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 –

Abstract

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.

Left ventricular assist devices (LVAD) have become a crucial option for advanced heart failure patients as a bridge to transplant (BTT), bridge to recovery, or bridge to decision and destination therapy (DT).^1–5 Because of the technological improvement and device miniaturization, the survival and quality of life of patients on DT with implantable LVAD (I-LVAD) has significantly improved.^6–9 DT has also become important under the circumstances of donor shortage for heart transplantation. In the USA, DT has been increasingly popular since 2010 after insurance reimbursement for HeartMate II^® (Thoratec Corp, Pleasanton, CA, USA) based on the Centers for Medicare and Medicaid Services (CMS) criteria.^4,10

On the other hand, DT has not yet been approved in Japan. Contraindications to BTT such as high age, persistent multi-organ dysfunction or pulmonary hypertension sometimes prevent a patient from being listed for heart transplantation even after receiving mechanical circulatory support. In Japan, when a patient with critical cardiogenic shock is refractory to optimal medical treatment and even temporary mechanical circulatory devices, extracorporeal VAD implantation is the only next step available. At present, if the patient proves to be unsuitable for BTT after a certain period of extracorporeal VAD support, there is no further treatment. It is a dismal situation for a patient being dependent on extracorporeal VAD indefinitely within the hospital and the long-term prognosis of such patients is poor owing to the high risk of infection, stroke, or bleeding complication because of the extracorporeal VAD.¹¹

However, once DT is approved, we would be able to consider another strategy for such patients, namely, bridge to I-LVAD as DT. Considering that the most common and non-modifiable contraindication of BTT is advanced age,¹² the significance of DT will be enormous in Japan with its rapidly aging population. Because the risk of device-related complications becomes higher with time after extracorporeal VAD implantation, it is highly recommended to bridge to I-LVAD as soon as possible while the patient’s general condition is stable without systemic organ dysfunction.

Recently, the academic consensus statement for DT eligibility in Japan was announced.¹³ According to the statement, it is essential to confirm that an aged patient with renal/hepatic dysfunction may be ineligible to DT. Therefore, the aim of this study was to investigate the preoperative predictors for ineligibility for bridge to I-LVAD for DT among patients who received extracorporeal VAD implantation.

Methods

Patient Selection

Between 2002 and 2014, 91 patients received extracorporeal VAD (Nipro-VAD^®), including biventricular assist devices (BiVAD), and were followed up for >6 months. After excluding those who lacked enough preoperative and postoperative data, we finally enrolled 85 patients. All participants gave written informed consent before enrollment.

Preoperative Variables

Demographic data, laboratory data obtained <24 h before the surgery, and hemodynamic/echocardiographic data obtained <1 week before the surgery, were collected as baseline variables. Among the patients receiving continuous hemodiafiltration (CHDF), the value of serum creatinine just before CHDF was adopted.

Definition of DT Ineligibility (DTI)

The recent academic consensus statement for DT in Japan was published in March 2015.¹³ Patients on chronic dialysis, or with liver cirrhosis, severe infection, right heart failure after VAD implantation and severe cerebral disorder are defined as unsuitable for DT. To assess systemic organ dysfunction, the statement uses the Japan-VAD risk score (J-VAD risk score), which is a modified version of the HeartMate II risk score.¹⁴ The J-VAD risk score is calculated as follows: 0.0274×age−0.723×serum albumin (g/dl)+0.74×serum creatinine (mg/dl)+1.136×PT-INR+0.807×(0 or 1) (dependent on the number of I-LVAD cases of the center).

According to the J-VAD risk score, patients are classified as low (<1.58), medium (1.58–2.48) or high risk (>2.48). The statement recommends that the J-VAD risk score should be low or medium in patients <65 years, but should be exclusively low for those ≥65 years to satisfy DT eligibility.¹³

Considering this recommendation, we defined patients who were ineligible for the bridge from extracorporeal VAD to I-LVAD for DT as follows: (1) those who died within 6 months post-LVAD; (2) those requiring BiVAD support; and (3) those with persistent organ dysfunction (medium or high J-VAD risk score) after 6 months’ LVAD support.

