Consensus Report on Destination Therapy in Japan　- From the DT Committee of the Council for Clinical Use of Ventricular Assist Device Related Academic Societies.

Destination therapy (DT) is the indication to implant a left ventricular assist device (LVAD) in a patient with stage D heart failure who is not a candidate for heart transplantation. The implantable LVAD has been utilized in Japan since 2011 under the indication of bridge to transplant (BTT). After almost 10 year lag, DT has finally been approved and reimbursed in May 2021 in Japan. To initiate the DT program in Japan, revision of the LVAD indication from BTT is necessary. Also, in-depth discussion of caregiver issues as well as end-of-life care is indispensable. For that purpose, we assembled a DT committee of multidisciplinary members in August 2020, and started monthly discussions via web-based communication during the COVID-19 pandemic. This is a summary of the consensus reached after 6 months' discussion, and we have included as many relevant topics as possible. Clinical application of DT has just started, and we are willing to revise this consensus to meet the forthcoming issues raised during real-world clinical experience.

Carbon Monoxide Diffusing Capacity Predicts Cardiac Readmission in Patients Undergoing Left Ventricular Assist Device Implantation in Japan.

Carbon monoxide diffusion capacity (DLCO) is impaired in heart failure patients; however, its clinical impact has not been well investigated in the left ventricular assist device (LVAD) population. We explored the predictive value of preoperative DLCO in the survival and cardiac readmission rates after LVAD implantation. Seventy-six patients who received continuous-flow LVAD as bridge-to-transplant therapy from November 2007 to September 2018 and underwent pulmonary function test before LVAD implantation were included. The primary study endpoints were death and readmission for heart failure or arrhythmia (cardiac readmission). Patients were stratified into two groups according to the percent of predicted DLCO (%DLCO). Pulmonary vascular resistance (PVR) was equivocal between the groups preoperatively, whereas the low DLCO group (%DLCO < 80%) showed significantly high PVR postoperatively. The mortality rate was not different between the groups. The 2 year cardiac readmission rate was 33.5% in the low DLCO group and 8.7% in the high DLCO group (%DLCO ≥ 80%) (P = 0.028). The %DLCO was associated with cardiac readmission in univariate and multivariate analyses (hazard ratio: 4.32; 95% CI: 1.50-15.9; P = 0.005). Low %DLCO was associated with high PVR postoperatively and was a risk factor for cardiac readmission after LVAD implantation.

Association between infectious event and de novo malignancy after heart transplantation.

The aim of the study was to investigate the incidence of and risk factors for de novo malignancy after heart transplantation (HTx) in a single center. We assessed 102 consecutive patients who received HTx and were followed-up in our center regularly for > 1 year from June 2006 to May 2018. We investigated the incidence of and risk factors for de novo malignancy. The cumulative incidence of each malignancy type during the follow-up period was one (0.98%) for skin cancer, four (3.92%) for nonskin solid organ cancer, and six (5.88%) for posttransplant lymphoproliferative disorder (PTLD). The percentage of patients with more than one infectious event ≤ 1 year after HTx was higher in the malignancy group than in the non-malignancy group. Furthermore, Kaplan-Meier analysis revealed that the incidence rate of infectious events was higher in patients with malignancies than in those without (log-rank P < 0.001). After dividing malignancies into a PTLD group and a solid organ malignancy group, we found that negative Epstein-Barr virus serostatus, cytomegalovirus-positive antigenemia, and the occurrence of any viral or gastrointestinal infectious event at ≤ 1 year were more frequent in patients with PTLD than in patients without it. The survival rate was significantly lower for patients with solid organ malignancy than for patients without malignancy. In conclusion, there was a correlation between infectious events and de novo malignancy, particularly in patients with PTLD. We should confirm this finding by conducting a larger cohort study.

Differences in the prognoses of patients referred to an advanced heart failure center from hospitals with different bed volumes.

