Incidence, Factors, and Prognostic Impact of Re-Exploration for Bleeding After Continuous-Flow Left Ventricular Assist Device Implantation　― A Japanese Single-Center Study ―

Abstract

Background: Continuous-flow left ventricular assist device (CF-LVAD) substantially improves survival in endstage heart failure patients. However, bleeding complications are common after CF-LVAD implantation and in some cases, re-exploration for bleeding is needed. We aimed to investigate the incidence, timing, and risk factors of bleeding requiring re-exploration after CF-LVAD implantation.

Methods and Results: We retrospectively reviewed 162 consecutive patients (age 43±13 years, 71% men) who underwent CF-LVAD implantation (HeartMateII 119, Jarvik2000 15, HVAD 13, EVAHEART 10, DuraHeart 5) from January 2012 to June 2019. During follow-up [median 662 days, interquartile range (IQR) 364–1,116 days], 35 (21.6%) experienced re-exploration for bleeding. The median timing of re-exploration was 6 (IQR 1–10) days. In the multivariate logistic regression analysis, postoperative platelet count was an independent predictor for re-exploration for bleeding after CF-LVAD implantation (per 10⁴/μL: odds ratio 0.83, 95% confidence interval 0.74–0.93, P=0.002). Patients who experienced re-exploration for bleeding had a significantly worse survival rate than patients who did not (at 4 years, 73.6% vs. 90.1%, P=0.039).

Conclusions: Re-exploration for bleeding is prevalent after CF-LVAD implantation, especially in patients with low postoperative platelet counts. As bleeding requiring re-exploration is associated with poor prognosis, risk stratification using the postoperative platelet count may be beneficial for these patients.

Advanced heart failure (HF) is a life-threatening condition, for which the 2-year survival is only 8% with optimal medical therapy.¹ The continuous-flow left ventricular device (CF-LVAD) has revolutionized the management of advanced HF, being associated with a 2-year survival rate exceeding 70% in these patients.² However, numerous complications still occur after CF-LVAD implantation, of which bleeding was the most common in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS),³ and accounting for one-third of the causes of re-hospitalization after CF-LVAD implantation.⁴

The recent Japanese registry for Mechanically Assisted Circulatory Support (J-MACS) reported that early bleeding events after CF-LVAD implantation are the most frequent complication within 30 days, and many of these early bleeding events arre reported to have a surgical cause and thus require re-exploration.⁵ Re-exploration for bleeding may delay recovery, prolong the length of stay in the intensive care unit, and cause hemodynamic instability. However, studies evaluating the risk factors and clinical effect of re-exploration for bleeding after CF-LVAD implantation are limited,⁶ maybe because the main focus has been on late gastrointestinal and neurological bleeding events.^7,8 Therefore, we aimed to investigate the incidence, timing, risk factors, and clinical effect of re-exploration for bleeding after CF-LVAD implantation.

Methods

Patient Selection

We retrospectively reviewed all consecutive patients who were implanted with a CF-LVAD at the National Cerebral and Cardiovascular Center between January 2012 and June 2019. In this study, only patients with an implantable CF-LVAD were included, and patients with a paracorporeal LVAD were excluded. In Japan, only patients younger than 65 years can be listed as a heart transplant candidate, and only implantable CF-LVAD has been approved to use as a bridge to transplantation (BTT) by the national insurance system. For these reasons, patients who are not listed on the Japanese heart transplantation waiting list but need immediate mechanical circulatory support should undergo paracorporeal LVAD implantation, and only after approval for heart transplantation listing can these patients undergo CF-LVAD implantation (bridge-to-bridge; BTB). BTB patients with stable hemodynamics during CF-LVAD implantation are classified as INTERMACS profile 3. All the study patients were younger than 65 years at the time of heart transplantation listing, which is the upper age limit of indication for heart transplantation in the Japanese heart transplantation program.

This study was approved by the Institutional Review Board of the National Cerebral and Cardiovascular Center and followed the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation (IRB No. M30-026-3). A waiver of consent was obtained due to the retrospective nature of the study.

