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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Preoperative beta-blocker treatment is a key for deciding left ventricular assist device implantation strategy as a bridge to recovery.

To date, there have been few reports demonstrating preoperative predictors for left ventricular reverse remodeling (LVRR) after LV assist device (LVAD) implantation, especially among patients with dilated cardiomyopathy (DCM). We retrospectively analyzed 60 patients with stage D heart failure due to DCM who had received LVAD treatment [pulsatile flow (PF) type, 26; continuous flow type, 34]. Data were evaluated at 6 months or just before explantation of the LVAD. We defined "LV reverse remodeling" (LVRR) by the achievement of an LV ejection fraction (LVEF) of ≥ 35 % after 6 months of LVAD support or explantation of LVAD within 6 months. LVRR occurred in 16 of our patients (26.7 %). Uni/multivariate logistic regression analyses for LVRR demonstrated that of the preoperative variables evaluated, PF LVAD usage and insufficient preoperative ß-blocker treatment were independent predictors for LVRR. Patients who accomplished LVRR had a better clinical course, including lower levels of aortic valve insufficiency and lower levels of plasma B-type natriuretic peptide. Of the six patients (10.0 %) in whom LVADs were eventually explanted, all had an LVEF of ≥ 35 % before explantation or at 6 months. Based on these results, we conclude that DCM patients with insufficient preoperative ß-blocker treatment have a chance to achieve LVRR under LVAD support as a bridge to recovery.

Cardiac allograft vasculopathy can be distinguished from donor-transmitted coronary atherosclerosis by optical coherence tomography imaging in a heart transplantation recipient: double layered intimal thickness.

Although survival after heart transplantation (HTx) has improved in recent years, cardiac allograft vasculopathy (CAV) is still the leading cause of remote morbidity and mortality in HTx recipients, partly because of difficulty with its diagnosis. In general, routine surveillance for CAV is advocated with coronary angiography accompanied by intravascular ultrasound (IVUS) if necessary. However, these modalities have limitations with respect to low spatial resolution, and sufficient qualitative/quantitative assessment of coronary intima has not been accomplished. Recently, optical coherence tomography (OCT) has emerged as a novel intracoronary imaging technique using an optical analogue of ultrasound with a spatial resolution of 10-20 µm, which is 10 times greater than IVUS. We here experienced a 49-year-old male who received a HTx 3 years ago, and OCT was executed during low molecular weight dextran injection. OCT demonstrated distinct double intimal layers probably consisting of a donor-transmitted atherosclerotic layer and an inner intimal proliferation due to CAV, which was indistinguishable by IVUS and virtual histological analyses. We believe that OCT imaging is not only a new loadstar during treatment of CAV but also a new generation modality for screening for early CAV in HTx recipients.

Preoperative levels of bilirubin or creatinine adjusted by age can predict their reversibility after implantation of left ventricular assist device.

BACKGROUND: It is often difficult to predict reversibility of liver or renal function after left ventricular assist device (LVAD) implantation in patients with stage D heart failure. METHODS AND RESULTS: Data were obtained for 69 patients who had received a LVAD (18 continuous-flow, 51 pulsatile). Persistent hepatic or renal dysfunction was defined as levels of total bilirubin (TB) or creatinine (Cre) >1.5mg/dl at 6 months after LVAD implantation. TB score or Cre score was calculated: 0.15 × age+1.1 × (preoperative TB) or 0.2 × age+3.6 × (preoperative Cre), in which coefficients were determined on the basis of odds ratios for persistent hepatic or renal dysfunction, respectively. Receiver-operating characteristics analyses showed good predictabilities for persistent end-organ dysfunction (area under curve: 0.794 for TB score and 0.839 for Cre score). High-risk strata of TB score (>11.0 points) or Cre score (>14.1 points) were associated with persistently higher levels of TB or Cre (TB, 1.32 ± 0.51; Cre, 1.23 ± 0.41 mg/dl; both P<0.001 vs. low-risk strata). CONCLUSIONS: Reversibility of end-organ function with LVAD implantation can be well predicted by our new risk scoring system that consists of the preoperative TB or Cre level adjusted by the patient's age. The scoring system would be beneficial, especially in considering the indication of a bridge to candidacy.

Everolimus-incorporated immunosuppressant strategy improves renal dysfunction while maintaining low rejection rates after heart transplantation in Japanese patients.

