increased proportionally with the number of additional vascular sites (p < 0.001): CAD alone, 1.8%; CAD and one site, 4.1%; CAD and two sites, 4.6%. The risk of bleeding complications was the highest among patients with a single ECVD compared to those without ECVD or with multiple ECVDs.

After multivariable adjustment, the presence of concurrent ECVD was associated with a higher risk of mortality (odds ratio [OR]: 1.586, 95% confidence interval [CI]: 1.084–2.322) and bleeding complications (OR: 1.460, 95% CI: 1.032–2.064) (Fig 3). The incidence of death increased progressively as the number of concurrent ECVDs increased (OR: 1.457, 95% CI: 1.055–2.012).

Fig 3 — Comparison of various in-hospital mortality rates (A) and bleeding complication rates (B) among patients with and without extra-cardiac lesion. Forest plots demonstrate comparative outcomes of acute coronary syndrome patients between those with and without extra-cardiac lesions. CI, confidence interval; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; TFI, transfemoral intervention; TRI, transradial intervention; UA, unstable angina.

Interaction between extra-cardiac vascular disease and procedural access site

Both multiplicative (OR: 0.864, 95% CI: 0.444–1.680) and additive interaction (RERI: −0.617, 95% CI: −2.432–1.208) showed that ECVD severity and procedural access site had no significant effect on in-hospital mortality (Table 3). On the contrary, interaction was detected between ECVD severity and procedural access site on in-hospital bleeding events on the multiplicative scale (OR: 2.105, 95% CI: 1.075–4.122), as well as on the additive scale (RERI: 0.669, 95% CI: −0.563–1.990) (Table 4).

Table 3. Modification of the effect of extra-cardiac vascular disease severity on in-hospital mortality by procedural site.

	Without extra cardiac lesion		With extra cardiac lesion
	Deceased/Alive, n	OR (95% CI)	Deceased/Alive, n	OR (95% CI)
Radial Access	27/2740	1.00	13/361	2.314 (1.160–4.616) p = 0.017
Femoral Access	95/4060	1.828 (1.175–2.844) p = 0.007	23/528	2.531 (1.441–4.444) p = 0.0012

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Measure of interaction on additive scale: RERI = -0.617 (95% CI: -2.432 to 1.208); p = 0.51. Measure of interaction on multiplicative scale: OR: 0.864 (95% CI: 0.444 to 1.680); p = 0.666.

Table 4. Modification of the effect of extra-cardiac vascular disease severity on in-hospital bleeding complication by procedural site.

	Without extra cardiac lesion		With extra cardiac lesion
	With/without bleeding complication, n	OR (95% CI)	With/without bleeding complication, n	OR (95% CI)
Radial Access	48/2719	1.00	10/364	1.228 (0.612–2.466) p = 0.563
Femoral Access	151/4004	1.805 (1.293–2.521) p<0.001	36/515	2.702 (1.730–4.221) p<0.001

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Measures of interaction on additive scale: RERI = 0.669 (95% CI: -0.563 to 1.900); p = 0.287. Measure of interaction on multiplicative scale: OR: 2.105 (95% CI: 1.075 to 4.122); p = 0.03.

Temporal trends among patients with or without extra-cardiac vascular disease

S1 and S2 Tables present the temporal trend in the clinical and procedural demographics of patients with ECVD undergoing PCI between 2008 and 2017. The patients’ age, sex, and baseline characteristics or proportion of complex PCIs did not change significantly over time. However, there was a considerable increase in the proportion of patients who received TRI, which quadrupled during the 9-year time period. In contrast, rates of TFI significantly decreased. With regard to medication, the rate of dual antiplatelet prescriptions upon arrival increased progressively. Furthermore, multivariate logistic regression analyses demonstrated that while the adjusted in-hospital mortality remained stable over time, the rate of bleeding complications declined significantly over the observed timespan (Tables 5 and 6 and S2 Fig). There was no significant decrease in deaths from 2008 through 2017, and the O/E mortality ratio remained unchanged (Table 5). In contrast, as illustrated in Table 6, there was a significant improvement in the O/E bleeding event ratio in the most recent period (2015–2017). Although there was a slight decrease, the O/E mortality ratio remained greater than 2 (Table 5). On the contrary, the O/E bleeding complication ratio declined progressively to 0.16 at the end of the study (years 2015–2017) (Table 6). Moreover, this decrease in the bleeding complication rate was inversely correlated with the increase in TRI (S2 Fig). Compared to TFI, TRI was associated with a reduced in-hospital bleeding complication rate (OR: 0.479; 95% CI: 0.232–0.990); however, there was no association with in-hospital mortality (OR: 0.965; 95% CI: 0.450–2.068) (data not shown). Comparison of the trends in primary and secondary outcomes between patients with ACS with and without ECVD is shown in Fig 4. The difference in in-hospital mortality rate persisted between the two groups over time (Fig 4A). Although the bleeding complication rate among patients with ECVD was higher at the beginning of the study (2008–2010), it declined significantly in the latter part of the study period (2015–2017), to a rate that was below that of patients without ECVD (Fig 4B).

Table 5. Observed/expected ratios and adjusted odds ratios of in-hospital mortality.

Study years	Crude frequency (%)	Expected rates (%)	Observed to expected ratios	Adjusted OR (95% CI)
2008 / 2010	4.4	1.3	3.38	1
2011 / 2014	4.1	1.7	2.41	0.814 (0.511, 1.299)
2015 / 2017	3.8	1.6	2.37	0.776 (0.450, 1.341)

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CI, confidence interval; OR, odds ratio

Table 6. Observed/Expected ratios and adjusted odds ratios of in-hospital bleeding complications.