The primary outcome of the study was re-exploration for bleeding, which was defined as the need for surgical hemostasis due to bleeding related to the CF-LVAD implantation procedure. The indication for re-exploration was decided by the Heart Team consisting of cardiovascular surgeons, cardiologists, and intensivists, based on the following criteria: hemodynamic instability and the need for inotropes or vasopressors due to tamponade/pericardial effusion (diagnosed by ultrasonography or computed tomography); reduced CF-LVAD flow despite optimal volume status; and hemothorax or persistent, excessive thoracic tube production. As death and re-operation for reasons other than bleeding were competing risks in this analysis, patients were censored at the time of death or re-operation for other reasons. The secondary outcome was all-cause death.

Data Collection and Protocol

All data on patients’ characteristics and clinical outcomes were extracted by medical record review. Preoperative laboratory, echocardiographic, and right heart catheterization data were collected for the day nearest to the CF-LVAD implantation day. The median period from echocardiography and right heart catheterization to CF-LVAD implantation was 8 (IQR 3–18) and 13 (IQR 4–29) days, respectively. Postoperative laboratory data were obtained for all patients on admission to the intensive care unit. Information regarding anticoagulation therapy was included if relevant drugs were administered within 7 days before CF-LVAD implantation.

After CF-LVAD implantation, unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH), warfarin, and aspirin were started according to the institutional protocol as follows. For patients without persistent bleeding, begin bridging with UFH or LMWH within 48 h of device implantation with partial thromboplastin time (PTT) goal of 40–45 s in the first 48 h, followed by up-titration to PTT of 50–60 s by 96 h. The presence of persistent bleeding was decided by the Heart Team based on absence of pericardial effusion, reduced CF-LVAD flow despite optimal volume status, hemothorax or persistent, excessive thoracic tube production. Warfarin was initiated within 48 h to obtain prothrombin time-international normalized ratio (PT-INR) goal of 2.0–2.5 (HeartMateII [Abbott Laboratories, Chicago, IL, USA]), 2.0–3.0 (Jarvik2000 [Jarvik Heart, Inc., New York, USA], HVAD [HeartWare^®, Medtronic, Minnesota, USA], and DuraHeart [Terumo Heart Inc., Ann Arbor, MI, USA]), and 2.5–3.5 (EVAHEART [Sun Medical, Nagano, Japan]) by postoperative days 5–7; at this time, UFH or LMWH may be discontinued. When there was no evidence of bleeding, aspirin therapy (100 mg daily) was initiated 1–5 days after CF-LVAD implantation. Chest drainage tubes were placed in the operation room at the end of the operation. If drained fluid volume became less than 100 mL/day, removal of each chest drainage tube was considered.

Statistical Analysis

Categorical variables are described as frequency (percentage), and continuous variables are described as mean±standard deviation (SD) or median (interquartile range [IQR]) as appropriate. All categorical variables were compared using Pearson’s chi-squared test or Fisher’s exact test as appropriate. For continuous variables, the groups were compared with the unpaired 2-tailed Student’s t-test or Wilcoxon rank-sum test based on the distribution. Kaplan-Meier curves were used to assess the incidence and timing of re-exploration for bleeding, with patients censored at the time of death or cardiac surgeries other than re-exploration of bleeding. In addition, Kaplan-Meier curves were used to evaluate the prognostic effect of bleeding requiring re-exploration, stratified by re-exploration for bleeding and compared by log-rank test. Univariate and multivariate logistic regression models were used to assess the predictors of re-exploration for bleeding. The multivariate logistic regression model included all variables of which the P value was <0.10 in the exploratory univariate analyses. A receiver-operating characteristic (ROC) curve was constructed to assess the ability of the independent variables to predict re-exploration for bleeding. For all analyses, P<0.05 was considered significant. All statistical analyses were conducted using JMP (version 9, SAS Institute Inc., Cary, NC, USA) and SAS (version 9.4, SAS Institute Inc.).