Few reports have discussed appropriate strategies for patient referrals to advanced heart failure (HF) centers with available left ventricular assist devices (LVADs). We examined the association between the characteristics and prognoses of referred patients with advanced HF and the bed volume of the referring hospitals. This retrospective analysis evaluated 186 patients with advanced HF referred to our center for consultation about the indication of LVAD between January 1, 2015, and August 31, 2018. We divided the patients into two groups according to the bed volume of their referring hospital (high bed volume hospitals (HBHs): ≥ 500 beds in the hospital; low bed volume hospitals (LBHs): < 500 beds). We compared the primary outcome measure, a composite of LVAD implantation and all-cause death, between the patients referred from HBHs and patients referred from LBHs. The 186 patients with advanced HF referred to our hospital, who were referred from 130 hospitals (87 from LBHs and 99 from HBHs), had a mean age of 43.0 ± 12.6 years and a median left ventricular ejection fraction of 22% [15-33%]. The median follow-up duration of the patients was 583 days (119-965 days), and the primary outcome occurred during follow-up in 42 patients (43%) in the HBH group and 20 patients (23%) in the LBH group. Patients referred from HBHs tended to require catecholamine infusion on transfer more often than those referred from LBLs (36.5% (HBH), 20.2% (LBL), P = 0.021). Kaplan-Meier analysis indicates that the occurrence of the primary outcome was significantly higher in the HBH patients than in the LBH patients (log-rank P = 0.0022). Multivariate Cox proportional hazards analysis revealed that catecholamine support on transfer and long disease duration were statistically significant predictors of the primary outcome. Patients from HBHs had a greater risk of the primary outcome. However, the multivariate analysis did not indicate an association between referral from an HBH and the primary outcome. In contrast, catecholamine support on transfer, long duration of disease, and low blood pressure were independent predictors of the primary outcome. Therefore, these should be considered when determining the timing of a referral to an advanced HF center, irrespective of the bed volume of the referring hospital.

Impact of tacrolimus versus cyclosporin A on renal function during the first year after heart transplant.

AIMS: Nephrotoxicity of calcineurin inhibitors (CNIs) is associated with adverse events in patients undergoing heart transplant (HTx), although studies directly comparing tacrolimus (TAC) versus cyclosporin A (CsA), especially in combination with everolimus and low-dose CNIs approach, are limited. Thus, we sought to investigate the associations of TAC and CsA with clinical outcomes in HTx recipients, with specific focus on renal function. METHODS AND RESULTS: From August 2007 to February 2017, 72 consecutive patients (39 treated with TAC vs. 33 with CsA) receiving de novo HTx in a single transplant centre were retrospectively evaluated. We used the instrumental variable method to account for unmeasured confounding. The study outcomes were percentage change in estimated glomerular filtration rates (eGFR) (safety endpoint) and biopsy-proven acute rejection (efficacy endpoint) within the first year after HTx. The enrolled patients (median age 40 years) were predominantly men (68%). There were no significant differences in baseline characteristics, including eGFR (64.8 [45.7-96.4] mL/min/1.73 m2 in TAC vs. 65.6 [57.9-83.0] mL/min/1.73 m2 for CsA; P = 0.48), other than sex (male, 49% for TAC vs. 91% for CsA; P < 0.001) between the two groups. Within the first year after HTx, 23 (59%) in the TAC group switched mycophenolate mofetil to everolimus, whereas 16 (48%) in the CsA group (P = 0.52). At 12 months, the rates of mortality and end-stage renal disease requiring renal replacement therapies were both 0%. In the instrumental variable analysis, no differences in renal function as well as graft rejection for 1 year after HTx existed between the TAC and CsA groups. These results were similar when taking into account of everolimus use. CONCLUSIONS: Irrespective of everolimus use with low-dose CNIs, our analysis using the instrumental variable method showed no differences in renal function as well as graft rejection during the first year after HTx between HTx recipients who received TAC or CsA.

Significant impact of left ventricular assist device models on the value of flow-mediated dilation: effects of LVAD on endothelial function.