Although BiVAD requirement is not an absolute contraindication for BTT, we consider BiVAD patients as DTI because extracorporeal BiVAD patients generally have a poor prognosis unless right ventricular assist device (RVAD) is able to be removed afterward.^4,15 Moreover, there has not been a definite method of predicting weaning from RVAD at the time of BiVAD implantation. Without knowing who can be successfully weaned from RVAD, we cannot help but hesitate to implant extracorporeal RVAD in transplant-ineligible patients because implantable RVAD system or total artificial heart for DT use is not yet available. Even if a LVAD is converted into an implantable type, the RVAD system remains extracorporeal and the patient is bound to be in hospital indefinitely with miserable quality of life.

We arbitrarily set the time limit of conversion to I-LVAD for DT at 6 months, because complications associated with extracorporeal VAD increase in a time-dependent manner.¹¹ Organ dysfunction was defined when the J-VAD risk score was medium or high. In younger patients, DT can also be recommended with a medium J-VAD risk score. Although our study population was all below the age of 65 years, under the current BTT strategy, the main target of upcoming DT should be the aged population, and we applied more strict criteria of the J-VAD risk score that allowed only a low-risk group as DT eligible. These composite endpoints were defined as DTI.

Statistical Analysis

Data were analyzed by SPSS Statistics^® ver.22 (SPSS Inc, Chicago, IL, USA). Statistical tests were two-tailed, and P<0.05 was assumed as significant. All data are expressed as mean±SD. Continuous variables were compared by unpaired t-test or Mann-Whitney U test, and categorical variables were compared by Chi-square test or Fisher’s exact test as appropriate.

Univariate logistic regression analysis for DTI was performed for each variable, and significant factors (P<0.05) were selected. Before enrolling factors for multivariate analysis, we performed correlation analyses between each pair of all significant factors in order to exclude multicollinearity. We defined 2 factors that showed an absolute value of the correlation coefficient >0.3 as significantly correlated. For such 2 factors, we only selected the factor that showed the higher odds ratio (OR) for DTI. For continuous variables, the cutoff value was defined from the receiver-operating characteristic curve for predicting DTI to convert continuous values to categorical data by using JMP Pro^® ver.11.0 (SAS Institute Inc, Cary, NC, USA).

We performed multivariate logistic regression analysis for DTI including factors that were significant (P<0.05) in the univariate analysis. We then constructed a new scoring system to predict DTI considering the OR of the multivariate analysis and stratified the subjects. Kaplan-Meier survival analysis was performed to assess the 6-month survival. Survivals were compared by log-rank test among these groups.

Results

Clinical Outcomes

Among the 85 patients who had received extracorporeal VAD, DTI was recorded for 32 patients: 18 patients (56.3%) required BiVAD support, 15 patients (46.9%) died within 6 months (5 received BiVAD), and 6 patients (18.8%) showed persistent organ dysfunction with medium or high J-VAD risk score at 6 months after extracorporeal VAD implantation (2 received BiVAD).

Among the non-DTI group, 12 patients (22.6%) were successfully bridged to I-LVAD within 6 months; 1 patient (1.9%) underwent heart transplantation and 7 patients (13.2%) were successfully weaned from extracorporeal VAD; 33 patients (62.3%) had low J-VAD risk scores on extracorporeal VAD at 6 months (Figure 1). The most common reason why extracorporeal VAD was not converted to I-LVAD in these patients was that I-LVAD had not been approved at the time. In some of them, local cannula site infection was the reason for continuing support on extracorporeal VAD, but we did not include them in the DTI group. In fact, local infection could be successfully managed by appropriate treatment in some cases, and we later converted extracorporeal VAD to I-LVAD.

Figure 1.

Summary of study design. DTI, destination therapy ineligibility; BiVAD, biventricular assist device; J-VAD risk score, Japan-VAD risk score; HTx, heart transplantation; VAD, ventricular assist device.

Preoperative Parameters

The mean age was 37.2±14.1 years and there were 61 (71.8%) males. The DTI group had higher body mass index (BMI), higher incidence of past history of cardiac surgery, CHDF, percutaneous cardiopulmonary support (PCPS) and INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile 1 compared with the non-DTI group (Table 1).