The long-term survival of heart transplantation (HTx) recipients has increased significantly in recent years, however, the nephrotoxic adverse effects of calcineurin inhibitors (CNIs) are still a major concern. Recently, an inhibitor of mammalian target of rapamycin, everolimus (EVL), has emerged as an alternative immunosuppressant drug that may allow CNI dosage reduction and thereby spare renal function. Data were collected from 20 HTx recipients who had received EVL (target trough level 3-8 ng/mL) along with a dose reduction of CNIs and/or mycophenolate mophetil (MMF) and had been followed for 1 year. Estimated glomerular filtration rate increased significantly with a reduction in the CNI dosage in a dose-dependent manner (P < 0.001, r = -0.807). Neutrophil count increased significantly (P < 0.05) with a reduction in the dosage of MMF (P = 0.009, r = -0.671). Cytomegalovirus antigenemia remained negative after EVL administration among all candidates without any antiviral agents (P = 0.001). There were no significant increases in the acute rejection rates among recipients with EVL compared to those without EVL (P = 0.132). An immunosuppressant strategy incorporating EVL could reduce the CNI and MMF dosages, which resulted in improvements in renal dysfunction and neutropenia while maintaining low rejection rates among HTx recipients.

Successful treatment of hemodynamic compromise caused by antibody-mediated and cellular rejection in a recipient 12 years after heart transplantation.

Heart transplantation (HTx) is an established therapy for stage D heart failure due to recent advances in immunosuppressive regimens. However, antibody-mediated rejection remains an unsolved problem because of its refractoriness to standard immunosuppressive therapy with high mortality and graft loss. We experienced a 16-year old patient with hemodynamic compromise caused by both cellular and antibody-mediated rejection 12 years after HTx. The rejection was refractory to repeated steroid pulse treatment, intravenous immunoglobulin administration, and intensifying immunosuppression including addition of everolimus. Eventually, she was successfully treated with repeated plasma exchange accompanied by a single administration of the anti-CD20 monoclonal antibody rituximab.

[Mid-long term result of implantable ventricular assist device treatment for end-stage heart failure in the University of Tokyo Hospital].

Two implantable left ventricular assist devices(I-LVADs)were approved in Japan in 2011. I-LVADs were used for end-stage heart failure of 20 patients in our institute until March 2012. We examine the clinical course of these 20 patients who were treated with I-LVADs. End points are transplantation, death, or weaning from I-LVADs. Mean hospital days after I-LVAD implantation were 58.1 days, and all 20 patients could discharge from hospital alive. Until September 2012, mean follow up interval was 515 days. Five patients reached heart transplantation, 2 died, weaning from an I-LVAD could be done in 1 patient, and 12 continued to wait for heart transplantation. Survival rate was 100% at 1 month, 95% at 3 months, and 89% at 1 year, respectively. Mean follow up duration after discharge were 457 days, and 16 patients(80%)needed a total of 41 times of readmission in this period. Freedom from readmission was 75% at 1 month, 60% at 3 months, and 25% at 1 year, respectively. In conclusion, prognosis of I-LVAD treatment was good, but many patients needed readmission after I-LVAD implantation and follow up system for I-LVAD treatment should be improved immediately.

Combination evaluation of preoperative risk indices predicts requirement of biventricular assist device.

BACKGROUND: Patients with biventricular assist device (BiVAD) placement have a poor prognosis, but preoperative risk factors for the necessity of BiVAD have not been fully elucidated. METHODS AND RESULTS: Data from 79 patients who received left ventricular assist device (LVAD) between November 2002 and December 2011 were retrospectively reviewed. Overall, 9 patients (11.4%) required BiVAD, and the survival rate of BiVAD patients was significantly lower than that of LVAD patients (P<0.001). Multivariate analysis for BiVAD requirement showed left ventricular diastolic diameter (LVDd) ≤62 mm (odds ratio [OR], 10.97; P=0.009) to be significantly associated with BiVAD requirement. Preoperative central venous pressure (CVP)/pulmonary capillary wedge pressure (PCWP) ratio ≥0.5 (OR, 13.09; P=0.028) was also significantly associated with BiVAD requirement. A new scoring system for predicting BiVAD requirement was created from the combination of CVP/PCWP ratio (≥0.5), body surface area (≤1.4 m(2)), preoperative continuous hemodiafiltration use, B-type natriuretic peptide (≥1,200 pg/ml) and LVDd (≤62 mm), and this had a significantly larger area under the curve (0.909; P=0.003) than right ventricular stroke work index on receiver operating characteristic analysis. A score >20 using the new scoring method indicated significantly high probability of BiVAD requirement (OR, 16.00; P=0.019). CONCLUSIONS: The new scoring method, which includes CVP/PCWP ratio, is a novel risk stratification tool for BiVAD therapy.