Variation in in-hospital mortality and its association with percutaneous coronary intervention-related bleeding complications: A report from nationwide registry in Japan.

Large-scale registries have demonstrated that in-hospital mortality after percutaneous coronary intervention (PCI) varies widely across institutions. However, whether this variation is related to major procedural complications (e.g., bleeding) is unclear. In this study, institutional variation in in-hospital mortality and its association with PCI-related bleeding complications were investigated. We analyzed 388,866 procedures at 718 hospitals performed from 2017 to 2018, using data from a nationwide PCI registry in Japan. Hospitals were stratified into quintiles according to risk-adjusted in-hospital mortality (very low, low, medium, high, and very high). Incidence of bleeding complications, defined as procedure-related bleeding events that required a blood transfusion, and in-hospital mortality in patients who developed bleeding complications were calculated for each quintile. Overall, 4,048 (1.04%) in-hospital deaths and 1,535 (0.39%) bleeding complications occurred. Among patients with bleeding complications, 270 (17.6%) died during hospitalization. In-hospital mortality ranged from 0.22% to 2.46% in very low to very high mortality hospitals. The rate of bleeding complications varied modestly from 0.27% to 0.57% (odds ratio, 1.95; 95% confidence interval, 1.58-2.39). However, mortality after bleeding complications markedly increased by quintile and was 6-fold higher in very high mortality hospitals than very low mortality hospitals (29.0% vs. 4.8%; odds ratio, 12.2; 95% confidence interval, 6.90-21.7). In conclusion, institutional variation in in-hospital mortality after PCI was associated with procedure-related bleeding complications, and this variation was largely driven by differences in mortality after bleeding complications rather than difference in their incidence. These findings underscore the importance of efforts toward reducing not only bleeding complications but also, even more importantly, subsequent mortality once they have occurred.

Introduction

Despite advances in percutaneous coronary intervention (PCI) over the last 40 years, bleeding has been regarded as one of the most serious procedure-related complications [1, 2]. Once bleeding complications occur, in-hospital mortality increases by approximately 12% [2]. The introduction of radial access has contributed to reductions in bleeding complications [3-5]; however, not only access site but also non-access site bleeding complications was independently associated with an increased risk of postprocedural mortality [6, 7]. Moreover, the recent advent of novel potent antithrombotic agents has increased bleeding events in exchange for a reduction in ischemic events [8, 9]. Especially recently, some populations receiving PCI comprise patients with a high risk of bleeding [10, 11]; therefore, PCI-related bleeding complications and their related mortality remain significant issues worldwide.

Large-scale registries have demonstrated that in-hospital mortality in patients underwent PCI varies widely across institutions [12-14], though the underlying reasons are not fully understood. We hypothesized that this variation may be involved in bleeding complications because their incidence or subsequent clinical outcomes can be largely dictated by hospital’s capacity (e.g., the ability to prevent, expeditiously recognize or properly manage complications). In this study, therefore, we aimed to investigate the association between institutional variation in in-hospital mortality and bleeding complications within a representative nationwide PCI registry in Japan. Identifying this association has the potential to improve the prognosis of PCI in the contemporary era when patients with a high risk of bleeding are commonly treated.

Material and methods

Data source and study patients

The Japanese Percutaneous Coronary Intervention (J-PCI) registry is an ongoing nationwide PCI registry endorsed by the Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT) that was designed to record clinical characteristics and in-hospital outcomes of patients undergoing PCI [15, 16]. In January 2013, the J-PCI registry was incorporated into the National Clinical Data system, a nationwide prospective Internet-based registry linked to board certification. Since all hospitals must participate in the J-PCI registry for board certification application and renewal, the degree of data completeness is high. Each hospital has a data manager who is responsible for collecting and recording PCI data. The CVIT holds an annual meeting of data managers to secure appropriate data collection and performs random audits (20 institutions annually) to check the quality of abstracted data. The definitions of variables in the J-PCI registries are available online from the CVIT. This study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Institutional Review Board of the Network for Promotion of Clinical Studies (a specialized nonprofit organization affiliated with Osaka University Graduate School of Medicine in Osaka, Japan). The requirement for written informed consent was waived because of the retrospective study design. In accordance with the Transparency and Openness Promotion Guidelines, the data that support the findings of this study are available from the corresponding author upon reasonable request.

This study population consisted of consecutive cases registered from January 2017 to December 2018 in the J-PCI registry. Then, cases with missing information in background characteristics were excluded. Also, we restricted the dataset to institutions that reported at least one in-hospital death during the study period (Fig 1).

Fig 1

Flowchart of study enrollment.