The precise physiological changes associated with the use of left ventricular assist device (LVAD) are not well characterized. We examined the impact of changes in hemodynamic state using LVAD on endothelial function. We measured flow-mediated vasodilation (FMD) to evaluate endothelial vasodilator function of the brachial artery in 53 patients (dilated cardiomyopathy: 39, ischemic cardiomyopathy: 4, and others: 10) with an implanted LVAD (DuraHeart, EVAHEART, or HeartMate II). We found that FMD value in the HeartMateII LVAD group (9.3% ± 2.9%) was significantly higher than those in the other two groups (EVAHEART: 6.7% ± 2.8% and DuraHeart: 6.2% ± 4.0%). Other factors that affected the FMD value were age (r = - 0.31, p = 0.026), Brinkman index (r = - 0.30, p = 0.029); however, aortic opening, aortic regurgitation, and other hemodynamic parameters such as cardiac index or pulmonary capillary wedge pressure did not correlate with FMD. Multivariate analyses revealed that the difference among the LVAD models most significantly affected the FMD values after adjusting for age and smoking status (t = 2.6, p = 0.014). Event free survival rate of death and cerebral infarction was not significantly different according to the value of FMD. The difference among the LVAD groups most significantly affected the state of endothelial function and it had more impact than other clinical factors.

Controlling Nutritional Status Score As a Predictive Marker for Patients With Implantable Left Ventricular Assist Device.

Although a correlation between the nutritional status and the prognosis of patients with heart failure has been suggested, a correlation between the nutritional status and outcomes after the left ventricular assist device (LVAD) implantation remains unclear. We aimed to investigate the efficacy of the Controlling Nutritional Status (CONUT) score (range 0-12, including serum albumin, total cholesterol, and lymphocytes) as a nutritional index in speculating the prognosis of patients undergoing LVAD implantation. We examined 63 consecutive patients who underwent the continuous-flow LVAD implantation. Using the preoperative CONUT score, patients were categorized into two groups: lower CONUT score (0-4: normal to mild malnutrition) and higher CONUT score (5-12: moderate to severe malnutrition). We compared for the backgrounds and the clinical events after LVAD implantation. The higher CONUT group exhibited a significantly higher mean right atrial pressure (10.9 ± 4.7 vs. 7.3 ± 4.1 mmHg; p = 0.0019). In that group, the mortality rate was significantly higher (25% vs. 2.6%; p = 0.0059) and the Kaplan-Meier analysis showed lower survival rate. Furthermore, more bleeding events significantly occurred in the higher CONUT group. The preoperative CONUT score may reflect systemic venous congestion and offer a useful prognostic index of clinical courses after LVAD implantation.

Abdominal skeletal muscle mass as a predictor of mortality in Japanese patients undergoing left ventricular assist device implantation.

AIMS: We assessed preoperative muscle wasting in patients undergoing left ventricular assist device (LVAD) implantations using abdominal skeletal muscle images on computed tomography (CT) and explored the associations between the preoperative muscle wasting and clinical outcomes after LVAD implantation. METHODS AND RESULTS: We retrospectively examined the records of 111 patients who underwent continuous-flow LVAD implantations as bridge-to-transplant therapy from January 2010 to December 2016 at our institution. After 33 patients were excluded, the study cohort consisted of 78 individuals. CT images used to calculate the skeletal muscle index (SMI) at the third lumbar vertebra level were obtained before the LVAD implantation procedures. Patients were classified as having muscle wasting if their SMI fell into the lowest gender-based tertile. The median SMI for the study patients was 37.6 cm2 /m2 . The SMI cut-off values for the lowest tertiles were 36.7 cm2 /m2 for men and 28.2 cm2 /m2 for women, resulting in 26 patients (33.3%) with muscle wasting in this study. During the mean follow-up of 738 ± 379 days, there were 10 deaths (12.8% mortality). Seven of the 26 patients with muscle wasting (26.9%) died, and 3 of the 52 patients without muscle wasting (5.8%) died. The times to all-cause mortality were significantly different between patients with and without muscle wasting (P = 0.0094). Muscle wasting was found to be associated with mortality in univariate and multivariate Cox analyses (hazard ratio: 4.32; 95% CI: 1.19-20.2). CONCLUSIONS: Preoperative muscle wasting was associated with a higher mortality in patients with LVAD. Assessment of the abdominal skeletal muscle area on CT prior to LVAD implantation can help predict mortality.

Evaluating the Effectiveness of a Fall Risk Screening Tool Implemented in an Electronic Medical Record System.

We investigated the effect of using a fall risk screening tool in an electronic medical record system by using data for 25 039 patients in 24 general wards of a single institution. The probability of the occurrence of falls decreased after the tool was implemented, but using the tool did not reduce the actual occurrence of falls. This indicates that we must improve not only the assessment of the risk of falls but also the interventions to prevent falls.