Results

Cohort and Patient Characteristics

From January 2012 to June 2019, 163 patients underwent CF-LVAD implantation (HeartMateII 119, Jarvik2000 15, HVAD 14, EVAHEART 10, DuraHeart 5) as BTT (Figure 1; Table 1). During a median follow-up period of 659 (IQR 363–1,116) days, 35 patients required re-exploration for bleeding. The mean age was 43±13 years, and 116 patients (71%) were men. The primary cardiac disease etiology was dilated cardiomyopathy in 89 patients (55%), followed by ischemic heart disease in 24 patients (15%). The numbers of patients in the INTERMACS profiles at CF-LVAD implantation are shown in Table 1. Among the study cohort, 47 were supported with paracorporeal LVAD, 2 with intra-aortic balloon pumping (IABP) and extracorporeal membrane oxygenation (ECMO), and 1 with IABP at CF-LVAD implantation. The mean preoperative platelet count was 19.4±7.7×10⁴/μL, and the mean postoperative platelet count was 12.6±4.9×10⁴/μL.

Figure 1.

Study flow diagram. From January 2012 to June 2019, 163 patients underwent CF-LVAD implantation as BTT. During the follow-up period, 35 patients underwent re-exploration for bleeding. BTT, bridge to transplant; CF-LVAD, continuous-flow left ventricular assist device.

Table 1. Patients’ Characteristics

Characteristics	All patients (n=163)
Demographics
Age, years	43±13
Men	116 (71%)
Body surface area, m2	1.64±0.20
Body mass index, kg/m2	21.1±3.9
Clinical baseline
Hypertension	21 (13%)
Diabetes mellitus	44 (27%)
Smoking	86 (53%)
Ischemic etiology	24 (15%)
Prior cardiac surgery	68 (42%)
INTERMACS profile
1	3 (2%)
2	25 (15%)
3	125 (77%)
≥4	10 (6%)
IABP	3 (2%)
ECMO	2 (1%)
VAD (BTB)	47 (29%)
Antiplatelet medication	54 (33%)
Anticoagulation medication	128 (79%)
Preoperative laboratory data
Hemoglobin, g/dL	11.3±2.0
Platelet count, 104/mL	19.4±7.7
Bilirubin, mg/dL	0.9 (0.6–1.3)
BNP, pg/mL	458 (256–810)
Albumin, g/dL	3.7±0.6
eGFR, mL/min/1.73 m2	78.5±37.5
Preoperative echocardiography
LV diastolic diameter, mm	66±15
LVEF, %	18±9
Left atrial diameter, mm	42±11
Aortic valve regurgitation grade	0.4±0.4
Mitral valve regurgitation grade	1.7±1.2
Tricuspid valve regurgitation grade	1.3±0.8
Preoperative hemodynamics
Heart rate, beats/min	82±18
Mean BP, mmHg	70±11
PCWP, mmHg	19±10
Mean PAP, mmHg	28±12
RAP, mmHg	8±5
Cardiac index, L/min/m2	2.11±0.64
RVSWI, mmHg/L/m2	911±704
Perioperative data
Operation time, min	304±126
CPB time, min	97±48
RBC transfusion during operation, units	8 (4–12)
Platelet transfusion during operation, units	30 (20–40)
FFP transfusion during operation, units	16 (10–27)
Concomitant RVAD implantation	11 (7%)
Concomitant other cardiac surgery	72 (44%)
AVP or AVR	17 (10%)
TAP	42 (26%)
Other	27 (17%)
LVAD model
HeartMateII	119 (73%)
Jarvik2000	15 (9%)
HVAD	14 (9%)
EVAHEART	10 (6%)
DuraHeart	5 (3%)
Postoperative factors
Postoperative platelet count, 104/mL	12.6±4.9
RBC transfusion within 48 h of operation, units	30 (20–40)
Platelet transfusion within 48 h of operation, units	40 (20–60)
FFP transfusion within 48 h of operation, units	30 (20–50)
Aspirin initiation, day	1 (1–2)
Warfarin initiation, day	1 (1–2)
Heparin initiation, day	1 (1–2)

AVP, aortic valvuloplasty; AVR, aortic valve replacement; BNP, B-type natriuretic peptide; BP, blood pressure; BTB, bridge-to-bridge; CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; FFP, fresh frozen plasma; IABP, intra-aortic balloon pumping; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; LVEF, left ventricular ejection fraction; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; RBC, red blood cell; RVSWI, right ventricle stroke work index; TAP, tricuspid annuloplasty; VAD, ventricular assist device.