Study years	Crude frequency (%)	Expected rates (%)	Observed to expected ratios	Adjusted or (95% CI)
2008 / 2010	7.1	8.3	0.85	1
2011 / 2014	4.9	9.1	0.53	0.653 (0.345, 1.237)
2015 / 2017	1.5	8.9	0.16	0.212 (0.048, 0.946)

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CI, confidence interval; OR, odds ratio

Fig 4 — Figures demonstrate (A) the in-hospital mortality and (B) bleeding complication trends among patients with acute coronary syndrome with or without extra-cardiac vascular disease, respectively. CAD, coronary artery disease; ECVD, extra-cardiac vascular disease.

Sensitivity and subgroup analyses

The results were unchanged after including patients who presented with cardiogenic shock or cardiopulmonary arrest with respect to the effect of concurrent ECVD on mortality (OR: 1.580; 95% CI: 1.212–2.061) and bleeding complications (OR: 1.397, 95% CI: 1.045–1.867) (S3–S5 Figs and S3 Table). Results of the subgroup analyses are presented in Fig 3. The interaction terms by access site (TRI/TFI) were significant in the adjusted analysis for bleeding complications, such that the effect of ECVD was more pronounced with TFI than with TRI.

Discussion

Key findings

Our study has three major findings. First, ACS patients with concurrent ECVD had worse in-hospital outcomes including mortality and bleeding complications compared to those without ECVDs. Second, although in-hospital mortality remained high among ECVD patients throughout the study period, the incidence of bleeding complications among patients with ECVD dropped significantly, owing to the increased use of TRI. Third, there was additive interaction between procedural access site and ECVD severity on bleeding events; the increased risk of bleeding associated with ECVD was more notable in patients undergoing PCI via the femoral artery. Our results add to the growing body of evidence that shows that the presence of ECVD is strongly associated with adverse in-hospital outcomes for patients with ACS undergoing PCI, even in the contemporary TRI-dominant PCI era. The current study is unique in that it integrated PAD and CVD and defined them as ECVD to assess the influence on various inpatient outcomes. We believe that this definition is more practical and may be easily utilized in clinical settings.

Interpretation of results

In our study population, 5.4% of patients had PAD, which is similar to the incidence of PAD in previous reports from the British Cardiovascular Intervention Society database,[26] but lower than the incidence reported in the GRACE registry (5.7%).[5] On the contrary, patients included in this study were older, reflecting the rapidly aging Japanese society, which could have led to the higher prevalence of ECVD, particularly CVD. While there is a relatively low incidence of atherosclerotic disease other than cerebrovascular disease among East Asians compared to their Western counterparts, they are also known to be at higher risk of bleeding complications during PCI.[27] Indeed, in this study, patients with ECVD were at higher risk of bleeding compared to patients without ECVD. Currently, the biological mechanism for the increased risk of bleeding among ACS patients with ECVD is not clear. Achterberg et al. have hypothesized that the fragility of vessels, together with the heavy atherosclerotic burden of these patients, leads to rupture of the vessels and subsequent bleeding due to decreased vascular elasticity.[28] Steg et al. also reported a higher risk of bleeding among patients with PAD.[14] Peri-procedural bleeding is reported to be an indicator of subsequent major ischemic events and mortality.[29] On the contrary, to our surprise, the bleeding event rate did not increase in a stepwise fashion with the number of ECVDs; patients with multiple ECVDs had lower incidence of bleeding event than patients with only one ECVD. This could in part be explained by the decreased use of intra-aortic balloon pump, which is reported to increase bleeding events, among patients with multiple ECVDs. However, this could rather be reflecting a power issue, which we will address in the limitations section.

It is well documented that CAD patients with concomitant ECVD are less likely to receive optimal secondary prevention medical therapies, although they are likely to benefit from evidence-based therapies.[30] [31] This tendency was also observed in our study; that is, notably, the prescription of statin was the lowest in patients with both PAD and CVD. One possible explanation could be that patients with more extra-cardiac lesions are more likely intolerant to statins, presumably because the risk factors reported to be associated with statin intolerance coincide with the characteristics of patients with ECVD, such as advanced age, small body frame, frailty, or multisystem disease.[32]

Conventionally, performing PCI in patients with concurrent ECVD has been associated with low procedural success rates and high complication rates.[1, 5, 6] Our trend analyses demonstrated that contrary to the consistency observed in the mortality trend over the 9-year study period, bleeding complication rates among patients with ECVD dropped sharply in the most recent period (2015–2017). Although the underlying reasons for this improvement could not be determined, it may be attributable to the recent increase in TRI. Notably, increases in the use of TRI and of dual antiplatelet therapy were the only factors that changed during the study period. Clearly, an increased rate of dual antiplatelet therapy would likely promote an increased rate of bleeding complications; therefore, its use cannot be attributed to the decline in bleeding events. Additionally, our data confirm that TRI is associated with a reduced bleeding complication rate. This is supported by our results of the effect of ECVD on worsening bleeding complications, which was more pronounced among patients receiving PCI via TFI compared with TRI in multiplicative and additive interaction analyses. In other words, increase on TRI had a stronger effect in the reduction of bleeding complications. Moreover, our results demonstrate the progressive decline of the O/E bleeding event ratio, which further supports the effect of TRI on the reduction of bleeding complications. In general, global use of TRI has risen dramatically in recent years and has been proven to be accompanied by parallel improvements of clinical outcomes among patients with ACS.[18] Shoji. et al analyzed our JCD KiCS multicenter registry data to report the favorable effect of TRI to reduce periprocedural stroke.[33]

This study has several important clinical implications. Given the high prevalence of poor outcomes in patients with ACS and concurrent ECVD, there remains a need to develop new treatment strategies. Patients with ECVD could benefit from early initiation of prophylactic treatments before being admitted for ACS. In the randomized controlled Viborg Vascular trial, combined screening and intervention for abdominal aortic aneurysms, PAD, and hypertension were effective at reducing mortality.[34] Our findings suggest that increased adoption of TRI has led to reduced bleeding complication rates in recent years. Despite the recent increase in utilization of TRI, 20% of patients still received PCI via other access sites between 2015 and 2017. Furthermore, given the increased risk of bleeding among patients with concurrent ECVD, the choice of antiplatelet therapy is essential. Finally, given the recent improvements in clinical outcomes among patients with ECVD, PCI can be performed for these patients relatively safely, and revascularization should not be avoided when it is deemed necessary.

