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

Abstract

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.

1. Preamble

Stage D heart failure (HF) is defined as having New York Heart Association III or IV symptoms after guideline-directed medical therapy,¹ with no other solution except cardiac replacement therapy (i.e., heart transplantation (HTx)) or mechanical circulatory support (MCS), to prolong survival or maintain good quality of life (QOL). HTx has been the gold standard treatment for stage D HF for decades, but has always faced donor shortage against a long waiting list. Japan is facing a particularly severe donor shortage, and as of the end of 2020, the average waiting period of patients listed for HTx is 1,500 days, according to the homepage of the Japanese Society for Heart Transplantation (http://www.jsht.jp/registry/japan). Left ventricular assist device (LVAD) has long been used to bridge already-listed patients awaiting transplant under stable hemodynamic condition. This indication of bridge to transplant (BTT) is extremely important in Japan because bridging is required for many years. Since 2011, implantable continuous flow LVAD has been reimbursed as BTT in Japan, and considerably good QOL at home has been achieved for most of the listed patients. Furthermore, excellent prognosis of Japanese BTT patients has been reported from the J-MACS registry.²

HF is a prevalent disease in the elderly population over 65 years of age, who do not qualify for HTx due to the age restriction and comorbidities. Even among younger patients, many are not immediate candidates for HTx listing due to poor adherence, lack of family support, history of malignancy, and/or end-organ dysfunction. The implantable LVAD is a viable alternative to save transplant ineligible patients with advanced HF, as demonstrated by the REMATCH study in 2001,³ which showed superiority in survival of implantable LVAD over optimal medical therapy among end-stage HF patients. Only 1 randomized study has compared LVAD to medical therapy to date, but the evidence led to approval of the LVAD for patients ineligible for HTx. This LVAD indication is called destination therapy (DT), and is an especially prevalent indication among older adults. Age is a non-modifiable factor for ineligibility for HTx, and older patients who receive LVAD will face death during the support of LVAD. For younger patients, their condition may improve after some time on the LVAD and they may eventually qualify for HTx, which is called bridge to candidacy (BTC). In the broadest sense, BTC is sometimes included as DT.

In the REMATCH era, the implantable LVAD was a pulsatile pump with numerous complications and less durability, but recent evolution in the mechanics of LVAD has led to significant reductions in complications and longer durability. The transition to a continuous flow pump was a turning point in the history of LVAD. The HeartMate II (HM II), a continuous axial flow LVAD, was approved for DT according to the results of the HM II DT trial⁴ that compared the HM II with pulsatile HeartMate XVE in 2007, and the device became the most widely implanted LVAD globally. Most recently, a fully magnetically levitated centrifugal pump has been developed, named HeartMate 3 (HM3). HM3 demonstrated nearly zero pump thrombosis with significantly less stroke and gastrointestinal bleeding compared with HM II in the MOMENTUM 3 trial in 2019.⁵ That study was characterized by the largest number of patients and the longest follow-up period in the LVAD history. In the meantime, DT grows year by year up to ∼70% of total implants in the USA, as shown by the most recent INTERMACS registry,⁶ and many developed countries have already approved implantation of LVAD under the indication of DT as of 2021.

Our Council started a discussion with the Pharmaceuticals and Medical Devices Agency (PMDA) in 2010 just before the implantable continuous flow LVAD was approved in Japan under the BTT policy. Since then, we have aimed for consensus among industry–government–academia, especially among Japanese cardiologists. To do so, we organized the 1st working group for DT guidelines, which were published on the homepage (https://www.jacvas.com/view-dt/) of the Japanese Association for Clinical Ventricular Assist System (JACVAS) in 2014. The 1st version of these guidelines consisted of patient inclusion/exclusion criteria, which are still reflected in the current guidelines. Based on the guidelines, a single-arm, open-labeled prospective trial using HM II for DT started in Japan in 2016. The trial enrolled 10 patients, all of whom underwent HM II implantation. The primary endpoint was 12-month survival free from pump exchange or stroke with a modified Rankin scale of >3, and it was achieved in only 6 patients (60%) at 12 months (results shown in the PMDA review report in Japanese, refer to https://www.pmda.go.jp/medical_devices/2021/M20210115001/390147000_23100BZI00006_A100_1.pdf), which was inferior to the HM II arm (74.8%) of the DT cohort in the MOMENTUM 3 trial.⁷ The overall survival rate was 80% at 12 months and 60% at 24 months, which was comparable to the HM II arm results of the HM II DT trial.⁴ During the evaluation of the trial results by PMDA, the MOMENTUM 3 trial results⁵ were published, showing superior results for HM3; hence, there was no reason to continue with HM II. Therefore, PMDA accepted the device change to HM3 for review. The J-MACS registry has shown more stroke events in the overall Japanese BTT patients with all devices,² as does the Japanese DT trial. However, HM3 is expected to markedly reduce stroke events,⁵ so HM3 use in the Japanese DT population should be acceptable and lead to improved outcomes.

Effective from government approval of DT for HM3, the academic group sought to develop the policy for patient selection and management. We organized the 2nd working group for DT guidelines, which took over from the existing working committee as of August 2020. Additional criteria were determined based on minute discussions between the committee members and PMDA officials.

2. Methods

2.1 Committee Composition

The DT working committee assembled to discuss detailed inclusion/exclusion criteria, indication/outcomes, review process, multidisciplinary management system, caregiver issues, advance directives, and end-of-life policy prior to the clinical initiation of DT in the Japanese patient population. The committee consisted of cardiologists/cardiac surgeons specialized in advanced HF, VAD coordinators, a perfusionist, a palliative care physician (cardiologist), a home healthcare provider (cardiologist), a medical ethicist, a legal scholar, and a medical mediator.