Incidence and Timing of Re-Exploration for Bleeding

The Kaplan-Meier curves describing the cumulative incidence of re-exploration for bleeding after CF-LVAD implantation are shown in Figure 2. As stated, 35 patients underwent re-exploration for bleeding during the follow-up period. The median period from CF-LVAD implantation to re-exploration for bleeding was 6 (IQR 1–10) days. The maximum time from CF-LVAD implantation to re-exploration for bleeding was 34 days, and no patients required re-exploration for bleeding after postoperative day 35. The cumulative incidence rate of re-exploration for bleeding at days 7, 14, 28, and 35 was 12.3%, 17.8%, 20.9%, and 21.6%, respectively. There were no significant difference in incidence of re-exploration between each LVAD systems, as described in Supplementary Table 1.

Figure 2.

Cumulative incidence of re-exploration for bleeding in the (A) days and (B) months after continuous-flow left ventricular assist device (CF-LVAD) implantation.

Factors Associated With Re-Exploration for Bleeding

The univariate and multivariate logistic regression analyses of re-exploration for bleeding are shown in Table 2 and Table 3. In the univariate analysis, postoperative platelet count was significantly associated with re-exploration for bleeding [per 10⁴/μL: odds ratio [OR] 0.82, 95% confidence interval (95% CI) 0.74–0.91, P<0.001]. Preoperative ECMO usage was not significantly associated with re-exploration for bleeding. Concerning postoperative antiplatelet and anticoagulation medications, because these were administered in most cases, except in patients who underwent re-exploration before the initiation of these treatments, we assessed the influence of these medications on re-exploration for bleeding using the day of initiating them. No significant relationship was found between the initiation day of these medications and re-exploration for bleeding. After multivariate adjustment, postoperative platelet count was significantly associated with re-exploration for bleeding (per 10⁴/μL: OR 0.82, 95% CI 0.74–0.92, P<0.001). An incremental risk was found in re-exploration for bleeding with increasing category of postoperative platelet count, with 67% of patients with postoperative platelet count <5.0×10⁴/μL requiring re-exploration for bleeding (Figure 3). ROC curve analysis for postoperative platelet count as a risk factor of re-exploration for bleeding found that postoperative platelet <11.0×10⁴/μL had a sensitivity of 68.6% and a specificity of 70.3% (area under curve 0.735) (Figure 4). Univariate linear regression analysis for postoperative platelet count are described in Supplementary Table 2.

Table 2. Univariate Logistic Regression Analysis of Re-Exploration for Bleeding

Characteristics	Univariate OR	95% CI	P value
Demographics
Age, years	1.00	0.97–1.03	0.893
Men	1.22	0.52–2.85	0.646
Body surface area, m2	1.54	0.24–10.03	0.649
Body mass index, kg/m2	1.02	0.93–1.12	0.649
Clinical baseline
Hypertension	0.84	0.26–2.69	0.772
Diabetes mellitus	1.11	0.48–2.54	0.813
Smoking	1.69	0.79–3.65	0.180
Ischemic etiology	0.74	0.24–2.34	0.608
Prior cardiac surgery	1.43	0.67–3.02	0.355
INTERMACS profile	1.55	0.88–2.72	0.131
IABP	1.85	0.16–21.05	0.619
ECMO	3.74	0.23–61.27	0.356
VAD (BTB)	1.39	0.62–3.08	0.423
Antiplatelet medication	1.47	0.68–3.18	0.331
Anticoagulation medication	1.12	0.44–2.83	0.811
Preoperative laboratory data
Hemoglobin, g/dL	1.04	0.86–1.25	0.707
Platelet count, 104/mL	0.95	0.90–1.00	0.061
Bilirubin, mg/dL	1.19	0.78–1.82	0.432
BNP, 100 pg/mL	0.99	0.93–1.05	0.683
Albumin, g/dL	1.04	0.56–1.93	0.903
eGFR, mL/min/1.73 m2	1.00	0.99–1.01	0.378
Preoperative echocardiography
LV diastolic diameter, mm	1.00	0.97–1.02	0.877
LVEF, %	0.99	0.95–1.04	0.795
Left atrial diameter, mm	1.00	0.96–1.03	0.804
Aortic valve regurgitation grade	0.56	0.21–1.52	0.253
Mitral valve regurgitation grade	0.95	0.69–1.30	0.740
Tricuspid valve regurgitation grade	0.81	0.51–1.31	0.392
Preoperative hemodynamics
Heart rate, beats/min	0.99	0.97–1.01	0.328
Mean BP, mmHg	1.00	0.96–1.03	0.839
PCWP, mmHg	1.01	0.97–1.04	0.760
Mean PAP, mmHg	1.01	0.97–1.04	0.734
RAP, mmHg	1.01	0.94–1.08	0.797
Cardiac index, L/min/m2	0.86	0.47–1.57	0.623
RVSWI, 100 mmHg/mL/m2	1.01	0.96–1.06	0.714
Perioperative data
Operation time, min	1.00	1.00–1.00	0.843
CPB time, min	1.00	0.99–1.01	0.952
RBC transfusion during operation, units	1.00	0.96–1.04	0.881
Platelet transfusion during operation, units	1.00	0.98–1.02	0.864
FFP transfusion during operation, units	1.01	0.99–1.02	0.952
Concomitant RVAD implantation	0.80	0.17–3.89	0.784
Concomitant other cardiac surgery	0.81	0.38–1.72	0.575
AVP or AVR	0.76	0.21–2.82	0.686
TAP	0.66	0.27–1.66	0.381
Other	1.35	0.52–3.51	0.538
Postoperative factors
Postoperative platelet count, 104/mL	0.82	0.74–0.91	<0.001
RBC transfusion within 48 h of operation, units	1.01	0.99–1.03	0.196
Platelet transfusion within 48 h of operation, units	1.02	1.00–1.03	0.027
FFP transfusion within 48 h of operation, units	1.01	1.00–1.02	0.127
Aspirin initiation, day	0.95	0.82–1.11	0.538
Warfarin initiation, day	0.95	0.75–1.19	0.633
Heparin initiation, day	1.12	0.77–1.63	0.553