Strengths and limitations

Our study has several limitations. First, this was a retrospective study consisting of registry data; therefore, it is susceptible to selection bias. Second, we lacked precise information on the location of disease among patients with PAD or CVD. We cannot draw inferences about the specific effect of lower extremity artery disease or abdominal aortic disease among patients with PAD because the JCD-KiCS PCI registry does not capture the differences between these factors. Third, the decision to measure ABI was at the discretion of the attending physician, and, therefore, was not performed in all patients. This could have led to underestimation of the prevalence of PAD and potentially created information bias. Presumably, patients in more critical conditions could have been exempted from undergoing ABI testing. To address this, we performed subgroup and sensitivity analyses across different clinical presentation conditions, which revealed similar overall results to the main analyses. Fourth, the number of patients with two ECVDs was small and may not be representative of the population. This could have led to the unexpected lower incidence of in-hospital bleeding complications among patients with two ECVDs in comparison to those with one ECVD. Nevertheless, analysis of this subgroup was not the main purpose of our study. Our entire sample size, with 7,980 patients, was large enough to ensure the reliability of the study. Fifth, given the broad definitions of PAD and CVD in the study, our results may not be comparable with past studies. Nevertheless, the purpose of the current study was to assess the effect of the presence of any ECVD upon clinical outcomes, and inclusion of various types of extra-cardiac lesions was necessary.

Conclusions

In an era in which the importance of extra-cardiac lesions is increasingly recognized, this study adds to the growing body of evidence of the prognostic significance of ECVD, inclusive of PAD or CVD, as a risk factor for adverse inpatient outcomes after PCI to treat ACS. Our data clarify the recent reduction in the magnitude of the effect of ECVD on the risk of adverse inpatient events, which can be attributed to the widespread use of TRI.

Supporting information

S1 Fig. In-hospital outcomes according to the extent of vascular disease.

Bar chart demonstrating the rates of in-hospital deaths (A) and bleeding complications (B) in the three groups.

ACS, acute coronary syndrome; CAD, coronary artery disease.

(TIF)

Click here for additional data file.^{(908KB, tif)}

S2 Fig

(A) Trends of in-hospital outcomes for patients with ACS and concomitant ECVDs in relation to the percentage of transradial intervention.

Forest plots illustrate comparative outcomes with reference to the most recent years (2008–2010).

(B) Trends in transradial intervention rate stratified by the presence of extra-cardiac vascular disease.

Figure demonstrate the rate of transradial coronary intervention rate with or without extra-cardiac vascular disease, respectively.

ACS, acute coronary syndrome; ECVD, extracardiac vascular disease; TRI, transradial intervention.

(TIF)

Click here for additional data file.^{(659.3KB, tif)}

S3 Fig. In-hospital outcomes according to the extent of vascular disease when patients with cardiogenic shock and cardiopulmonary arrest were included.

Bar chart demonstrating the rates of in-hospital deaths (A) and bleeding complications (B) in the three groups.

ACS, acute coronary syndrome; CAD, coronary artery disease.

(TIFF)

Click here for additional data file.^{(49.9KB, tiff)}

S4 Fig. Risk-adjusted outcomes and subgroup analysis across key subgroups when patients with cardiogenic shock and cardiopulmonary arrest were included.

Comparison of various in-hospital mortality rates (A) and bleeding complication rates (B) among patients with and without extra-cardiac lesion. Forest plots demonstrate comparative outcomes of acute coronary syndrome patients between those with and without extra-cardiac lesions.

CI, confidence interval; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; TFI, transfemoral intervention.

TRI, transradial intervention; UA, unstable angina.

(TIF)

Click here for additional data file.^{(760.9KB, tif)}

S5 Fig. Trends in primary and secondary outcomes among all patients with ACS stratified by the presence of ECVD when patients with cardiogenic shock and cardiopulmonary arrest were included.

Figures demonstrate the in-hospital mortality (A) and bleeding complication (B) trends among patients with ACS with or without ECVD, respectively.

ACS, acute coronary syndrome; CAD, coronary artery disease; ECVD, extracardiac vascular disease.

(TIF)

Click here for additional data file.^{(226.4KB, tif)}

S1 Table. Trends in clinical characteristics among patients with extra-cardiac lesion.

BMI, body mass index; CAD, coronary artery disease; CABG, coronary artery bypass grafting; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.

(DOCX)

Click here for additional data file.^{(61.7KB, docx)}

S2 Table. Trends in procedural and prescription characteristics among patients with extra-cardiac lesion.

CTO, chronic total occlusion; DAPT, dual antiplatelet therapy; IABP, intra-aortic balloon pump; LAD, left arterial descending; LMT, left main trunk.

(DOCX)

Click here for additional data file.^{(60.2KB, docx)}

S3 Table

Modification of the effect of extra-cardiac vascular disease severity on in-hospital mortality (A) and bleeding complication (B) by procedural site when patients with cardiogenic shock and cardiopulmonary arrest were included.

(A) Measure of interaction on additive scale: RERI (relative excess risk due to interaction) = -0.0528 (95% CI: -1.354 to 1.248); p = 0.9366.

Measure of interaction on multiplicative scale: OR: 0.680 (95% CI: 0.399 to 1.158); p = 0.156.