2.2 Consensus Development and Review Process

Monthly discussions occurred over 6 months using web-based communication. The topic of each meeting was announced in advance by the Chair, and the minutes of the meeting were reviewed by all committee members. A draft of the meeting was created by the Chair and reviewed by all committee members and PMDA officials. The draft was then sent for review to the potential certified DT centers for questions. After addressing questions and holding further discussions with PMDA officials, a collective report was developed. The finalized Japanese version of this report can be found on the homepage (https://j-vad.jp/dt-lvad/) of the Council for Clinical Use of Ventricular Assist Device Related Academic Societies as of April 2, 2021.

3. Patient Selection for DT

3.1 Key Inclusion Criteria

The DT patient selection criteria are an expansion of the BTT criteria previously published on the homepage of JACVAS in 2010 (https://www.jacvas.com/application/2/standard/). Table 1 presents the detailed inclusion/exclusion criteria for the DT patient. To introduce the DT program in Japan, we initially set stringent conditions to aim for better outcomes after DT-LVAD implantation. Some conditions, marked with asterisks, are considered provisional, and may be revised in the future.

Table 1. Patient Selection Criteria for Destination Therapy

Target patients	Diseases/etiologies	Advanced heart failure ineligible for heart transplantation Etiologies include dilated cardiomyopathy, dilated phase hypertrophic cardiomyopathy, ischemic heart disease, valvular disease, congenital heart disease, drug-induced cardiomyopathy, post-myocarditis, cardiac sarcoidosis, etc.
Inclusion criteria	New York Heart Association class	III–IV (with a history of class IV, in principle)
	Stage classification	D
	INTERMACS profile	2–4 (excluding profile 2 for those aged ≥65 years*)
	Drug treatment	Guideline-directed medical therapy with diuretics, angiotensin-converting enzyme inhibitor/angiotensin II type 1 receptor blocker/angiotensin-neprilysin inhibitor, β-blocker, mineralocorticoid receptor antagonist, and sodium-glucose transporter 2 inhibitor (potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 inhibitor if indicated) should be implemented
	Dependence on inotropes and mechanical circulatory support	Dependent on dobutamine, dopamine, norepinephrine, phosphodiesterase-3 inhibitors, etc., or on an intra-aortic balloon pump, catheter-based transaortic microaxial pumps, or paracorporeal VAD, etc.
	J-HeartMate Risk Score	Take into consideration in order to discuss indication
	Age	For those aged ≥65 years, hemodynamics, end-organ function, nutritional status or cognitive function should be examined more carefully
	Body surface area	Determined individually with each device system
	Functional status	Patients with significantly impaired quality of life, who cannot expect a survival benefit with other treatments but can expect improved quality of life for long-term at home and rehabilitation after receiving an implantable LVAD
	Comorbidities	≥5-year life expectancy determined based on comorbidities
	Caregivers	At least one caregiver who can live with the patient for about 6 months after the first discharge is necessary (desirably, caregivers or public services can continue to provide nursing care for longer than 6 months)
	Self-management ability	Those aged ≥65 years shall have a Mini-Mental State Examination score ≥24 points and a Trail Making Test-B score ≤300 s before surgery* For those aged <65 years, their self-management abilities are determined at the implant center before surgery. In all cases, sufficient self-management abilities shall be reconfirmed before discharge to plan the level of nursing care by a caregiver
	Understanding of treatment	Good adherence to medication, continued abstinence from alcohol and smoking, understanding of the limitations and complications of VAD therapy, and adequate support of family members in cooperation with the patient
	Understanding of end-of-life care	Patients and their family members understand and consent to the end-of-life care of DT
Exclusion criteria	Infection	Severe infection
	Respiratory disease	Pulmonary artery embolism that developed within 30 days
	Cardiovascular diseases	Early after cardiotomy
		High possibility of postoperative right heart failure
		Untreatable abdominal aneurysm or severe peripheral vascular disease
		Thoracic aortic aneurysm/ventricular aneurysm/ventricular septal perforation
		Untreatable moderate or severe aortic regurgitation
		Mechanical aortic valve that cannot be replaced with a biological valve
		Severe calcification in the thoracic aorta
	Psychiatric/neurologic disorders	Severe central nervous system disorders
		History of substance abuse or alcohol dependence
		Encephalopathy, psychiatric disorders or neuromuscular disorders that may preclude self-management of a device
	End-organ failure	Maintenance dialysis
		Liver cirrhosis
	Pregnancy	Being pregnant
	Other	Severe obesity, administration of immunosuppressive drugs other than low-dose steroids,* administration of anticancer drugs,* refusal of blood transfusion, or conditions that are considered as ineligible by the institutional committee

*Provisional criteria.

Primarily, DT is a policy to implant LVAD in patients who are ineligible to HTx. Ineligible conditions may be modifiable or non-modifiable. The never-modifiable condition is age. Japanese HTx listing is restricted to those who are <65 years old, and patients ≥65 years old are HTx-ineligible due to age. Still, for those <65 years, not all qualify for HTx listing due to other factors. For patients <65 years of age, a candidate may not immediately meet the listing criteria for HTx, and therefore may be implanted as DT, but eventually become eligible for HTx after a length of support by implantable LVAD (i.e., BTC), and several scenarios of BTC are assumed.

One of these is a late referral. Patients who are referred late have a relatively long history of treatment for HF managed at a non-advanced HF hospital. They have already developed hepatic/renal end-organ dysfunction disqualifying them from the listing criteria. In these patients, temporary MCS is too short for an assessment of the reversibility of end-organ damage. The implantable LVAD is a better alternative for stabilizing the patient’s hemodynamics for a longer duration prior to listing.