PCI indicates percutaneous coronary intervention.

Definition of variables

Bleeding complication was defined as a PCI-related bleeding event that required a blood transfusion during the index PCI hospitalization. In-hospital mortality was defined as death from any cause. Other study variables, including patient characteristics, clinical presentation, angiographic and procedural details, and in-hospital outcomes were defined as previously reported [15].

Model of risk adjusted in-hospital mortality

To account for differences in patient variables that affect mortality, hospitals were stratified into quintiles according to risk-adjusted in-hospital mortality, which was calculated as follows: (i) with reference to previous study [17], a multivariable logistic regression model was created to predict individual patient probability of death using age, sex, smoking within 1 year, hypertension, dyslipidemia, chronic kidney disease, maintenance dialysis, peripheral vascular disease, previous PCI, previous coronary artery bypass graft surgery, previous heart failure, cardiogenic shock within 24 hours, clinical presentation (ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, unstable angina, or others), access site, number of diseased vessels, antiplatelet agents given at the time of PCI, and anticoagulant agents given at the time of PCI as explanatory variables (C-statistic of 0.91); (ii) crude mortality at each hospital was calculated and predicted probability of death for each patient at each hospital was averaged to obtain expected mortality; (iii) finally, risk-adjusted mortality at each hospital was calculated by dividing crude mortality by expected mortality and multiplying it by overall database mortality. We then ranked the hospitals according to risk-adjusted mortality and stratified them into quintiles (very low, low, medium, high, and very high mortality).

Main analysis and subanalysis

As a main analysis, we calculated incidence of bleeding complications and mortality in patients who developed bleeding complications for each quintile. As a subanalysis, access and non-access site bleeding events were assessed individually. In addition, access site bleeding events were assessed separately for transfemoral access (TFA) and transradial access (TRA). The incidence of TFA- and TRA-related bleeding events was calculated among only patients treated via TFA and TRA, respectively.

Statistical analysis

Categorical data are reported as numbers with percentage and were compared using the chi-square test. Continuous data with normal distribution are expressed as means with standard deviation. Continuous data with non-normal distribution are expressed as medians with interquartile range. One-way analysis of variance and the Kruskal–Wallis test were used to compare continuous data. Incidence of bleeding complications and mortality in patients who developed bleeding complications are presented as numbers with percentage. Odds ratios (ORs) with 95% confidence interval (CI) were calculated in each quintile relative to very low mortality hospitals using mixed model logistic regression. Institutions were included in the models as random intercepts. The Cochran–Armitage test was used to assess trends in complication incidence and mortality after complications among the quintiles. Two-sided P <0.05 was considered significant. All statistical analyses were performed using R software version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

A total of 388,866 cases at 718 hospitals were included for analysis. Overall, 4,048 (1.04%) in-hospital deaths occurred. Patient characteristics according to risk-adjusted mortality quintiles are summarized in Table 1. In-hospital mortality ranged from 0.22% to 2.46% in very low to very high mortality hospitals. Compared to other quintiles, the very low mortality quintile of hospitals had a 1.5-fold higher proportion of hospitals that performed >500 PCI cases per year (Table 2). TFA was used more frequently in the lower mortality hospitals, whereas TRA was used more frequently in the higher mortality hospitals. The prevalence of acute clinical presentation, including ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction, was highest in medium mortality hospitals. Complex PCI cases requiring rotational atherectomy or directional coronary atherectomy were performed predominantly in elective PCI cases and were more frequent in lower mortality hospitals.

Table 1

Patient characteristics.