Abbreviations as in Table 1.

Table 3. Univariate and Multivariate Logistic Regression Analyses for Re-Exploration for Bleeding

	Univariate HR	95% CI	P value	Adjudged HR	95% CI	P value
Preoperative platelet count, 104/mL	0.95	0.90–1.00	0.061	0.99	0.93–1.05	0.766
Platelet transfusion within 48 h of operation, units	1.02	1.00–1.03	0.027	1.00	0.99–1.02	0.613
Postoperative platelet count, 104/mL	0.82	0.74–0.91	<0.001	0.83	0.74–0.93	0.002

CI, confidence interval; HR, hazard ratio.

Figure 3.

Incidence of re-exploration for bleeding according to postoperative platelet count.

Figure 4.

Receiver-operating characteristics curve analysis of the ability to predict re-exploration for bleeding using postoperative platelet count.

Survival of Patients With and Without Re-Exploration for Bleeding

During the median follow-up period of 659 (IQR 363–1,116) days, 35 patients required re-exploration for bleeding, 42 patients underwent heart transplantation (median 1,084 days, IQR 929–1,298 days), 1 patient had explantation of CF-LVAD for cardiac recovery and pump pocket infection, and 12 patients died. During the follow-up period, 14.3% and 5.5% of patients with and without re-exploration for bleeding, respectively, died. The Kaplan-Meier curves showing the survival of patients with and without re-exploration for bleeding are shown in Figure 5. Patients who underwent re-exploration for bleeding had lower survival rates than those who did not (at 4 years: 73.6% vs. 90.2%, P=0.038). The causes of death in the cohort are described in Supplementary Table 3.

Figure 5.

Survival of patients with and without bleeding requiring re-exploration. LVAD, left ventricular assist device.

Discussion

This study investigated the incidence, timing, and risk factors of re-exploration for bleeding after CF-LVAD implantation. Based on the results, we found the following: (1) the incidence of re-exploration for bleeding after CF-LVAD implantation was 21.6% and the median period from CF-LVAD implantation to re-exploration for bleeding was 6 (IQR 1–10) days; (2) postoperative platelet count was an independent predictor of re-exploration for bleeding after CF-LVAD implantation; and (3) patients who needed re-exploration for bleeding had significantly worse survival than patients who did not.