The second scenario is cardiomyopathy due to anthracyclines. Some HF caused by anthracyclines temporarily worsens to inotrope dependency, such as in a patient with a recent history of malignant lymphoma. These patients may have completed treatment and be in remission, as deemed by a hematologist. However, the current Japanese HTx listing requires complete remission of at least for 5 years for any type of cancer (from the JCS Statement for Heart Transplantation, https://www.j-circ.or.jp/cms/wp-content/uploads/2020/02/JCS2016_isobe_h.pdf). To maintain stable hemodynamics while waiting for remission to reach 5 years these patients may receive an implantable LVAD as DT. After 5 years following the complete remission of any cancer, patients can be listed for HTx and the waiting period will start at the time of listing.

The third scenario is occult cancer found by chance during evaluation for HTx listing. Intramucosal cancer in the gastrointestinal tract or papillary thyroid cancer has a 5-year survival rate of >95% after resection. But again, Japanese transplantation guidelines have restrictions against listing such patients for 5 years, and DT will be a solution until revision of the criteria for HTx.

Until now, BTT has been indicated only up to profile 3 inotrope- or MCS-dependent patients, but in the new consensus, we have expanded the indication of DT to profile 4. There is always a trade-off between prolonging life and the risk of LVAD complications. Ambulatory patients have a better prognosis after receiving a LVAD, but at this stage the patients are often reluctant to choose MCS due to the risk of post-LVAD complications. Recent reports suggest that profile 4 patients have only 50–60% 1-year VAD-free survival rate,^8,9 and are sick enough to receive an LVAD. On the other hand, profile 2 patients aged ≥65 years are excluded from DT because older adults with highly compromised hemodynamics are unlikely to spend more time to consider DT and clinicians are hard to test self-management ability before surgery.

In addition to the hemodynamic profile, the selection of not-too-sick patients is calculated with the J-HeartMate Risk Score (J-HMRS) derived from the HeartMate II Risk Score.¹⁰ The J-HMRS is defined as: 0.0274 × age (years) − 0.723 × serum albumin (g/dL) + 0.74 × serum creatinine (mg/dL) + 1.136 × international normalized ratio (INR) + 0.807 × (0 or 1) (1 if LVAD center volume is <3 implants per 2 years). INR should be measured in the absence of all anticoagulation agents under heparinization. A center’s volume factor should be 0, because ≥3 implants are expected within 2 years. Scores <1.58, 1.58–2.48, and >2.48 are assigned as low-risk, medium-risk, and high-risk, respectively. For example, if a 70-year-old patient has 3.5 g/dL of albumin, 1.0 mg/dL of creatinine, and INR of 1.0, the J-HMRS is calculated as 1.26, which is in the low-risk group. These values may be coincident to profiles 3 and 4. Of those aged ≥65 years, the indication is preferably limited to low-risk patients. If a 45-year-old patient has 3.0 g/dL of albumin, 2.5 mg/dL of creatinine, and INR of 1.2, the J-HMRS is calculated as 2.28, which is in the medium-risk group. These values may be relevant to profile 2. Among those aged <65 years, low- or medium-risk patients can be indicated. Throughout all ages, the decision to implant a patient assigned to the high-risk group by J-HMRS should be carefully discussed within the implant center.

For those <65 years old with severe cardiogenic shock (profile 1), paracorporeal LVAD is sometimes implanted to improve organ damage and stabilize hemodynamics, followed by conversion to an implantable LVAD. This strategy is called bridge to bridge (BTB). The data from J-MACS registry show that age and the BTB strategy are independent poor prognostic factors.¹¹ Therefore, BTB may be difficult for older adults, and indication should be considered carefully with J-HMRS <1.58 at the time of conversion.

As in BTT, any comorbidity should be examined and prognosis should be evaluated by specialists. Written confirmation is required from the specialists, indicating the patient’s prognosis and life expectancy over 5 years. Systemic examination to exclude occult malignancy is important. Especially in those aged ≥65 years, preoperative examination of the gastrointestinal tract by fiberscope is highly recommended. BTC candidates <65 years are often too sick to receive complete surveys before LVAD implantation, but they will eventually need extensive examination before HTx listing during LVAD support.

3.2 Caregiver Issues and Self-Management Ability of DT Patients

We prefer that a caregiver lives with the DT patient as with BTT. However, DT with LVAD is a life-long therapy, especially for those ≥65 years old, requiring the caregiver to care for the patient indefinitely. The long-term mental/social/economic burden of the caregiver can be overwhelming. Ideally, DT candidates can take care of themselves with minimal support from caregivers. Therefore we only ask 1 or more caregivers to live with the DT patient for 6 months if several conditions are met. (1) The patient can manage activities of daily living (ADL) independently, including the LVAD system, as assessed by a trained psychiatrist or clinical psychologist at the implant/management center, 6 months after discharge. (2) There is a network of contacts available to share relevant clinical information between patients and their families prior to living independently. For example, a social networking group of friends and family surrounding the patient would allow communication and contact throughout the LVAD support period. If a patient cannot maintain a contact network, management of ADL is assumed to be low. In such a case, the patient should continue to live with a caregiver. (3) Additionally, an emergency call system, provided by local governments for emergency measures, home visits covered by insurance, and additional private security service, if financially possible, should be considered. The emergency call system is not currently intended for LVAD patients and is independently operated by each local government. Therefore, an implant center should consult with the local government where the patient resides. Regarding home visits, we submitted a petition for reimbursement for advanced HF patients to the Ministry of Health, Labor and Welfare.

If the caregiver requires leave of absence for any reason, an alternative caregiver should be arranged. If that is not possible, a public nursing service should be utilized based on evaluation of the patient’s self-management ability.