	Overall	Very low mortality	Low mortality	Medium mortality	High mortality	Very high mortality	P value
Number of PCI cases	388,866	106,591	73,323	69,096	71,206	68,650
In-hospital death	4,048 (1.04)	232 (0.22)	419 (0.57)	665 (0.96)	1,040 (1.46)	1,692 (2.46)	<0.001
Age, years	71 ± 11	70 ± 11	71 ± 11	70 ± 11	71 ± 11	70 ± 11	<0.001
Male	297,464 (76)	81,702 (77)	56,083 (76)	53,224 (77)	54,043 (76)	52,412 (76)	<0.001
Smoking within 1 year	119,873 (31)	36,263 (34)	20,373 (28)	20,000 (29)	23,310 (33)	19,927 (29)	<0.001
Diabetes	173,147 (45)	47,151 (44)	32,592 (44)	29,787 (43)	32,723 (46)	30,894 (45)	<0.001
Hypertension	291,399 (75)	79,640 (75)	54,403 (74)	51,973 (75)	54,306 (76)	51,077 (74)	<0.001
Dyslipidemia	254,172 (65)	69,010 (65)	47,421 (65)	45,134 (65)	48,336 (68)	44,271 (64)	<0.001
Chronic kidney disease	76,229 (20)	20,493 (19)	13,744 (19)	13,029 (19)	15,263 (21)	13,700 (20)	<0.001
Maintenance dialysis	27,059 (7.0)	7,692 (7.2)	5,082 (6.9)	4,533 (6.6)	5,349 (7.5)	4,403 (6.4)	<0.001
COPD	10,088 (2.6)	2,627 (2.5)	2,140 (2.9)	1,572 (2.3)	1,997 (2.8)	1,752 (2.6)	<0.001
Peripheral vascular disease	30,292 (7.8)	7,784 (7.3)	5,710 (7.8)	5,406 (7.8)	5,824 (8.2)	5,568 (8.1)	<0.001
Previous PCI	180,453 (46)	51,093 (48)	34,781 (47)	31,119 (45)	32,536 (46)	30,924 (45)	<0.001
Previous CABG	14,148 (3.6)	3,570 (3.3)	2,709 (3.7)	2,552 (3.7)	2,970 (4.2)	2,347 (3.4)	<0.001
Previous heart failure	57,042 (15)	14,883 (14)	11,486 (16)	9,731 (14)	11,132 (16)	9,810 (14)	<0.001
Cardiogenic shock within 24 hours	13,419 (3.5)	3,568 (3.3)	2,710 (3.7)	2,481 (3.6)	2,513 (3.5)	2,147 (3.1)	<0.001
Baseline hemoglobin, g/dL	13.2 ± 2.0	13.1 ± 2.0	13.2 ± 2.1	13.2 ± 2.0	13.2 ± 2.1	13.2 ± 2.1	0.002
Clinical presentation							<0.001
Acute setting	148,715 (38)	37,878 (36)	27,998 (38)	27,591 (40)	28,476 (40)	26,772 (39)
STEMI	68,910 (18)	17,355 (16)	12,755 (17)	12,963 (19)	12,799 (18)	13,038 (19)
NSTEMI	21,217 (5.5)	5,285 (5.0)	3,779 (5.2)	4,163 (6.0)	4,047 (5.7)	3,943 (5.7)
UA	58,591 (15)	15,238 (14)	11,467 (16)	10,465 (15)	11,630 (16)	9,791 (14)
Access site							<0.001
Transfemoral	98,625 (25)	29,931 (28)	20,493 (28)	17,816 (26)	15,694 (22)	14,691 (21)
Transradial	270,838 (70)	70,475 (66)	49,230 (67)	48,565 (70)	51,593 (72)	50,975 (74)
Number of diseased vessels
One	237,110 (61)	65,293 (61)	45,205 (62)	41,736 (60)	43,912 (62)	40,964 (60)	<0.001
Two	92,749 (24)	25,375 (24)	17,089 (23)	16,868 (24)	16,409 (23)	17,008 (25)	<0.001
Three	42,796 (11)	11,501 (11)	8,070 (11)	7,658 (11)	7,672 (11)	7,895 (12)	<0.001
Left main	16,211 (4.2)	4,422 (4.1)	2,959 (4.0)	2,834 (4.1)	3,213 (4.5)	2,783 (4.1)	<0.001
Target vessel
RCA	130,262 (33)	35,714 (34)	24,453 (33)	22,857 (33)	23,930 (34)	23,308 (34)	0.01
LMCA and/or LAD	204,398 (53)	55,981 (53)	37,876 (52)	35,790 (52)	38,159 (54)	36,592 (53)	<0.001
LCX	95,475 (25)	26,517 (25)	18,043 (25)	15,989 (23)	17,849 (25)	17,077 (25)	<0.001
Antithrombotic agents given at time of PCI
Antiplatelet agents	357,447 (92)	97,149 (91)	65,072 (89)	63,565 (92)	67,774 (95)	63,887 (93)	<0.001
Aspirin	345,703 (89)	93,953 (88)	62,893 (86)	61,652 (89)	65,597 (92)	61,608 (90)	<0.001
Clopidogrel	135,698 (35)	37,721 (35)	24,565 (34)	26,661 (39)	24,292 (34)	22,459 (33)	<0.001
Prasugrel	191,263 (49)	50,054 (47)	35,993 (49)	31,079 (45)	37,380 (52)	36,757 (54)	<0.001
Ticagrelor	468 (0.1)	219 (0.2)	94 (0.1)	68 (0.1)	53 (0.1)	34 (0.05)	<0.001
Anticoagulant agents	26,309 (6.8)	6,694 (6.3)	4,950 (6.8)	4,962 (7.2)	5,129 (7.2)	4,574 (6.7)	<0.001
Warfarin	10,378 (2.7)	2,793 (2.6)	1,972 (2.7)	1,805 (2.6)	2,014 (2.8)	1,794 (2.6)	<0.001
Dabigatran	1,410 (0.4)	348 (0.3)	260 (0.4)	297 (0.4)	236 (0.3)	269 (0.4)	0.01
Rivaroxaban	5,004 (1.3)	1,326 (1.2)	834 (1.1)	907 (1.3)	1,026 (1.4)	911 (1.3)	<0.001
Apixaban	5,388 (1.4)	1,260 (1.2)	1,078 (1.5)	1,110 (1.6)	1,037 (1.5)	903 (1.3)	<0.001
Edoxaban	4,128 (1.1)	1,046 (1.0)	824 (1.1)	799 (1.2)	795 (1.1)	664 (1.0)	0.051
Dual antiplatelet therapy	316,061 (81)	84,998 (80)	58,456 (80)	55,841 (81)	59,763 (84)	57,003 (83)	<0.001
Triple therapy*	19,205 (4.9)	4,623 (4.3)	3,727 (5.1)	3,550 (5.1)	3,951 (5.5)	3,354 (4.9)	<0.001
Therapeutic devices
Balloon	335,129 (86)	95,165 (89)	61,721 (84)	60,228 (87)	57,895 (81)	60,120 (88)	<0.001
BMS	3,169 (0.81)	764 (0.72)	657 (0.90)	527 (0.76)	817 (1.1)	404 (0.59)	<0.001
DES	329,590 (85)	89,029 (84)	61,966 (85)	58,776 (85)	60,893 (86)	58,926 (86)	<0.001
Rotational atherectomy	15,772 (4.1)	5,108 (4.8)	2,733 (3.7)	2,436 (3.5)	2,906 (4.1)	2,589 (3.8)	<0.001
DCA	2,256 (0.58)	746 (0.70)	619 (0.84)	446 (0.65)	198 (0.28)	247 (0.36)	<0.001