(B) Measures of interaction on additive scale: RERI = 0.383 (95% CI: -0.723 to 1.489); p = 0.497.

Measure of interaction on multiplicative scale: OR: 2.005 (95% CI: 1.511 to 2.661); p<0.001.

(DOCX)

Click here for additional data file.^{(20.7KB, docx)}

Acknowledgments

The authors thank all the investigators, clinical coordinators, and institutions involved in the JCD- KiCS.

Investigators: Yohei Numasawa, Toshiki Kuno, Makoto Tanaka(Japanese Red Cross Ashikaga Hospital), Yutaka Okada (Eiju General Hospital), Soushin Inoue, Iwao Nakamura (Hino Municipal Hospital), Takaharu Katayama, Shunsuke Takagi, Takashi Matsubara (Hiratsuka City Hospital), Masashi Takahashi, Keishu Li, Koichiro Sueyoshi (Kawasaki City Municipal Hospital), Atsushi Anzai, Kentaro Hayashida, Takashi Kawakami, Hideaki Kanazawa, Shunsuke Yuasa, Yuichiro Maekawa (Keio University School of Medicine), Masahiro Suzuki, Keisuke Matsumura (National Hospital Organization Saitama National Hospital) Ryota Tabei, Yukinori Ikegami, Jun Fuse, Munehisa Sakamoto, Yukihiko Momiyama (National Hospital Organization Tokyo Medical Center), Ayaka Endo, Tasuku Hasegawa, Toshiyuki Takahashi, Susumu Nakagawa (Saiseikai Central Hospital), Fumiaki Yashima, Koji Ueno, Kenichiro Shimoji, Shigetaka Noma (Saiseikai Utsunomiya Hospital), Masahito Munakata, Takashi Akima, Shiro Ishikawa, Takashi Koyama (Saitama City Hospital), Atsushi Mizuno (St Luke’s International Hospital Heart Center), Toshimi Kageyama, Kazunori Moritani, Masaru Shibata (Tachikawa Kyosai Hospital), Hiroaki Sukegawa, Yoshinori Mano, Takahiro Oki (Tokyo Dental College Ichikawa General Hospital), Daisuke Shinmura, Koji Negishi, and Takahiro Koura (Yokohama Municipal Hospital)

Clinical Coordinators: Junko Susa, Ayano Amagawa, Hiroaki Nagayama, Miho Umemura, Itsuka Saito, and Ikuko Ueda

Data Availability

Data are from the Japan Cardiovascular Database-Keio interhospital Cardiovascular Studies whose authors may be contacted at hqa-adm@umin.ac.jp. Data are available only upon request according to the “Act on the Protection of Personal Information” Law (as of May 2017) and the “Ethical Guidelines for Medical and Health Research Involving Human Subjects” (as of March 2015). The current study data was obtained from the JCD-KiCS PCI registry and would be available upon request to University of Tokyo, Healthcare Quality Assessment. (E-mail: hqa-adm@umin.ac.jp.)

Funding Statement

This research was funded by a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan (KAKENHI No. 21790751, 16H05215).

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PLoS One. doi: 10.1371/journal.pone.0223215.r001

Decision Letter 0

Corstiaan den Uil

1 Aug 2019

PONE-D-19-17185

Outcomes of acute coronary syndrome patients with concurrent extra-cardiac vascular disease in the era of transradial coronary intervention: a retrospective multicentre cohort study

PLOS ONE

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As the authors mention, the MATRIX trial suggested clinical benefits with radial compared to femoral access in patients with ACS. In MATRIX, there was no significant interaction between the presence of PVD and the treatment effect of transradial access. Furthermore, the results of SAFARI (presented at ACC 2019 but not yet published) did not demonstrate a difference in clinical outcomes (including bleeding) with radial versus femoral access in patients undergoing primary PCI for STEMI.

The authors should be commended for their work. Their analysis is based on a large dataset and addresses an important clinical question. In addition, manuscript is well written with meticulous methodology. However, as with any observational study, there are important limitations. In particular, inferring casualty from a non-randomized comparison.

Comments/suggestion:

Methods

1) For multivariate logistic regression, how were explanatory variables chosen?

2) Do the authors have data on additional clinical outcomes (e.g. stroke, myocardial infarction, etc)? Some interventionalists worry about radial access in patients with cerebrovascular disease due to concerns about stroke. Additional data would be informative if available.

Results

1) As a reader, I found differences in pharmacotherapy in relation to ECVD interesting (Table 2). These may be reflect differences in practice patterns, which may not have been captured in multivariate logistic regression. Addressing these in the discussion would be of value.

2) The trends highlighted in figure 4b are interesting. Between 2011/2014 and 2015/2017, there appears to be a disproportionate decrease in bleeding complications in patients with versus without ECVD. Do the authors have a hypothesis as to why this occurred? If the hypothesis is changes in TRI frequency, was there a concomitant disproportionate increase in TRI during the same period in patients with versus without ECVD?

3) In-hospital bleeding in relation to ECVD (as highlighted in fig S1B) suggests that bleeding is higher with 1 ECVD as opposed to 2 ECVD (which has the lowest observed bleeding rate among all groups). Do the authors have a potential explanation for this observation? Based on the authors’ hypothesis, you should expect similar or more bleeding in patients with more ECVD.

4) In Fig S4B, p value for interaction for radial access is <0.001 even though the odds ratios point estimates are very similar. Could there be an error?

Discussion

1) In line 432, the authors suggest favoring clopidogrel versus ticagrelor to avoid bleeding events. In my opinion, the reference provided and the observations in the current analysis do not provide enough substrate for this recommendation. I would consider removing this statement.

Conclusion

1) Both statements in the conclusion (TRI has reduced bleeding and TRI should be used in patients with ECVD) are too strong as they imply causality. Suggest a more conservative conclusion highlighting observed associations only.