As described, we expect DT patients to manage their ADL. Cognitive function evaluation may be highly subjective if performed by non-specialists. However, to start DT in Japan, unified criteria for self-management abilities prior to implantation are necessary to determine patients’ cognitive function. For this reason, we recommend a standard evaluation by Mini-Mental State Examination (MMSE) and Trail Making Test-B (TMT-B). These tests are not intended to guarantee sufficiently high self-management abilities but to exclude those with low abilities. An MMSE score <24 is a generalized criterion for dementia.¹² The standard value of TMT-B in those with normal cognitive function in their 60 s is 216 s and the +1 SD value is 300 s (Table 2).¹³ According to Kashiwa et al, of 77 individuals in the BTT population, only 5 patients deviated from the criteria of an MMSE score ≥24 and TMT-B <mean value standardized by age +1 SD (personal communication). Therefore, we do not anticipate the criteria excluding many patients for DT.

Table 2. Standard Values of Trail Making Test-B by Age

Age (years)	Average (s)	Standard deviation (s)
20–29	83.9	23.7
30–39	90.1	25.3
40–49	121.2	48.6
50–59	150.2	51.3
60–69	216.2	84.7

Created from Toyokura et al.¹³

Most patients <65 years old fall into the category of BTC, and in principle, caregivers are required to live with the patients, and the self-management ability of the patients should be determined at each facility in a similar fashion to that already established for BTT. BTC profile 2 patients may be too ill to undergo MMSE and TMT-B examinations. Of note, the standard value of the TMT-B is unavailable for those aged <18 years, hence neither TMT-B nor MMSE is required for these young patients because of the absence of a comparator.

When the caregiver no longer lives with the patient, the patient’s self-management ability and the degree of cognitive impairment should be examined regularly (at least annually), as well as mental health, by professionals. When decreases in self-management ability and progression in cognitive impairment are observed, reimplementation of the caregiver system should be considered (i.e., a caregiver lives with the patient again or patients are hospitalized in the implant or management center).

3.3 Exclusion Criteria

The nature of DT does not call for the stringent requirements necessary for HTx, and we eliminated some of the exclusion criteria for BTT. For example, severe pulmonary hypertension or uncontrolled insulin-dependent diabetes mellitus is not a contraindication for implantable LVAD as DT. Notably, most cases of the pulmonary hypertension caused by high left atrial pressure and low cardiac output may be reversed by LVAD implantation.¹⁴ Hepatorenal function will be assessed by J-HMRS, and LVAD can be implanted as long as the score is acceptable for the indication of DT. Liver cirrhosis or dialysis-dependence is still considered irreversible end-organ dysfunction and remains contraindicated in DT.

Body mass index (BMI) >25 is an ineligibility to HTx in the Japanese listing criteria, but DT allows a higher BMI. Severe obesity is defined as BMI ≥35 by the Japan Society for the Study of Obesity. The prognosis of LVAD patients with a BMI ≥35 is comparable with that of patients with a BMI <35, despite the higher risk of complications such as thrombosis or driveline infection.^15,16 The Japanese Guidelines for Implantable Left Ventricular Assist Device for Patients with Severe Heart Failure (https://www.j-circ.or.jp/cms/wp-content/uploads/2021/03/JCS2021_Ono_Yamaguchi.pdf) also state that caution should be taken with those with BMI ≥35. Therefore, the indications for DT should be applied carefully in those with BMI ≥35, although they cannot be excluded solely based on BMI values.

For DT exclusion, we add persistent right heart failure as a criterion. Although the definite predictors have not yet been established for persistent right ventricular (RV) failure after LVAD implantation, several risk factors before LVAD implantation have been proposed, such as high pulmonary vascular resistance, low RV stroke work index, echocardiographic RV dysfunction, the RV/LV volume ratio, and longitudinal systolic strain of the RV free wall, and small LV size.^17–19 Therefore, these factors should be taken into consideration prior to DT-LVAD implantation. DT in older adults aims for long-term high QOL on LVAD support, and the existence of concomitant RV failure may not be an ideal indication for DT. Before conversion from central extracorporeal membrane oxygenation to implantable LVAD, the right heart function should be thoroughly evaluated so that postoperative right heart failure is unlikely to become chronic.

Regarding alcohol, the Japanese Guidelines for Diagnosis and Treatment of Acute and Chronic Heart Failure²⁰ recommend reduction of, but not abstaining from alcohol consumption. However, these recommendations may be revised in the future. Abstinence should be encouraged for DT patients because alcohol may contribute to worsening of advanced HF. Patients who declare abstinence from alcohol and smoking should be included. Discretion should be given to each implant center to determine appropriate candidacy based on the history of alcohol consumption or smoking.

4. Implant and Management Centers

Of the facilities certified for LVAD implantation by the Council for Clinical Use of Ventricular Assist Device Related Academic Societies, only DT clinical trial facilities will initiate DT therapy in Japan. The limited number of DT implant centers may cause geographic disparities in access for patients requiring treatment. To address this issue, DT-LVAD can be implanted in a distant hospital, and managed in the patient’s locale. As certified LVAD management centers have become more available nationwide, patients are expected to have follow-ups at their local management centers. In such cases, a regular conference should be held between the implant and management centers to share relevant information. The criteria for the DT implant centers will be revised in the future to expand the centers nationwide.

Physicians who implant or manage DT patients require certification by the Council for Clinical Use of Ventricular Assist Device Related Academic Societies. The criteria for certification are can be found on the homepage of the Council for Clinical Use of Ventricular Assist Device Related Academic Societies (https://j-vad.jp/certification/).

5. Flowchart of DT-LVAD Process

Figure 1 is a flowchart of DT-LVAD. Before implantation, the attending physician supplies the basic information, criteria for indications, and exclusion criteria in the checklist (Table 3) for review by the DT committee. Also, before pump exchange, the attending physician supplies the pump exchange information in the checklist (Table 4) to be reported to the DT committee. Urgent pump exchange may preclude preoperative reporting, but a report should be submitted immediately after surgery.