Values are expressed as means ± standard deviation or numbers (%). Chronic kidney disease was defined as the presence of proteinuria, and/or a serum creatinine level ≥1.3 mg/dL, and/or an estimated glomerular filtration rate level ≤60 mL/min per 1.73 m2.

BMS, bare metal stent; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; DCA, directional coronary atherectomy; DES, drug-eluting stent; LAD, left anterior descending artery; LCX, left circumflex artery; LMCA, left main coronary artery; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.

*Triple therapy indicates an anticoagulant agent plus dual antiplatelet therapy.

Table 2

Institutional characteristics.

	Overall	Very low mortality	Low mortality	Medium mortality	High mortality	Very high mortality	P value
Number of institutions	718	144	143	144	143	144
Number of PCI cases	452 (268–702)	634 (461–875)	429 (294–650)	420 (244–630)	398 (204–610)	383 (210–672)	<0.001
Number of institutions by PCI cases per year							<0.001
<100 cases	116 (16)	1 (0.7)	17 (12)	28 (19)	35 (24)	35 (24)
100 to <500 cases	534 (74)	117 (81)	117 (81)	107 (74)	95 (66)	98 (68)
500 to <1000 cases	60 (8.4)	23 (16)	8 (5.6)	9 (6.3)	10 (6.9)	10 (6.9)
≥1000 cases	8 (1.1)	3 (2.1)	1 (0.7)	0 (0.0)	3 (2.1)	1 (0.7)
In-hospital mortality, %
Expected mortality	1.0 (0.7–1.4)	1.1 (0.8–1.3)	1.1 (0.8–1.5)	1.0 (0.8–1.4)	1.0 (0.7–1.4)	0.9 (1.6–1.2)	0.004
Crude mortality	0.9 (0.4–1.7)	0.2 (0.2–0.3)	0.5 (0.4–0.8)	1.0 (0.7–1.2)	1.4 (1.0–2.0)	2.4 (1.6–3.3)	<0.001
Risk-adjusted mortality	0.9 (0.5–1.7)	0.2 (0.2–0.3)	0.5 (0.5–0.6)	0.9 (0.8–1.0)	1.5 (1.3–1.7)	2.6 (2.2–3.4)	<0.001

Values are expressed as medians (interquartile range) or numbers (%).

PCI, percutaneous coronary intervention.