Edits

1) In line 109, “fulfill” is misspelled

2) As a reader, in line 206, it was not readily apparent to me that the third type of vascular disease refers to CAD. I would suggest rewording to avoid confusion.

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PLoS One. 2019 Oct 16;14(10):e0223215. doi: 10.1371/journal.pone.0223215.r002

Author response to Decision Letter 0

14 Sep 2019

14 September, 2019

Dr. Corstiaan Den Uil

Academic Editor

PLoS ONE

Re: Resubmission of manuscript ID: PONE-D-19-17185

Dear Dr. Uil,

Please find enclosed our manuscript titled, “Outcomes of acute coronary syndrome patients with concurrent extra-cardiac vascular disease in the era of transradial coronary intervention: a retrospective multicenter cohort study,” which we are resubmitting to PLoS ONE.

We thank you and the reviewers for your thoughtful suggestions and insights. We believe that the comments allowed us to improve the quality of our manuscript. Our point-by-point responses to the comments are shown below. Changes to our manuscript are highlighted in yellow.

Please let us know if any further clarification is required. We trust that our manuscript is now suitable for publication in the PLoS ONE. We look forward to hearing from you.

Yours sincerely,

Masaki Kodaira, M.D. Ph.D.

Department of Cardiology, Japanese Red Cross Ashikaga Hospital

284-1 Yobe-cho, Ashikaga, Tochigi 326-0843, Japan

Tel: +81-284-21-0121

Fax: +81-284-21-6810　

E-mail: m.kodaira@ashikaga.jrc.or.jp

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

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We have formatted with these requirements. If something is wrong, please let us know.

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Data are available only upon request according to the “Act on the Protection of

Personal Information” Law (as of May 2017) and the “Ethical Guidelines for Medical and Health Research Involving Human Subjects” (as of March 2015). The current study data was obtained from the JCD-KiCS PCI registry and would be available upon request to the author Dr. Shun Kohsaka MD (E-mail: sk@keio.jp).

3. Thank you for stating the following in the Competing Interests section:

[ have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Kohsaka has received grants from Bayer Yakuhin and Daiichi-Sankyo; has received lecture fees from Bayer Yakuhin and Bristol-Myers Squibb.].

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Dr. Kohsaka has received grants from Bayer Yakuhin and Daiichi-Sankyo; has received lecture fees from Bayer Y.akuhin and Bristol-Myers Squibb. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Reviewer #1: I read with interest the manuscript by Kodaira et al. In this study, the authors used data from a large multicenter registry to examine clinical outcomes in patients with ECVD undergoing PCI for ACS. The main objectives of the study were: 1) to examine the impact of ECVD on in-hospital outcomes in patients with ACS, and 2) determine whether access site (radial versus femoral) has a modulating effect on the association between ECVD and in hospital outcomes.  As the authors mention, the MATRIX trial suggested clinical benefits with radial compared to femoral access in patients with ACS. In MATRIX, there was no significant interaction between the presence of PVD and the treatment effect of transradial access. Furthermore, the results of SAFARI (presented at ACC 2019 but not yet published) did not demonstrate a difference in clinical outcomes (including bleeding) with radial versus femoral access in patients undergoing primary PCI for STEMI.  The authors should be commended for their work. Their analysis is based on a large dataset and addresses an important clinical question. In addition, manuscript is well written with meticulous methodology. However, as with any observational study, there are important limitations. In particular, inferring casualty from a non-randomized comparison.

Comments/suggestion:  Methods 1) For multivariate logistic regression, how were explanatory variables chosen?

As described in lines 161–163 of the Methods section, our multivariate logistic regression analysis was performed using explanatory variables which were incorporated in the National Cardiovascular Data Registry (NCDR) risk models for in-hospital mortality (1) and bleeding risk.(2)

As for its details, the NCDR for catheterization (CathPCI) registry provides the ideal infrastructure to derive procedure risk models with more than 1500 participating centers, which is co-sponsored by the American College of Cardiology and the Society for Cardiovascular Angiography and Intervention (http://www.ncdr.com) In addition, Peterson et al. developed the relevant risk model for 30-day PCI mortality by analyzing 600,533 consecutive PCI admissions between January 2004 and March 2007 recorded in the NCDR CathPCI registry.(1) The risk model was applied to prospective validation sample sets to demonstrate excellent discrimination (c-index: 0.91). Moreover, Rao et al. identified factors associated with major complications occurring within 72 hours after PCI by analyzing 1,043,759 PCI procedures in the NCDR CathPCI registry performed between February 2008 and April 2011.(2) The model also had good discrimination in the validation sample with c-index of 0.77.

2) Do the authors have data on additional clinical outcomes (e.g. stroke, myocardial infarction, etc.)? Some interventionists worry about radial access in patients with cerebrovascular disease due to concerns about stroke. Additional data would be informative if available.

Thank you for your interest in additional clinical outcomes. Yes, we have data on these clinical outcomes.

Recently, we examined the effect of TRI on periprocedural stroke by analyzing 17,966 patients who underwent PCI between 2008 and 2016 in our JCD KiCS registry.(3) Within this paper, multivariable logistic regression analysis (odds ratio; 0.33; 95% CI, 0.16–0.71; p = 0.004) and propensity score matching analysis (0.1% versus 0.4%; p = 0.014) revealed that TRI, in comparison with TFI, was associated with lower risk of periprocedural stroke. Shoji et al. attributed this favorable effect of TRI to its less catheter contact with the aortic arch (4) and avoidance of contact with the abdominal or descending thoracic portions of the aorta.(5)

As regards to periprocedural myocardial infarction, analysis of our current study population demonstrated that patients who underwent TRI had significantly lower incidence of periprocedural myocardial infarction than those who underwent TFI (0.89% versus 1.78%, p = 0.001). However, we decided not to include this result in our revised manuscript, because cardiac biomarker testing is not performed routinely after PCI. Arai et al. reported from our JCD KiCS registry that only 25.2% of the patients received cardiac biomarker assessment after PCI.(6) This low rate of cardiac biomarker assessment was also reported in the United States, at 24.7%.(7)

Please find the following sentences added to the revised manuscript on Shoji’s work on the favorable effect of TRI on the reduction of periprocedural stroke after PCI.