Quality of life of family caregivers of patients with a left ventricular assist device in Japan.

BACKGROUND: The role of caregivers is important for the successful support of left ventricular assist device (LVAD) patients. We aimed to (1) evaluate quality of life (QoL) of caregivers pre-and post-LVAD implant and (2) identify factors associated with caregivers' QoL. METHODS: The caregivers' QoL was assessed with the Short Form-8 before implant, at 3 and 6 months after LVAD implantation. The physical and mental component summary (PCS and MCS) scores were calculated. Caregiver burden was evaluated using the 8-item Zarit Caregiver Burden Interview. RESULTS: Data were collected from LVAD patients as bridge-to-transplant and their family caregivers in Japan. No significant changes were found in caregivers' PCS scores during the follow-up (before 52.7±7.1; at 3 months 49.7±6.5, and at 6 months 50.7±6.4, n=20). Compared with the scores before implant (38.9±9.3), the caregivers' MCS scores improved after LVAD implantation at 3 months (44.2±7.7; p=0.03) and at 6 months (46.2±7.4, p=0.003), but they were still lower than those of the Japanese general population (p<0.01). In multiple regression analysis at 3 months (n=40), caregivers' lower PCS scores were associated with older patient age [standard partial regression coefficients (sß)=-0.36, p=0.02] and caregiver unemployment (sß=0.30, p=0.04), whereas being female (sß=-0.26, p=0.03), being the patient's spouse (sß=-0.23, p=0.03), and having a mild to moderate caregiving burden (sß=-0.63, p<0.001) were associated with lower MCS scores among caregivers. CONCLUSIONS: LVAD implantation improves caregivers' mental QoL. Since caregivers' MCS scores are lower than the general population, it is important to identify family caregivers at risk for low QoL and reduce their caregiving burden.

Establishing a Classification System for High Fall-Risk Among Inpatients Using Support Vector Machines.

We constructed a model using a support vector machine to determine whether an inpatient will suffer a fall on a given day, depending on patient status on the previous day. Using fall report data from our own facility and intensity-of-nursing-care-needs data accumulated through hospital information systems, a dataset comprising approximately 1.2 million patient-days was created. Approximately 50% of the dataset was used as training and testing data. A multistep grid search was conducted using the semicomprehensive combination of three parameters. A discriminant model for the testing data was created for each parameter to identify which parameter had the highest score by calculating the sensitivity and specificity. The score of the model with the highest score had a sensitivity of 64.9% and a specificity of 69.6%. By adopting a method that relies on daily data recorded in the electronic medical record system and accurately predicts unknown data, we were able to overcome issues described in previous studies while simultaneously constructing a discriminant model for patients' fall risk that does not burden nurses and patients with information gathering.

Readmissions after continuous flow left ventricular assist device implantation.

Continuous flow left ventricular assist device (CF-LVAD) therapy has improved the survival of patients with advanced heart failure. However, the readmission rate of CF-LVAD patients is still relatively high. A total of 90 patients who received CF-LVADs between April 2011 and March 2016 at our institute and were discharged home were analyzed retrospectively. They were followed up through March 2017. Clinical data, including frequency, length and etiology of readmission, were obtained from medical records. The mean observation period after initial discharge was 713 ± 322 days. In total, 73 patients (81%) had 236 readmissions, 214 unplanned and 22 planned. The overall and unplanned readmission rates were 1.34 and 1.22 per patient-year, respectively. The rate of freedom from unplanned first readmission at 1 year after initial discharge was 39%. The median interval between the previous hospital discharge and first and second readmissions was 311 and 213 days, respectively (log-rank test, p = 0.117). The rate of readmission after more than three readmissions was significantly higher than that of first or second readmission (log-rank test, p < 0.001). The most common etiology of readmission was driveline infection (DLI) (36%), followed by stroke (9%). The median length of hospital stay due to DLI was 23 days. The patients with repeated unplanned readmissions had significantly lower EuroQol 5 dimensions questionnaire utility score than those with no or just one readmission. Readmission was common in CF-LVAD patients, and the most common etiology of readmissions was DLI. The interval to the next readmission seemed shorter for patients with repeated readmissions.