Bleeding complications occurred in 1,535 cases overall (0.39%) and modestly increased from 0.27% in very low mortality hospitals to 0.57% in very high mortality hospitals (OR, 1.95; 95% CI, 1.58–2.39; Table 3A). Mortality in patients who developed bleeding complications is summarized in Table 3B. Of the 1,535 patients with overall bleeding complications, 270 (17.6%) died during hospitalization. Unlike the trend for incidence of bleeding complications, in-hospital mortality after bleeding complications increased markedly by quintile (Fig 2) and was 6-fold higher in very high mortality hospitals compared to very low mortality hospitals (29.0% vs. 4.8%; OR, 12.2; 95% CI, 6.90–21.7). Incidence of bleeding at the access site (0.21%) and non-access sites (0.19%) was similar. Incidence of bleeding complications at non-access sites tended to be higher in the higher mortality hospitals: the bleeding at non-access sites was 3 times higher in very high mortality hospitals than very low mortality hospitals (0.34% vs. 0.098%; OR, 3.17; 95% CI, 2.41–4.16). However, this tendency was weaker for access site bleeding complications (0.24% vs. 0.18%; OR, 1.33; 95% CI, 1.03–1.71; Table 3A). In-hospital mortality was twice as high after bleeding complications at non-access sites (25.4%) than after bleeding complications at the access site (11.1%). Mortality after bleeding complications differed greatly between very high and very low mortality hospitals for both bleeding complications at non-access sites (35.2% vs. 6.7%; OR, 17.7; 95% CI, 8.07–38.8) and the access site (20.9% vs. 3.7%; OR, 7.52; 95% CI, 3.29–17.2; Table 3B).

Table 3

Incidence of bleeding complications and in-hospital death in patients who developed bleeding complications.

	Overall	Very low mortality	Low mortality	Medium mortality	High mortality	Very high mortality	P for trend
(A) Incidence of bleeding complications
Overall	1,535 (0.39)	291 (0.27)	245 (0.33)	322 (0.47)	284 (0.40)	393 (0.57)	<0.001
		Reference	1.25 (1.01–1.55)	1.72 (1.39–2.12)	1.57 (1.27–1.94)	1.95 (1.58–2.39)
Non-access site	744 (0.19)	104 (0.098)	98 (0.13)	160 (0.23)	149 (0.21)	233 (0.34)	<0.001
		Reference	1.36 (1.00–1.85)	2.34 (1.76–3.11)	2.25 (1.69–3.00)	3.17 (2.41–4.16)
Access site	829 (0.21)	190 (0.18)	161 (0.22)	170 (0.25)	145 (0.20)	163 (0.24)	0.02
		Reference	1.28 (0.99–1.64)	1.40 (1.09–1.80)	1.21 (0.94–1.57)	1.33 (1.03–1.71)
(B) In-hospital death in patients who developed bleeding complications
Overall	270 (17.6)	14 (4.8)	30 (12.2)	52 (16.1)	60 (21.1)	114 (29.0)	<0.001
		Reference	3.10 (1.62–5.94)	5.63 (3.07–10.3)	6.64 (3.65–12.1)	12.2 (6.90–21.7)
Non-access site	189 (25.4)	7 (6.7)	24 (24.4)	35 (21.9)	41 (27.5)	82 (35.2)	<0.001
		Reference	4.96 (2.11–11.7)	7.61 (3.34–17.3)	9.06 (4.01–20.5)	17.7 (8.07–38.8)
Access site	92 (11.1)	7 (3.7)	10 (6.2)	19 (11.2)	22 (15.2)	34 (20.9)	<0.001
		Reference	2.07 (0.78–5.49)	4.15 (1.72–9.99)	4.76 (2.01–11.3)	7.52 (3.29–17.2)

The upper row of each line shows the number of events (%) and the lower row shows the odds ratio (OR) with 95% confidence interval (CI) in each quintile (calculated relative to very low mortality hospitals).

Fig 2

Incidence of overall bleeding complications and in-hospital mortality in patients who developed bleeding complications.

When divided hospitals into quintiles according to their risk-adjusted mortality, the bleeding complication rate increased modestly from 0.27% to 0.57% in very low to very high mortality hospitals. However, the mortality rate in patients who developed bleeding complications markedly increased from 4.8% to 29.0% in very low to very high mortality hospitals.