Discussion section (page 34, lines 421–422):

Shoji. et al analyzed our JCD KiCS multicenter registry data to report the favorable effect of TRI to reduce periprocedural stroke.

Reference 33 (Circ Cardiovasc Interv. 2018;11(12):e006761) was added to support this.

 Results  1) As a reader, I found differences in pharmacotherapy in relation to ECVD interesting (Table 2). These may reflect differences in practice patterns, which may not have been captured in multivariate logistic regression. Addressing these in the discussion would be of value.

Thank you for having interest in our data on pharmacotherapy. The prescription rate of cardio-protective drugs recommended in the guidelines, statin, and beta-blockers were significantly lower in those with concomitant ECVD than in those without ECVD. This finding had been observed in past reports. We have added the following paragraph and added references 30–32.

Discussion section (page 32, lines 391–399):

It is well documented that CAD patients with concomitant ECVD are less likely to receive optimal secondary prevention medical therapies, although they are likely to benefit from evidence-based therapies. This tendency was also observed in our study; that is, notably the prescription of statin was the lowest in patients with both PAD and CVD. One possible explanation could be that patients with more extra-cardiac lesions are more likely intolerant to statins, presumably because the risk factors reported to be associated with statin intolerance coincide with the characteristics of patients with ECVD, such as advanced age, small body frame, frailty, or multisystem disease.

Thank you for commenting on the most essential finding of our study. As we stated in page 34, lines 422–435, our hypothesis is that increase in transradial intervention (TRI) during the period led to the disproportionate decrease in bleeding complications in ACS patients with ECVD versus without ECVD. However, this increase in TRI was not disproportionate between patients with and without ECVD. We have added supplemental figure (S2B Fig) to demonstrate this. In addition, we have edited Supplemental Figure S2A to include the rate of TRI according to the presence of ECVD. Although its increase during this period was proportionate, increase in TRI may play a role by causing disproportionate decrease in bleeding complications between patients with and without ECVD. Both our multiplicative and additive interaction analyses supported that the effect of ECVD on worsening bleeding complications was more pronounced among ACS patients undergoing transfemoral intervention (TFI) compared with those undergoing TRI (page 33 lines 412–414). In other words, increase in TRI (=decrease in TFI) had a stronger effect in the reduction of bleeding complications among ACS patients with ECVD compared to those without ECVD.

The following sentences from our original manuscript should clarify the points:

Discussion section (page 33, lines 403–415)

Our trend analyses demonstrated that contrary to the consistency observed in the mortality trend over the 9-year study period, bleeding complication rates among patients with ECVD dropped sharply in the most recent period (2015–2017). Although the underlying reasons for this improvement could not be determined, it may be attributable to the recent increase in TRI. Notably, increases in the use of TRI and of dual antiplatelet therapy were the only factors that changed during the study period. Clearly, an increased rate of dual antiplatelet therapy would likely promote an increased rate of bleeding complications; therefore, its use cannot be attributed to the decline in bleeding events. Additionally, our data confirm that TRI is associated with a reduced bleeding complication rate. This is supported by our results of the effect of ECVD on worsening bleeding complications, which was more pronounced among patients receiving PCI via TFI compared with TRI in multiplicative and additive interaction analyses.

As our explanation was not clear, we added the following sentence to the Discussion section in our revised manuscript.

Discussion section (page 33, lines 415–416)

In other words, increase in TRI had a stronger effect in the reduction of bleeding complications among patients with compared to those without ECVD.

We thank the reviewer for the comments and deep insights. We were also surprised to find lower incidence of in-hospital bleeding complications among patients with multiple ECVDs. This result is difficult to interpret because it conflicts with what can be expected from the unfavorable baseline characteristics shown in Table 1; patients with multiple ECVDs were the oldest, had the lowest body mass index, most frequently had past history of PCI, and possessed chronic kidney disease. All these variables are reported to be associated with higher incidence of in-hospital bleeding complications.

On the other hand, Table 2 provides another interesting aspect on the procedural characteristic of patients with multiple ECVDs. Notably, these patients had significantly lower incidence of intra-aortic balloon pump (IABP) insertion (4.6%) compared those with only one ECVD (8.9%) or CAD only (7.7%). Lee et al. demonstrated in their meta-analysis that the use of IABP, which requires insertion of a relatively large size sheath via the femoral artery, was associated with increased risk of moderate to severe bleeding compared with medical therapy (relative risk 1.41, 95% CI 1.01–2.08).(8) Although the reason for this difference in the rate of IABP use is not clear, we speculate that the physicians avoided using IABP for patients with two ECVDs, considering their unfavorable condition.

Finally, most of all, we recognize that this is more of a power issue. The number of patients with two ECVDs was small (n = 87) and may not be representative of the population. In other words, the small sample size of this subpopulation with multiple ECVDs subjects its results to sampling variation and random error.(9) Nevertheless, we would like to underline that our study population as a whole had a large sample size of 7,980 patients to ensure the integrity of the results. We, therefore, added the following sentences below.

Discussion section (page 31, lines 382 to page 32, line 388):

On the contrary, to our surprise, the bleeding event rate did not increase in a stepwise fashion with the number of ECVDs; patients with multiple ECVDs had lower incidence of bleeding event than patients with only one ECVD. This could in part be explained by the decreased use of intra-aortic balloon pump, which is reported to increase bleeding events, among patients with multiple ECVDs. However, this could rather be reflecting a power issue, which we will address in the limitations section.