Figure 1.

Flow diagram of DT-LVAD. To implant LVAD as DT, submission of a preoperative checklist is necessary. The checklist should be completed by 6 months after LVAD implantation, and is subjected to review by the DT committee. DT, destination therapy; LVAD, left ventricular assist device; MMSE, Mini-Mental State Examination; TMT-B, Trail Making Test-B.

Table 3. Checklist for First Implantation of DT-LVAD (Preoperative and 6-Month Postoperative Reports)

Basic information	Date of preoperative report: MM/DD/YY
Implant center
Initial	□.□
Age	□□ years
Sex	□ Male　□ Female
Etiology of heart failure	□ Dilated cardiomyopathy　□ Hypertrophic cardiomyopathy (including dilated phase)　□ Ischemic heart disease　□ Congenital heart disease　□ Valvular disease　□ Drug-induced myocarditis　 □ Post-myocarditis　□ Cardiac sarcoidosis　□ Other (　　)
Scheduled LVAD implantation date	MM/DD/YY
Planned device
Exclusion criteria for transplantation	□ Age　□ Renal dysfunction　□ Liver dysfunction　□ Pulmonary hypertension　□ Obesity　□ Diabetes with poorly controlled complications　□ History of malignancy　□ Other (　　)
Specify the exclusion criteria for transplantation in detail
Indication criteria (before implantation)
INTERMACS profile	□ 2　□ 3　□ 4
Mechanical circulatory support	□ None　□ IABP　□ IMPELLA　□ Paracorporeal LVAD □ Other (　　)
J-HeartMate Risk Score	Age 　years, Alb 　g/dL, Cre 　mg/dL, INR 　, Center volume index 　. Score 　,　□ Low　□ Medium　□ High
Mini-Mental State Examination	points (≥24 for those aged ≥65 years)
Trail Making Test-B	seconds (≤300 s for those aged ≥65 years)
≥5-year life expectancy for comorbidities	□ Yes　□ No
A caregiver who can live with the patient for ≥6 months after discharge, or equivalent support is available	□ Yes　□ No
The patient and his/her family understand and consent to DT and end-of-life care	□ Yes　□ No
Exclusion criteria (before implantation)
During maintenance dialysis	□ Yes　□ No
Complicated by liver cirrhosis	□ Yes　□ No
Complicated by severe infection	□ Yes　□ No
High probability of postoperative right heart failure	□ Yes　□ No
Self-management of the device may be difficult for complicating brain disorders and neuromuscular diseases	□ Yes　□ No
Conditions 6 months after implantation	Date of 6-month report: MM/DD/YY
J-MACS ID
LVAD implantation date	MM/DD/YY
Implanted device
Survival	□ Yes　□ No (date of death□□□□.□□.□□)
Discharged and followed on outpatient basis	□ Yes　□ No
Living with a caregiver	□ Yes　□ No
Listed for transplantation or preparing for listing	□ Yes　□ No

Alb, serum albumin; Cre, serum creatinine; DT, destination therapy; IABP, intra-aortic balloon pump; INR, international normalized ratio; LVAD, left ventricular assist device.

Table 4. Checklist for DT-LVAD Pump Exchange (Preoperative and 6-Month Postoperative Reports)

Basic information	Date of preoperative report: MM/DD/YY
J-MACS ID
Previous implant center
Previous implant date	MM/DD/YY
Previous implant device
Previous pump exchange	□ No　□ Yes (□ times)
Initial	□.□
Age	□□ years
Sex	□ Male　□ Female
Etiology of heart failure	□ Dilated cardiomyopathy　□ Hypertrophic cardiomyopathy (including dilated phase)　□ Ischemic heart disease　□ Congenital heart disease　□ Valvular disease　□ Drug-induced myocarditis　 □ Post-myocarditis　□ Cardiac sarcoidosis　□ Other (　　)
Exclusion criteria for transplantation	□ Age　□ Renal dysfunction　□ Liver dysfunction　□ Pulmonary hypertension　□ Obesity　□ Diabetes with poorly controlled complications　□ History of malignancy　□ Other (　　)
Information before pump exchange
Scheduled exchange center
Scheduled exchange date	MM/DD/YY
Device to be exchanged
Indicators of various organ functions	Alb 　g/dL, Cre 　mg/dL, TB 　mg/dL, CRP 　mg/dL, LDH 　U/L.
Reasons for exchange (including suspected cases)	□ Pump thrombus　□ Device failure (other than thrombus)　 □ Pump infection　□ Other (　　)
Detailed reasons for exchange
Conditions 6 months after the exchange	Date of 6-month report: MM/DD/YY
New J-MACS ID after exchange
Date of exchange	MM/DD/YY
Exchanged device
Survival	□ Yes　□ No (date of death: MM/DD/YY)
Discharged and followed on outpatient basis	□ Yes　□ No
Living with a caregiver	□ Yes　□ No

Alb, serum albumin; Cre, serum creatinine; DT, destination therapy; IABP, intra-aortic balloon pump; INR, international normalized ratio; LDH, serum lactate dehydrogenase; LVAD, left ventricular assist device; TB, serum total bilirubin.

After implantation of LVAD, device education, home environment check, out-of-hospital training with caregivers, including an overnight stay at home, and registration on the J-MACS are the same mandatory process as for BTT. At 6 months post implantation, additional conditions arising since implantation or post pump exchange as described in the checklist (Tables 3,4) should be submitted by the facility for review by the DT committee.

Death within 6 months after implant should be reported to the DT committee as soon as possible. If the review by the DT committee reveals an alarming deviation from DT indication or high mortality within 6 months in a single center, the committee advises the Council to discuss the certification for the implant center.