Development of the Japanese version of the Pediatric Quality of Life Inventory™ Transplant Module.

BACKGROUND: Health-related quality of life (HRQOL) is an important outcome in pediatric solid organ transplantation. Considering the emerging problems after transplantation, an evaluation of transplant-specific aspects of HRQOL is essential, but no validated HRQOL measure is available in Japan. The aim of this study was therefore to develop the Japanese version of the Pediatric Quality of Life Inventory™ (PedsQL) Transplant Module Child Self-Report and to investigate its feasibility, reliability, and validity. METHODS: Based on the PedsQL linguistic validation process, the Japanese version of the PedsQL Transplant Module was developed through translation and cognitive interviews (patient testing). The scale's reliability and validity were investigated, using statistical analyses of field tests of the target population. RESULTS: Eighty-seven pairs of pediatric liver-transplant recipients and their parents participated in the field test. The pediatric patients completed the measure in 3-7 min, and the rate of missing items was low (0.27%). Excellent internal consistency and test-retest reliability were confirmed. Known-groups validity, concurrent validity, and convergent and discriminant validity also were confirmed. CONCLUSIONS: Excellent feasibility, reliability, and validity of this Japanese self-report version of the PedsQL Transplant Module Child Self-Report were verified. As a measure of transplant-specific aspects of HRQOL in Japanese pediatric patients who have undergone organ transplants, the Japanese version of the PedsQL Transplant Module is appropriate for use in clinical and research settings.

Evaluation of a Fall Risk Prediction Tool Using Large-Scale Data.

To support nursing care for the prevention of falls among inpatients at our institution, we developed and implemented a fall risk prediction tool. To evaluate its effectiveness, we compared the number of falls among inpatients before and after its implementation. The odds ratio for the probability of falling was 0.79 (95% confidence interval: 0.69-0.91) (p < 0.001), which was adjusted based on institutional data comprising 573,216 records from 25,039 patients in 24 general wards. Although whether nurses used the tool completely or whether the dissemination of fall prevention measures led to behavioral changes among the nurses in relation to their care remained unclear, the fall risk of inpatients appeared to be reduced after implementation of the prediction tool.

Successful Pregnancy and Delivery in a Heart Transplantation Recipient.

For 6 years after heart transplantation, a 23-year old female recipient had been treated with immunosuppressants including tacrolimus and mycophenolate mofetil (MMF), without any major rejection or graft dysfunction. She unexpectedly became pregnant for the first time, and we converted MMF to azathioprine (AZA), but she soon experienced a spontaneous abortion. After careful counseling under the continuation of AZA, she became pregnant again 3 months after the abortion. We closely monitored the concentration of immunosuppressive agents, cardiac function, fetal condition, and serological assay including human leukocyte antigen (HLA) sensitization, and she eventually delivered a normal male infant at 38 weeks gestation without any complications. AZA was converted to MMF soon after the delivery. There have been no complications in either the patient or infant after the delivery.Because pregnancy itself involves a risk of cardiac graft rejection in the recipient as well as fetal complications, it is important to educate HTx recipients about planned pregnancy and to conduct careful follow-up after pregnancy.

Novel Scoring System to Predict Ineligibility for Bridge to Implantable Left Ventricular Assist Device as Destination Therapy Before Extracorporeal Ventricular Assist Device Implantation - For the Coming Era of Destination Therapy in Japan.

BACKGROUND: Although destination therapy (DT) is now expected to be a promising strategy for those who are not suitable for heart transplantation in Japan, there has not been any investigation into ineligibility for bridging to implantable left ventricular assist device (I-LVAD) as DT among patients with extracorporeal LVAD. METHODS AND RESULTS: We retrospectively studied 85 patients who had received an extracorporeal LVAD. To assess ineligibility for a bridge to I-LVAD for DT, we defined DT ineligibility (DTI) as BiVAD requirement, death within 6 months, and persistent end-organ dysfunction (medium or high J-VAD risk score) at 6 months after extracorporeal LVAD implantation. DTI was recorded for 32 patients. Uni/multivariate analysis showed that smaller left ventricular diastolic dimension (<64 mm; [odds ratio (OR) 4.522]), continuous hemodiafiltration (OR 4.862), past history of cardiac surgery (OR 6.522), and low serum albumin level (<3.1 g/dl; OR 10.064) were significant predictors of DTI. By scoring 2, 2, 3, 4 points, respectively, considering each OR, we constructed a novel scoring system for DTI (DTI score), which stratified patients into 3 risk strata: low (0-3 points), medium (4-6 points), and high (7-11 points), from the view point of DTI risk (low 8%, medium 46%, high 93%, respectively). CONCLUSIONS: DTI score is a promising tool for predicting ineligibility for I-LVAD as DT before extracorporeal VAD implantation.