TFA was associated with an approximately 10-fold higher incidence of bleeding complications than TRA (0.61% vs. 0.065%). As shown in Fig 3A, TFA-related bleeding complications tended to occur more frequently in higher mortality hospitals. Incidence of TFA-related bleeding in very high and very low mortality hospitals was 0.76% and 0.44%, respectively. In contrast, incidence of TRA-related bleeding complications was relatively similar across quintiles. Mortality after bleeding complications was identical in the TFA and TRA groups (12%). Consistent with the main analysis results, mortality after TFA-related bleeding differed greatly between very high and very low mortality hospitals (22.5% vs. 3.0%), but the trend was weaker in the TRA-related bleeding group (20.5% vs. 7.1%; Fig 3B). Therefore, among TFA patients, the incidence of bleeding complications and subsequent death increased by quintile. Incidence of bleeding and subsequent death for very high and very low mortality hospitals was 0.17% and 0.013%, respectively. This trend was also observed in TRA patients, but the absolute number of events was extremely low. In these patients, incidence of bleeding and subsequent death for very high and very low mortality hospitals was 0.016% and 0.0043%, respectively (Fig 3C).

Fig 3

Comparison between transfemoral and transradial access.

Hospitals were stratified into quintiles according to risk-adjusted mortality. The blue and green bars indicate the following rates for transfemoral access (TFA) and transradial access (TRA), respectively: (A) Incidence of bleeding complications. (B) Mortality in patients who developed bleeding complications. (C) Incidence of bleeding complications and subsequent in-hospital death.

Discussion

This study examined 388,866 PCI procedures performed at 718 hospitals and registered within the J-PCI registry. Our main findings are as follows: (i) institutional variation in in-hospital mortality after PCI was associated with procedure-related bleeding complications; (ii) this variation was mainly caused by differences in mortality of patients who developed bleeding complications rather than crude incidence of bleeding complications; (iii) this trend was consistently observed in both bleeding complications from non-access and access site.

In-hospital mortality after PCI varies widely between hospitals [12-14]. Our results are in agreement, as in-hospital mortality in this study ranged from 0.22% to 2.46% in very low to very high mortality hospitals. Incidence of PCI-related bleeding events has also been reported to vary widely across institutions [18]. However, we found only modest variation across the studied hospitals. In contrast, mortality after bleeding complications varied significantly. Failure to rescue, defined as death in patients who develop a major procedural complication, is well established as an indicator of surgical quality of care [19]. In addition, institutional differences in failure-to-rescue rates underlie the wide variation in in-hospital mortality after surgery [20, 21]. The results obtained from our study were consistent with these reports, this concept may be applied to PCI (i.e., institutional differences in failure-to-rescue rates after bleeding complications underlie the wide variation in in-hospital mortality after PCI).

In this study, a tendency that variation in in-hospital mortality was mainly driven by difference in mortality after bleeding complications was consistently observed in both those from access and non-access site. Moreover, among access site-related bleeding complications, TRA and TFA showed a similar trend. Previous studies revealed that TRA for PCI is associated with lower risk of complications than TFA [3-5]. Similarly, our study showed a 10-fold lower incidence of bleeding complications for TRA compared to TFA. However, given that higher mortality hospitals had higher mortality rate after bleeding complications even in patients treated via TRA, appropriate management after bleeding complications will be required regardless method of access. Of note, higher mortality hospitals used TRA more frequently. In those hospitals, TFA patients were more prone to develop bleeding complications as well as subsequent in-hospital death. Similarly, in the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) trial, prognosis of TFA patients was worse in institutions with higher use of TRA. The incidence of net ischemic and bleeding events in TFA patients according to low, intermediate, and high use of TRA was 8.9%, 9.5%, and 17.1% [5]. The worse prognosis in institutions that more frequently use TRA might be caused by increased incidence of TFA-related adverse events.

This study has several important limitations. First, the definition of bleeding complications in the current study was different from standardized definitions, such as the definition from Thrombolysis in Myocardial Infarction trial [22], the Global Use of Strategies to Open Occluded Arteries trial [23], or the Bleeding Academic Research Consortium [24]. This may have underestimated the actual incidence of bleeding complications in this study. Second, we cannot determine the causality between bleeding complications and death during hospitalization. However, failure to rescue, defined by all-cause death after major perioperative complications, is well established as an indicator of the surgical quality of care [19]. The results in our study were equivalent to these reports, and this concept may be applied to PCI. Third, blood transfusion practices and thresholds vary between hospitals [25], which may have affected our results. Fourth, the number of variables in the J-PCI registry is limited and measured or unmeasured confounders were present. Although we used a logistic regression model to reduce potential confounding, we cannot completely eliminate this limitation. Finally, the quality of the database used in this study is a significant issue. However, data in the J-PCI registry are audited regularly to ensure accuracy.