6. Special Considerations During Follow-up

Table 5 summarizes the points to be checked during follow-up of DT-LVAD patients. Many of the considerations have already been mentioned in the preceding sections of this Statement.

Table 5. Follow-up Schedules for DT-LVAD on Outpatient Basis

	Person in charge	Frequency	Contents	Other
(1) Items that patients themselves should record and keep in mind daily	Patient	Daily	(A) General condition (B) Device parameters (C) Medication adherence (including anticoagulant therapy) (D) Infection (including driveline) (E) Compliance with restrictions	If any abnormality is found, contact the team members of the implant center or the management center for consultation
(2) Medical examination at VAD implant or management center	Team members of implant or management center	1–2 times/month	(A) General condition (including hemodynamics) (B) Anticoagulant therapy (C) Device system (including battery and alarm) (D) Driveline and its exit site (E) Medications (F) Compliance with restrictions	If the management center encounters a contingency that is difficult to deal with, contact the implant center team. Additionally, during the follow-up at the management center, information shall be shared through regular conferences with the implant center
(3) Evaluation of treatment by registering on the J-MACS	Team members of the implant or management center	Once every 6–12 months	(A) Hemodynamics (blood pressure, ECG) (B) Volume status (peripheral edema, ascites, etc.) (C) Transthoracic echocardiography (D) Exercise tolerance (6-min walking distance or cardiopulmonary exercise test, etc.) (E) Quality of life (EQ-5D), neuropsychiatric test (Mini- Mental State Examination, Trail Making Test-B) (F) Adverse events (infection, neurological disorders, renal dysfunction, right heart failure, arrhythmias, etc.)	Evaluate the progress of VAD treatment and confirm the safety and efficacy of the device. An adverse event should be reported to J-MACS as soon as it happens. Especially, stroke should be reported with modified Rankin scale
(4) Mental care for patients and caregivers	VAD coordinators or nurses at the implant or management center are mainly in charge (in-charge person may be different in each center) and consult with a clinical psychologist or liaison team as needed	At 6 months after implant as needed (at least once per year)	(A) Mental health check (including evaluation of self-management ability) (B) Reconfirmation of advance directive	Patients and caregivers are interviewed individually as needed. In case of any change in self- management ability, consider reviewing the nursing care system

DT, destination therapy; LVAD, left ventricular assist device.

First of all, it is crucial to establish a system that allows patients to return home, including a medical team that handles DT-LVAD, and criteria for follow-up at home. Details are shown in Table 5. We emphasize regular mental care for patients and caregivers. Currently, medical fees are not reimbursed if a clinical psychologist provides regular mental care for those who are not diagnosed with a mental illness. Therefore, it may be difficult to involve a clinical psychologist as a member of the VAD team in some hospitals. A more realistic clinical option is for the VAD coordinators to provide on-going mental care, by consulting clinical psychologists and psychiatric teams as needed.

Secondly, healthcare providers need to establish the requirements for compliance by patients and caregivers (details should be given in the manual for each facility). Generally, patients and caregivers shall comply with the following items: (1) obeying the instructions of the training program at the hospital (usage and precautions for use); (2) carrying a patient card that describes emergency contact information and first-aid; (3) patients are prohibited from driving a vehicle and as a passenger in a car, contact between the seat belt and cables or extracorporeal devices should be avoided; (4) consultation with both the airline and the follow-up center prior to travel; (5) strict adherence to medication and refraining from drinking or smoking; (6) patients are prohibited from participating in extreme sports with the risk of driveline damage and deterioration of the exit site.

Thirdly, criteria for discharge, including housing conditions, must be established (details should be given in the manual of each facility). We have already discussed caregiver issues in Section 3.2.

Fourthly, emergency measures for patients, caregivers, and hospitals are important. (1) Hospitals should regularly cooperate with emergency organizations (i.e., fire departments, etc.) through conferences (ideally including explanations of the device to firefighters/emergency paramedics). The explanations do not necessarily require emergency personnel to operate the devices in an emergency. Therefore, it is recommended that patients carry a card to allow anyone to perform emergency first-aid when necessary. (2) Patients should confirm their safety in an emergency as instructed by the hospital. As a caregiver may not be available in all environments, such as school or work, emergency measures should be taught in the patient’s specific social environments. For that purpose, educational tools such as DVDs, videos, and web-content are recommended. Based on our experience, setting the bar too high for VAD knowledge and skills for the patient’s social groups jeopardizes the patient returning to work/school. Therefore, device training is not mandatory as long as colleagues or teachers in the company or school have basic knowledge of emergency procedures.

All follow-up systems should be reconfirmed and revised accordingly based on changes in the patient’s and/or caregiver’s circumstances. In this regard, a re-education system is also indispensable. Re-education items include device handling and trouble-shooting, management and fixation of a driveline, adherence to medication, weight control, etc.

7. Advance Directives and End-of-Life Care

7.1 Advance Directives and Advance Care Planning (ACP)

End-of-life care for DT patients has long been discussed before this committee was assembled. Advance directives (ADs) are of the utmost importance, so we have created a standard version (Figure 2) for DT-LVAD. Before LVAD implantation, healthcare providers should always provide an explanation of potential complications of the therapy to patients and caregivers. Current hospital-specific forms of informed consent vary among facilities. However, the DT committee suggests a nationwide common standard to avoid confusion, especially when a patient is being managed by multiple centers.

Figure 2.

Advance Directive form on the end-of-life care for patients with implantable left ventricular assist device.