An Experience of Landiolol Use for an Advanced Heart Failure Patient With Severe Hypotension.

Tachyarrhythmias such as atrial fibrillation (AF) or atrial flutter (AFL) sometimes invoke life-threatening collapse of hemodynamics in patients with severe heart failure. Recently, landiolol, an ultra-short acting ß1-selective antagonist, has been reported to be safe and useful for the treatment of supraventricular tachyarrhythmias with reduced left ventricular function. Here we report a case of advanced heart failure with severe hypotension who was treated successfully by landiolol for rapid AF. The patient was a 20-year old male with dilated cardiomyopathy. He presented with low output syndrome in spite of optimal medical therapy and was referred to our department to consider ventricular assist device implantation and heart transplantation. Soon after admission, he developed rapid atrial fibrillation at 180 beats per minute (bpm) followed by severe hypotension and liver enzyme elevation. Low dose landiolol at 2 µg/kg/minute was started because digoxin was not effective. After landiolol administration, his heart rate decreased to 110 bpm, and finally returned to sinus rhythm without hemodynamic deterioration. Intra-aortic balloon pumping was inserted soon after sinus recovery and he was discharged successfully with an implantable left ventricular assist device.

Quality of Life and Influential Factors in Patients Implanted With a Left Ventricular Assist Device.

BACKGROUND: Improving quality of life (QOL) has become an important goal in left ventricular assist device (LVAD) therapy. We aimed (1) to assess the effect of an implantable LVAD on patients' QOL, (2) to compare LVAD patients' QOL to that of patients in different stages of heart failure (HF), and (3) to identify factors associated with patients' QOL. METHODS AND RESULTS: The QOL of 33 Japanese implantable LVAD patients was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and Short-form 8 (SF-8), before and at 3 and 6 months afterwards. After LVAD implantation, QOL significantly improved [MLHFQ, SF-8 physical component score (PCS), SF-8 mental component score (MCS), all P<0.05]. Implanted LVAD patients had a better QOL than extracorporeal LVAD patients (n=33, 32.1±21.9 vs. n=17, 47.6±18.2), and Stage D HF patients (n=32, 51.1±17.3), but the score was comparable to that of patients who had undergone a heart transplant (n=13). In multiple regression analyses, postoperative lower albumin concentration and right ventricular failure were independently associated with poorer PCS. Female sex and postoperative anxiety were 2 of the independent factors for poorer MCS (all P<0.05). CONCLUSIONS: Having an implantable LVAD improves patients' QOL, which is better than that of patients with an extracorporeal LVAD. Both clinical and psychological factors are influence QOL after LVAD implantation.

Health-related quality of life in parents of pediatric solid organ transplant recipients in Japan.

Few studies have examined HRQOL in pediatric Tx recipients' parents. This study investigated HRQOL in these parents and relationships between HRQOL and perceived burden of nurturing, family functioning, and social support. Self-report anonymous questionnaires and a survey of medical records were completed between September and December 2013. The SF-36v2, which evaluates physical, psychological, and social health, was used to measure HRQOL. While values for physical and psychological health were higher than standard values (Cohen's d = 0.34 and 0.17, respectively), social health scores were lower (d = 0.21). "Parental consultation unrelated to donation" (standardized partial regression coefficient: ß = -0.52) was associated with physical health. "Family functioning" and "Commuting time between home and primary follow-up hospital" (ß = 0.57 and -0.31) were related to psychological health. "Total score for perceived burden of nurturing" (ß = -0.31) was related to social health. Regarding parental HRQOL, while physical and psychological health was favorable, social health was impaired. In clinical practice, interventions targeting parents' physical conditions and facilitation of community and family understanding and support to share recipients' nurturing are important in improving parental HRQOL.