In conclusion, institutional variation in in-hospital mortality after PCI was associated with procedure-related bleeding complications, and this variation was largely driven by differences in mortality after bleeding complications. These findings underscore the importance of efforts toward reducing not only bleeding complications but also, even more importantly, subsequent mortality once they have occurred. Further study is warranted on strategies for enabling improvement of clinical outcomes after bleeding complications.

22 Oct 2021

PONE-D-21-20850Variation in in-hospital mortality and its association with percutaneous coronary intervention-related bleeding complications: A report from nationwide registry in JapanPLOS ONE

Dear Dr. Nakagawa,

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PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

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

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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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: Sawayama and colleagues have demonstrated a prognostic value of PCI-related bleeding complications. The study is of interest and timely, albeit with the inherent limitations of an observational retrospective study, as the need for more studies on the role of PCI-related bleeding is needed.

I have a few questions/clarifications that will be helpful in making it a stronger study:

1) The definition of bleeding complications in the current study was different from standardized definitions as the authors highlighted, but it is not clear how many patients had a fatal bleeding.

2) Haemoglobin and platelet values are not reported as the definition of Chronic Kidney Disease (eFGR < 60 ?).

3) It is not reported what type of intensive care unit (ICU) was present (cardiac surgery, neurosurgery) in the different hospitals: different ICUs means different types of treatment.

4) I think it is important to know what kind of antiplatelet agents and what kind of anticoagulant agents were used; moreover, how many patients were in triple (DAPT + anticoagulant) antithrombotic therapy?

5) It is not reported the use of intravascular imaging (IVUS, OCT).

6) It would be interesting to know if and which mechanical support (IABP, ECMO, Impella) was used in cardiogenic shock patients and how it could affect bleeding complications.

Reviewer #2: This paper reports results from the Japanese national PCI registry on bleeding complications from 388,866 procedures performed at 718 hospitals between 2017-2018. The authors found substantial variability in bleeding complications and mortality among the centers and provided some insights into associations of complications with center characteristics.

The paper adds valuable information on complications from PCI in contemporary practice. The authors acknowledge the study limitations, i.e., observational study design, which limits conclusions on causal relationships. Foremost, the authors should be careful ascribing all issues to bleeding complications since the latter, of course, may just be a result from vascular injury not from excessive anticoagulation. The authors do address this to some extent by differentiating access site vs. other complications but nevertheless, further information is needed to understand the nature of complications leading to bleeding.

**********

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Reviewer #1: No

Reviewer #2: No

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9 Nov 2021

Response to the Reviewer #1

1) The definition of bleeding complications in the current study was different from standardized definitions as the authors highlighted, but it is not clear how many patients had a fatal bleeding.

Response

We appreciate the comment from the reviewer. The J-PCI registry’s definition of bleeding complications is largely equivalent to Bleeding Academic Research Consortium (BARC) 3A-C or above. Previous studies demonstrated that the ratio of fatal bleeding among patients with BARC 3A-C or above was approximately 10% (Vranckx P, et al. J Am Coll Cardiol 2016, Ratcovich H, et al. Am J Cardiol 2021, Gargiulo G, et al. J Am Coll Cardiol 2018). Unfortunately, direct information on fatal bleeding was not available on the registry, but we believe the rate of fatal bleeding would be roughly the same for our study. We acknowledge that the causality between bleeding complications and in-hospital death cannot be proven; thus, we have added the descriptions in the Discussion section:

2) Haemoglobin and platelet values are not reported as the definition of Chronic Kidney Disease (eFGR < 60 ?).

Response

We had no data for platelet values in the J-PCI registry, but have added hemoglobin levels in Table 1 in the revised manuscript. CKD was defined as the presence of proteinuria, and/or a serum creatinine level ≥1.3 mg/dL, and/or an estimated glomerular filtration rate level ≤60 mL/min/1.73 m2. Based on these points, we have modified the descriptions in the Results section.

3) It is not reported what type of intensive care unit (ICU) was present (cardiac surgery, neurosurgery) in the different hospitals: different ICUs means different types of treatment.

Response

We agree it is also important in dealing with clinical outcomes such as in-hospital death. In Japan, the ICU is a place to treat patients with critical acute dysfunction, regardless of internal medicine or surgery. According to the report from Ministry of Health, Labour and Welfare in 2017 (https://www.e-stat.go.jp/dbview?sid=0003289748), the number of hospitals advocating ICU, coronary or cardiac care unit (CCU), and stroke care unit (SCU) is 713, 287, and 162, respectively. Other high care units, such as neurosurgical care unit, are practically very few and unreported. Some hospitals have multiple care units (e.g., ICU and SCU, etc), whereas others only have an ICU. Since the name varies from hospital to hospital, the J-PCI registry collects data under the name ICU. There is no data, but it is assumed that most of them mean CCU.