Obtaining the ADs is important for the process of DT-LVAD as shown in Figure 1. DT implantation should be performed after sufficient understanding of the treatment and thorough discussion of end-of-life care with detailed documentation. However, the AD form may still have blanks before surgery, giving the patient the right to further contemplate some end-of-life issues. In this situation, the patient should not be forced to complete the form, with a consensus between the patient and the caregiver being reached by approximately 6 months after LVAD surgery. It is extremely important to update the ADs at least annually in consideration of the mental status of both the patient and the caregiver. ACP focuses on the sharing of the process of decision making among the patient, a surrogate decision-maker, and healthcare providers based on the patient’s values and preferences.²¹ The decision-making process described here, which emphasizes the voluntary intention of the patient to obtain ADs, is consistent with the concept of ACP.

A caregiver is often appointed as a surrogate decision-maker, but not always. A caregiver is usually a family member who lives with the patient but a surrogate decision-maker is not necessarily related by blood. A caregiver must be designated before LVAD implantation, but not always a surrogate decision-maker at that time. Even if a surrogate decision-maker is not designated before LVAD implantation, the patient can undergo DT if he/she can make a decision and fully understands DT. Of course, a surrogate decision-maker must be selected soon after LVAD implantation in that case. If the patient cannot make a decision for DT without a surrogate decision-maker before LVAD implantation, the medical team is still able to perform DT at the discretion of the medical team in the following instances: (1) when there is a good reason to assume that the patient wishes to receive DT, or (2) when the treatment strategy most suitable for the patient is considered to be DT even though the patient’s will for DT cannot be assumed as either positive or negative. In either case, a decision by the medical team should be made after discrete discussion.

How should ADs be handled for minors, aged <18 years? Generally, elementary school or younger children cannot easily understand the ADs, eliminating the need for their preparation. However, if the team at an implant center considers that the ADs are understandable for junior high school or older children, it can be created in the same format. In this case, guardians (mainly one or both parents) are to be surrogate decision-makers. For minors, as legally advised, both parents should jointly sign as the surrogate decision-maker whenever possible, although we usually expect a single surrogate decision-maker to be appointed, to avoid conflict between decision-makers. Minors mostly undergo DT as BTC and are likely classified as profile 2, eliminating the need for preparation of ADs before implantation. Conventional instructions for BTT patients in each facility are followed by subsequent listing for HTx. However, if the patient has not been listed for transplant after 6 months, the healthcare providers shall consider preparation of ADs.

7.2 LVAD Deactivation

What are the prerequisites for LVAD deactivation? Issues surrounding deactivation are patient-specific and extremely difficult. First of all, the patient’s wishes for discontinuation of LVAD support at the end-of-life should be clear on the ADs. In addition, the medical record should state that the patient and the surrogate decision-maker have received and accepted detailed explanations from medical professionals regarding deactivation of the LVAD. Subsequently, the patient is medically determined to be at the end-of-life. The Guidelines for the End-of-Life Care in Emergency/Intensive Care - Statements from 3 Joint Academic Societies (https://www.jsicm.org/pdf/1 guidelines1410.pdf) have the following definitions for the status of end-of-life: (1) irreversible total brain dysfunction (including after diagnosis of brain death and confirmation of cessation of cerebral blood flow) is present over a sufficient time; (2) the patient’s life depends on artificial devices, multiple end-organ dysfunction has become irreversible, and no alternatives, such as transplantation, are available; (3) no further treatment can be performed, resulting in death shortly, even if the current treatment is continued; and (4) the patient is in the terminal stage of irreversible disease, for example, malignancy after aggressive treatment. To examine these 4 points, a clinical ethics committee should be established in the hospital. After repeatedly confirming the intent of the patient (who generally cannot make a confirmation due to impaired consciousness) and his/her family, including the surrogate decision-maker, and after taking detailed medical records, LVAD operation may be discontinued if continuation of LVAD treatment may exacerbate the patient’s pain or impair the patient’s dignity. This is substantially the same as terminating mechanical ventilation or temporary MCS. If the clinical ethics committee of each institution has difficulty in decision making due to lack of experience, they may consult with an institution with sufficient experience. Therefore, if a patient who is not in the end-of-life status wants to deactivate LVAD, the treatment cannot be terminated immediately. A palliative care team should repeatedly discuss with the patient and his/her family, including the surrogate decision-maker, regarding the presence of physical and mental pain and the continuation of LVAD treatment. Subsequently, treatment termination may be considered if informed consent cannot be obtained for continuation of LVAD treatment.

Acknowledgment

The authors thank Yuki Fujimura for the critical reading of this manuscript.

Conflict of Interest Disclosures

• Koichiro Kinugawa, Nipro/Abbott (lecture fees)

• Yasushi Sakata, Nirpo/Abbott (research funds), Abbott (scholarship funds)

• Minoru Ono, Nipro (lecture fees), Nipro (scholarship funds)

• Shinichi Nunoda, none

• Koichi Toda, none

• Norihide Fukushima, none

• Akira Shiose, Abbott (lecture fees), Abbott (scholarship funds)

• Shogo Oishi, none

• Dai Yumino, none

• Teruhiko Imamura, none

• Miyoko Endo, none

• Yumiko Hori, none

• Koichi Kashiwa, none

• Kaoruko Aita, none

• Hiroyuki Kojin, none

• Yutaka Tejima, none

• Yoshiki Sawa, Nipro/Abbott (endowed department), Nipro (research funds), Nipro/Abbott (scholarship funds)

Appendix

Chair of Committee

• Koichiro Kinugawa, Second Department of Internal Medicine, Faculty of Medicine, University of Toyama

Committee Members

• Kaoruko Aita, Graduate School of Humanities and Sociology, The University of Tokyo

• Miyoko Endo, Department of Nursing, The University of Tokyo Hospital

• Norihide Fukushima, Department of Transplant Medicine, National Cerebral and Cardiovascular Center

• Yumiko Hori, Department of Transplant Medicine, National Cerebral and Cardiovascular Center

• Teruhiko Imamura, Second Department of Internal Medicine, Faculty of Medicine, University of Toyama