Discussion, Strength and limitations section (page 36, lines 453–459):

Fourth, the sample size of patients with multiple ECVDs was small and may not be representative of the population. This could have led to the unexpected lower incidence of in-hospital bleeding complications among patients with multiple ECVDs in comparison to those with one ECVD. Nevertheless, analysis of this subgroup was not the main purpose of our study. Our entire sample size, with 7,980 patients, was large enough to ensure the reliability of the study.

 4) In Fig S4B, p value for interaction for radial access is <0.001 even though the odds ratios point estimates are very similar. Could there be an error?

Thank you for bringing this to our attention. We reexamined our analysis for Fig S4B to find an error in our calculation for the p value of interaction for radial access. It should be 0.718, and we have edited Fig S4B accordingly. We apologize for the miscalculation. We also performed recalculation for other analyses to make sure that other values were correct.

  Discussion 1) In line 432, the authors suggest favoring clopidogrel versus ticagrelor to avoid bleeding events. In my opinion, the reference provided and the observations in the current analysis do not provide enough substrate for this recommendation. I would consider removing this statement.

Thank you for pointing out. We agree with the reviewer that there is not enough evidence to support this statement, and the sentence has been omitted accordingly.

  Conclusion  1) Both statements in the conclusion (TRI has reduced bleeding and TRI should be used in patients with ECVD) are too strong as they imply causality. Suggest a more conservative conclusion highlighting observed associations only.

We agree with the reviewer that our statements in the conclusion of the abstract were rather strong. In our revised manuscript, our conclusion in the abstract is now in lined with the conclusion of the main text.

Abstract conclusions (page 4, lines 46–49):

Overall, the presence of ECVD was a risk factor for adverse outcomes after PCI for ACS, both mortality and bleeding complications. In the most recent years, the incidence of bleeding complication among patients with ECVD decreased significantly coinciding with the rapid increase of TRI.

  Edits  1) In line 109, “fulfill” is misspelled.

PLoS One’s submission guideline plainly states “English” as the preferred language and does not indicate whether British English or US English is preferred. We, therefore, submitted our initial manuscript in British English, including “fulfill.” After acknowledging that the reviewer prefers US English, we have edited the manuscript, including the title. Please find below the changes made from British English to US English.

Title (page 1, line 3), Abstract (page 3, line 31):

multicentre > multicenter

Methods and materials section (page 8, line 109):

fulfil > fulfill

Methods and materials section (page 11, line 162) and (page 13, line 187):

haemoglobin > hemoglobin

Discussion section (page 31, line 377):

hypothesised > hypothesized

 2) As a reader, in line 206, it was not readily apparent to me that the third type of vascular disease refers to CAD. I would suggest rewording to avoid confusion.

We apologize for the unintelligibility. Taking the reviewer’s advice, we have modified the sentence as shown below to make it clear to the readers that the third type was CAD.

Results section (page 14, lines 201–204):

References for the rebuttal letter

1. Peterson ED, Dai D, DeLong ER, Brennan JM, Singh M, Rao SV, et al. Contemporary mortality risk prediction for percutaneous coronary intervention: results from 588,398 procedures in the National Cardiovascular Data Registry. J Am Coll Cardiol. 2010;55(18):1923-32.

2. Rao SV, McCoy LA, Spertus JA, Krone RJ, Singh M, Fitzgerald S, et al. An updated bleeding model to predict the risk of post-procedure bleeding among patients undergoing percutaneous coronary intervention: a report using an expanded bleeding definition from the National Cardiovascular Data Registry CathPCI Registry. JACC Cardiovascular interventions. 2013;6(9):897-904.

3. Shoji S, Kohsaka S, Kumamaru H, Sawano M, Shiraishi Y, Ueda I, et al. Stroke after percutaneous coronary intervention in the era of transradial intervention. Circ Cardiovasc Interv. 2018;11(12):e006761.

4. Khoury Z, Gottlieb S, Stern S, Keren A. Frequency and distribution of atherosclerotic plaques in the thoracic aorta as determined by transesophageal echocardiography in patients with coronary artery disease. Am J Cardiol. 1997;79(1):23-7.

5. Roberts WC, Schussler JM. Frequency of plaque dislodgement and embolization in transradial vs transfemoral approaches for left-sided cardiac catheterization: clinically silent vs clinically apparent embolism. JAMA Cardiol. 2018;3(7):551-2.

6. Arai T, Yuasa S, Miyata H, Kawamura A, Maekawa Y, Ishikawa S, et al. Incidence of periprocedural myocardial infarction and cardiac biomarker testing after percutaneous coronary intervention in Japan: results from a multicenter registry. Heart Vessels. 2013;28(6):714-9.

7. Wang TY, Peterson ED, Dai D, Anderson HV, Rao SV, Brindis RG, et al. Patterns of cardiac marker surveillance after elective percutaneous coronary intervention and implications for the use of periprocedural myocardial infarction as a quality metric: a report from the National Cardiovascular Data Registry (NCDR). J Am Coll Cardiol. 2008;51(21):2068-74.

8. Lee JM, Park J, Kang J, Jeon KH, Jung JH, Lee SE, et al. The efficacy and safety of mechanical hemodynamic support in patients undergoing high-risk percutaneous coronary intervention with or without cardiogenic shock: Bayesian approach network meta-analysis of 13 randomized controlled trials. Int J Cardiol. 2015;184:36-46.

9. Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14(5):365-76.