4) I think it is important to know what kind of antiplatelet agents and what kind of anticoagulant agents were used; moreover, how many patients were in triple (DAPT + anticoagulant) antithrombotic therapy?

Response

We agree it is important in addressing the clinical outcome of bleeding complications, and we have added the information about status of antithrombotic therapy in Table 1 in the revised manuscript.

5) It is not reported the use of intravascular imaging (IVUS, OCT).

Response

We have no data for imaging devices for PCI in the J-PCI registry, but referring to studies from Japan in the same period (Watanabe H, et al. JAMA 2019, Nakamura M, et al. Circ J 2020), it is estimated that imaging devices were used in more than 80% of PCI cases during this period. Moreover, the real-world use of IVUS was associated with reduction in coronary dissection, but not bleeding complications (Kuno T, et al. Heart an Vessels 2019). Therefore, the impact of the use of imaging devices on bleeding complications or subsequent fatal events may not be significant.

6) It would be interesting to know if and which mechanical support (IABP, ECMO, Impella) was used in cardiogenic shock patients and how it could affect bleeding complications.

Response

We also recognize that the data on the use of mechanical support against cardiogenic shock would help us further understand bleeding complications or subsequent fatal events. However, the J-PCI registry during this study periods does not have sufficient data on these mechanical devices for cardiogenic shock (the registry became mandatory in the middle of 2018).

Response to the Reviewer #2

Reviewer #2

This paper reports results from the Japanese national PCI registry on bleeding complications from 388,866 procedures performed at 718 hospitals between 2017-2018. The authors found substantial variability in bleeding complications and mortality among the centers and provided some insights into associations of complications with center characteristics. The paper adds valuable information on complications from PCI in contemporary practice. The authors acknowledge the study limitations, i.e., observational study design, which limits conclusions on causal relationships. Foremost, the authors should be careful ascribing all issues to bleeding complications since the latter, of course, may just be a result from vascular injury not from excessive anticoagulation. The authors do address this to some extent by differentiating access site vs. other complications but nevertheless, further information is needed to understand the nature of complications leading to bleeding.

Response

We appreciate the Reviewer’s helpful comments and agree that we should be careful about ascribing all issues to bleeding complications. We acknowledge that the causality between bleeding complications and in-hospital death cannot be proven. First of all, we had no data to what extent bleeding complications were fatal. The J-PCI registry’s definition of bleeding complications is largely equivalent to Bleeding Academic Research Consortium (BARC) 3A-C or above. Previous studies demonstrated that the ratio of fatal bleeding among patients with BARC 3A-C or above was approximately 10% (Vranckx P, et al. J Am Coll Cardiol 2016, Ratcovich H, et al. Am J Cardiol 2021, Gargiulo G, et al. J Am Coll Cardiol 2018). Unfortunately, direct information on fatal bleeding was not available on the registry, but we believe the rate of fatal bleeding would be roughly the same for our study. Second, failure to rescue, defined by all-cause death after major perioperative complications, is well established as an indicator of the surgical quality of care (Silber JH, et al. Med Care 1992). Moreover, institutional differences in failure-to-rescue rates underlie the wide variation in in-hospital mortality after surgery (Ghaferi AA, et al. N Engl J Med 2009). We think that the results in our study were equivalent to these reports, and this concept may be applied to PCI. Third, hemoglobin level and status of antithrombotic agent use (i.e., whether DAPT or Triple therapy) at the time of index PCI are crucial factors when considering bleeding complications. Based on these points, we have added the descriptions in the Results and Discussion sections.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

1 Dec 2021

Variation in in-hospital mortality and its association with percutaneous coronary intervention-related bleeding complications: A report from nationwide registry in Japan

PONE-D-21-20850R1

Dear Dr. Nakagawa,

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.

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Kind regards,

Marcelo Arruda Nakazone, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. 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

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. 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: No

**********

5. 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

**********

6. 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: Well done!

I think prognostic value of PCI-related bleeding complications remains a "hot topic" and Japanese national PCI registry

could be very useful in the future.

Reviewer #2: The authors' responses are satisfactory and added explanations as well as additional text acknowledging limitations.

**********

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

3 Dec 2021

PONE-D-21-20850R1

Variation in in-hospital mortality and its association with percutaneous coronary intervention-related bleeding complications: A report from nationwide registry in Japan

Dear Dr. Nakagawa:

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.

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on behalf of

Professor Marcelo Arruda Nakazone

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