• Koichi Kashiwa, Department of Medical Engineering, The University of Tokyo Hospital

• Hiroyuki Kojin, Department of Quality and Patient Safety, Graduate Faculty of Interdisciplinary Research, Faculty of Medicine, University of Yamanashi

• Shinichi Nunoda, Department of Therapeutic Strategy for Severe Heart Failure, Graduate School of Medicine, Tokyo Women’s Medical University

• Shogo Oishi, Department of Cardiology, Himeji Brain and Heart Center

• Minoru Ono (Council Vice-chair), Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo

• Yasushi Sakata (Council Vice-chair), Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine

• Akira Shiose, Department of Cardiovascular Surgery, Faculty of Medical Sciences, Kyushu University

• Yutaka Tejima, Graduate School of Law, Kobe University

• Koichi Toda, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine

• Dai Yumino, Yumino Heart Clinic

Council Chair

• Yoshiki Sawa, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine

(Listed in alphabetical order)

References

• 1.   Kinugawa K. How to treat stage D heart failure?: When to implant left ventricular assist devices in the era of continuous flow pumps? Circ J 2011; 75: 2038–2045.
• 2.   Kinugawa K, Nishimura T, Toda K, Saiki Y, Niinami H, Nunoda S, et al. The second official report from Japanese registry for mechanical assisted circulatory support (J-MACS): First results of bridge to bridge strategy. Gen Thorac Cardiovasc Surg 2020; 68: 102–111.
• 3.   Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001; 345: 1435–1443.
• 4.   Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009; 361: 2241–2251.
• 5.   Mehra MR, Uriel N, Naka Y, Cleveland JC Jr, Yuzefpolskaya M, Salerno CT, et al. A fully magnetically levitated left ventricular assist device: Final report. N Engl J Med 2019; 380: 1618–1627.
• 6.   Molina EJ, Shah P, Kiernan MS, Cornwell WK 3rd, Copeland H, Takeda K, et al. The Society of Thoracic Surgeons Intermacs 2020 Annual Report. Ann Thorac Surg 2021; 111: 778–792.
• 7.   Goldstein DJ, Naka Y, Horstmanshof D, Ravichandran AK, Schroder J, Ransom J, et al. Association of clinical outcomes with left ventricular assist device use by bridge to transplant or destination therapy intent: The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) randomized clinical trial. JAMA Cardiol 2020; 5: 411–419.
• 8.   Shah KB, Starling RC, Rogers JG, Horstmanshof DA, Long JW, Kasirajan V, et al. Left ventricular assist devices versus medical management in ambulatory heart failure patients: An analysis of INTERMACS Profiles 4 and 5 to 7 from the ROADMAP study. J Heart Lung Transplant 2018; 37: 706–714.
• 9.   Kittleson MM, Shah P, Lala A, McLean RC, Pamboukian S, Horstmanshof DA, et al. INTERMACS profiles and outcomes of ambulatory advanced heart failure patients: A report from the REVIVAL Registry. J Heart Lung Transplant 2020; 39: 16–26.
• 10.   Cowger J, Sundareswaran K, Rogers JG, Park SJ, Pagani FD, Bhat G, et al. Predicting survival in patients receiving continuous flow left ventricular assist devices: The HeartMate II risk score. J Am Coll Cardiol 2013; 61: 313–321.
• 11.   Imamura T, Kinugawa K, Ono M, Fukushima N, Shiose A, Matsui Y, et al. Bridge-to-bridge left ventricular assist device implantation strategy vs. primary left ventricular assist device implantation strategy. Circ J 2020; 84: 2198–2204.
• 12.   Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.
• 13.   Toyokura M, Tanaka H, Furukawa T, Yamanouchi Y, Murakami K. Normal aging effect on cognitive task performance of information-processing speed: Analysis of paced auditory serial addition task and trail making test. Brain Sci Ment Disord 1996; 7: 401–409.
• 14.   Mikus E, Stepanenko A, Krabatsch T, Loforte A, Dandel M, Lehmkuhl HB, et al. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg 2011; 40: 971–977.
• 15.   Clerkin KJ, Naka Y, Mancini DM, Colombo PC, Topkara VK. The Impact of obesity on patients bridged to transplantation with continuous-flow left ventricular assist devices. JACC Heart Fail 2016; 4: 761–768.
• 16.   Akay MH, Nathan SS, Radovancevic R, Poglajen G, Jezovnik MK, Candelaria IN, et al. Obesity is associated with driveline infection of left ventricular assist devices. ASAIO J 2019; 65: 678–682.
• 17.   Imamura T, Kinugawa K, Kato N, Muraoka H, Fujino T, Inaba T, et al. Late-onset right ventricular failure in patients with preoperative small left ventricle after implantation of continuous flow left ventricular assist device. Circ J 2014; 78: 625–633.
• 18.   Imamura T, Kinugawa K, Kinoshita O, Nawata K, Ono M. High pulmonary vascular resistance in addition to low right ventricular stroke work index effectively predicts biventricular assist device requirement. J Artif Organs 2016; 19: 44–53.
• 19.   Bellavia D, Iacovoni A, Scardulla C, Moja L, Pilato M, Kushwaha SS, et al. Prediction of right ventricular failure after ventricular assist device implant: Systematic review and meta-analysis of observational studies. Eur J Heart Fail 2017; 19: 926–946.
• 20.   Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, et al; on behalf of the Japanese Circulation Society and the Japanese Heart Failure Society Joint Working Group. JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure: Digest version. Circ J 2019; 83: 2084–2184.
• 21.   Anzai T, Sato T, Fukumoto Y, Izumi C, Kizawa Y, Koga M, et al; on behalf of the Japanese Circulation Society Joint Working Group. JCS/JHFS 2021 statement on palliative care in cardiovascular diseases. Circ J 2021; 85: 695–757.