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PLoS One. doi: 10.1371/journal.pone.0223215.r003

Decision Letter 1

Corstiaan den Uil

17 Sep 2019

Outcomes of acute coronary syndrome patients with concurrent extra-cardiac vascular disease in the era of transradial coronary intervention: a retrospective multicenter cohort study

PONE-D-19-17185R1

Dear Dr. Kodaira,

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Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0223215.r004

Acceptance letter

Corstiaan den Uil

27 Sep 2019

PONE-D-19-17185R1

Outcomes of acute coronary syndrome patients with concurrent extra-cardiac vascular disease in the era of transradial coronary intervention: a retrospective multicenter cohort study

Dear Dr. Kodaira:

I am 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.

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Associated Data

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

Supplementary Materials

S1 Fig. In-hospital outcomes according to the extent of vascular disease.

Bar chart demonstrating the rates of in-hospital deaths (A) and bleeding complications (B) in the three groups.

ACS, acute coronary syndrome; CAD, coronary artery disease.

(TIF)

Click here for additional data file.^{(908KB, tif)}

S2 Fig

(A) Trends of in-hospital outcomes for patients with ACS and concomitant ECVDs in relation to the percentage of transradial intervention.

Forest plots illustrate comparative outcomes with reference to the most recent years (2008–2010).

(B) Trends in transradial intervention rate stratified by the presence of extra-cardiac vascular disease.

Figure demonstrate the rate of transradial coronary intervention rate with or without extra-cardiac vascular disease, respectively.

ACS, acute coronary syndrome; ECVD, extracardiac vascular disease; TRI, transradial intervention.

(TIF)

Click here for additional data file.^{(659.3KB, tif)}

S3 Fig. In-hospital outcomes according to the extent of vascular disease when patients with cardiogenic shock and cardiopulmonary arrest were included.

Bar chart demonstrating the rates of in-hospital deaths (A) and bleeding complications (B) in the three groups.

ACS, acute coronary syndrome; CAD, coronary artery disease.

(TIFF)

Click here for additional data file.^{(49.9KB, tiff)}

S4 Fig. Risk-adjusted outcomes and subgroup analysis across key subgroups when patients with cardiogenic shock and cardiopulmonary arrest were included.

CI, confidence interval; NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; TFI, transfemoral intervention.

TRI, transradial intervention; UA, unstable angina.

(TIF)

Click here for additional data file.^{(760.9KB, tif)}

S5 Fig. Trends in primary and secondary outcomes among all patients with ACS stratified by the presence of ECVD when patients with cardiogenic shock and cardiopulmonary arrest were included.

Figures demonstrate the in-hospital mortality (A) and bleeding complication (B) trends among patients with ACS with or without ECVD, respectively.

ACS, acute coronary syndrome; CAD, coronary artery disease; ECVD, extracardiac vascular disease.

(TIF)

Click here for additional data file.^{(226.4KB, tif)}

S1 Table. Trends in clinical characteristics among patients with extra-cardiac lesion.

(DOCX)

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S2 Table. Trends in procedural and prescription characteristics among patients with extra-cardiac lesion.

CTO, chronic total occlusion; DAPT, dual antiplatelet therapy; IABP, intra-aortic balloon pump; LAD, left arterial descending; LMT, left main trunk.

(DOCX)

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S3 Table

(A) Measure of interaction on additive scale: RERI (relative excess risk due to interaction) = -0.0528 (95% CI: -1.354 to 1.248); p = 0.9366.

Measure of interaction on multiplicative scale: OR: 0.680 (95% CI: 0.399 to 1.158); p = 0.156.

(B) Measures of interaction on additive scale: RERI = 0.383 (95% CI: -0.723 to 1.489); p = 0.497.

Measure of interaction on multiplicative scale: OR: 2.005 (95% CI: 1.511 to 2.661); p<0.001.

(DOCX)

Click here for additional data file.^{(20.7KB, docx)}

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Data Availability Statement

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PERMALINK

Outcomes of acute coronary syndrome patients with concurrent extra-cardiac vascular disease in the era of transradial coronary intervention: A retrospective multicenter cohort study

Masaki Kodaira

Mitsuaki Sawano

Toshiki Kuno

Yohei Numasawa

Shigetaka Noma

Masahiro Suzuki

Shohei Imaeda

Ikuko Ueda

Keiichi Fukuda

Shun Kohsaka

Roles

Abstract

Background

Methods and results

Conclusions

Introduction

Methods and materials

Study population and study design

Fig 1. Study flow chart.

Study definitions and outcomes

Statistical analysis

Results

Sample characteristics

Fig 2. Distribution of the study population according to the location of extra-cardiac atherosclerosis.

Table 1. Baseline clinical characteristics in relation with the number of extra-cardiac lesions.

Table 2. Procedural characteristics according to the number of extra-cardiac lesions.

Outcomes according to the number of extra-cardiac vascular diseases

Fig 3. Risk-adjusted outcomes and subgroup analysis across key subgroups.

Interaction between extra-cardiac vascular disease and procedural access site

Table 3. Modification of the effect of extra-cardiac vascular disease severity on in-hospital mortality by procedural site.

Table 4. Modification of the effect of extra-cardiac vascular disease severity on in-hospital bleeding complication by procedural site.

Temporal trends among patients with or without extra-cardiac vascular disease

Table 5. Observed/expected ratios and adjusted odds ratios of in-hospital mortality.

Table 6. Observed/Expected ratios and adjusted odds ratios of in-hospital bleeding complications.

Fig 4. Trends in primary and secondary outcomes among all patients with acute coronary syndrome stratified by the presence of extra-cardiac vascular disease.

Sensitivity and subgroup analyses

Discussion

Key findings

Interpretation of results

Strengths and limitations

Conclusions

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Corstiaan den Uil

Roles

Author response to Decision Letter 0

Decision Letter 1

Corstiaan den Uil

Roles

Acceptance letter

Corstiaan den Uil

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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