Early bleeding events are the most common complication in the early postoperative period after CF-LVAD implantation, and many bleeding events have a surgical cause and require re-exploration.⁵ In this study, the incidence of bleeding requiring re-exploration after CF-LVAD implantation was 21.6%, which was considerably higher than for other cardiac surgeries at 2.6–3.4%.^9–11 Several studies have reported the incidence of re-exploration for bleeding after CF-LVAD implantation. In the HeartMateII BTT trial, the incidence of bleeding requiring surgery was 31%.¹² In the HeartMateII vs. HeartMate XVE trial, the incidence rates of bleeding requiring surgery were 30% in HeartMateII patients and 15% in HeartMate XVE patients.¹³ In the HeartMate3 vs. HeartMateII trial, the incidence rates of bleeding requiring surgery were 10% with HeartMate3 and 14% with HeartMateII.¹⁴ Thus, the incidence of re-exploration for bleeding in our study was consistent with these previous studies in CF-LVAD patients. Although we did not have enough original data to explain why bleeding requiring re-exploration is very common after CF-LVAD implantation, early initiation of antiplatelet and anticoagulation therapy, platelet depletion, and acquired von Willebrand syndrome in CF-LVAD patients may be major reasons.¹⁵

Interestingly, the timing of re-exploration for bleeding in our study was considerably later than for other cardiac surgeries. Charalambous et al reported that among patients who required heart surgery, 95% underwent re-exploration within 24 (median, 5–6) h.¹¹ By contrast, the median period from CF-LVAD implantation to re-exploration for bleeding in the present study was 6 (IQR 1–10) days, and the maximum period from CF-LVAD implantation to re-exploration for bleeding was 34 days. A previous retrospective observational study focusing on CF-LVAD patients also reported that the median period from CF-LVAD implantation to early bleeding events was 6 (IQR 1–10) days. However, the definition of early bleeding in that study included not only bleeding events requiring surgical re-exploration but also transfusion with >4 units of packed red blood cells.⁶ Therefore, our study confirmed that re-exploration for bleeding could be needed even 24 h after CF-LVAD implantation surgery.

Moreover, we demonstrated that the postoperative platelet count is an independent predictor of re-exploration for bleeding after CF-LVAD implantation, and patients who needed re-exploration for bleeding had a significantly worse survival than patients who did not. However, as this study was retrospective and observational, it remains unclear whether low platelet count was the direct cause of re-exploration for bleeding or whether it solely reflects the underlying bleeding tendency. In addition, it is unclear whether re-exploration for bleeding is the direct cause of death and whether reducing the need for re-exploration for bleeding is beneficial for improving prognosis after CF-LVAD implantation. Therefore, further interventional studies evaluating whether aggressive platelet transfusion prevents re-exploration for bleeding and subsequently reduces the mortality rate are needed.

Study Limitations

First, this was a retrospective single-center study. Although we used a logistic model to adjust for multivariate analyses, a large-scale multicenter prospective study is recommended. Second, we did not have enough data regarding bleeding sites at re-exploration because of the retrospective nature of this study. Unfortunately, there were few records of the bleeding site in the medical records in our center. Third, we could not adequately evaluate the effect of antiplatelet and antithrombic therapy because the initiation and intensity of these therapies in the early postoperative period were highly influenced by the need for re-exploration for bleeding. Fourth, all cases of CF-LVAD implantation were performed with a full median sternotomy and classic chest tube drainage. Therefore, a further study addressing CF-LVAD implantation with less-invasive technique¹⁶ and active tube clearance drainage¹⁷ is needed. Finally, we did not evaluate platelet function or von Willebrand factor.

Conclusions

Re-exploration for bleeding is prevalent after CF-LVAD implantation, especially in patients with low postoperative platelet count. As bleeding events requiring re-exploration are associated with poor prognosis, risk stratification using postoperative platelet count may be beneficial for these patients.

Acknowledgments

We thanked for both centers; NCVC and Okayama University. This work was supported by Japan Society for the Promotion of Science KAKENHI (Grant No. 19K17580). We thank Editage (www.editage.com) for English language editing.

Disclosures

H.I. is a member of Circulation Journal ’ Editorial Team. The other authors declare no conflicts of interest associated with this manuscript.

IRB Information

Name of the ethics committee: An Institutional Review Board of the National Cerebral and Cardiovascular Center (reference no.: M30-026-3).

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-0238

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