Table 1. Baseline Characteristics of Study Patients With Extracorporeal LVAD

	Total (n=85)	DTI (n=32)	Non-DTI (n=53)	P value
Demographic variables
Age, years	37.2±14.1	39.6±16.3	35.8±12.5	0.262
Male, n (%)	61 (71.8)	23 (71.9)	38 (71.7)	0.986
BMI (kg/m2)	20.5±4.7	21.9±5.5	19.7±4.0	0.037*
BSA (m2)	1.61±0.24	1.62±0.27	1.60±0.22	0.652
Heart rate (beats/min)	103.1±23.0	99.7±23.0	105.3±23.0	0.283
SBP (mmHg)	89.4±17.5	93.7±19.7	86.9±15.6	0.082
Etiology of heart failure, n (%)				0.054**
Dilated cardiomyopathy	44 (51.8)	10 (31.3)	34 (64.2)
Dilated phase hypertrophic cardiomyopathy	4 (4.7)	2 (6.3)	2 (3.8)
Ischemic cardiomyopathy	18 (21.2)	9 (28.1)	9 (17.0)
Myocarditis	8 (9.4)	4 (12.5)	4 (7.5)
Others	11 (12.9)	7 (21.9)	4 (7.5)
Past history, n (%)
Diabetes mellitus	9 (10.6)	4 (12.5)	5 (9.4)	0.723
Cardiac surgery	17 (20.0)	11 (34.4)	6 (11.3)	0.010*
Concomitant medication, n (%)
β-blocker	23 (27.1)	8 (25.0)	15 (28.3)	0.701
RAS-inhibitor	32 (37.6)	10 (31.3)	22 (41.5)	0.293
Diuretics	50 (58.8)	18 (56.3)	32 (60.4)	0.593
Inotropes	76 (89.4)	28 (87.5)	48 (90.6)	0.366
Vasodilators	28 (32.9)	14 (43.8)	14 (26.4)	0.114
Mechanical devices, n (%)
IABP	61 (71.8)	21 (65.6)	40 (75.5)	0.329
CHDF	17 (20.0)	11 (34.4)	6 (11.3)	0.010*
PCPS	34 (40.0)	18 (56.3)	16 (30.2)	0.017*
Mechanical ventilation	57 (67.1)	25 (78.1)	32 (60.4)	0.092
INTERMACS Profile, n (%)
1	60 (70.6)	28 (87.5)	32 (60.4)	0.008*

*P<0.05 by Chi-square test, Fisher’s exact test, unpaired t-test or Mann-Whitney’s test as appropriate. **Chi-square test for all distribution of etiology. LVAD, left ventricular assist device; BMI, body mass index; BSA, body surface area; SBP, systolic blood pressure; RAS, renin-angiotensin-aldosterone system; IABP, intra-aortic balloon pumping; CHDF, continuous hemodiafiltration; PCPS, percutaneous cardiopulmonary support; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; DTI, destination therapy ineligibility.

Hemoglobin and serum albumin were significantly lower (P<0.05, respectively) in the DTI group. Lower pulmonary capillary wedge pressure (PCWP) and smaller left ventricular diastolic dimension (LVDd) were observed in the DTI group (P<0.05) (Table 2).

Table 2. Baseline Laboratory, Hemodynamic and Echocardiographic Variables of Study Patients With Extracorporeal LVAD

	Total (n=85)	DTI (n=32)	Non-DTI (n=53)	P value
Laboratory values
Hemoglobin (g/dl)	10.2±1.4	9.8±1.0	10.5±1.5	0.008*
Platelet (×104/μl)	13.6±8.2	11.6±7.6	14.8±8.3	0.084
Serum sodium (mEq/L)	133.4±7.2	134.5±6.5	132.7±7.5	0.250
Serum albumin (g/dl)	3.1±0.6	2.87±0.72	3.26±0.49	0.004*
Serum aspartate aminotransferase (U/L)	180.3±323.8	182.0±385.3	179.2±284.4	0.970
Serum alanine transaminase (U/L)	183.2±376.6	123.5±214.8	220.0±446.2	0.187
Serum total bilirubin (mg/dl)	3.5±4.3	4.7±5.7	2.9±3.0	0.110
Blood urea nitrogen (mg/dl)	27.0±15.1	27.2±15.1	26.9±15.2	0.917
Serum creatinine (mg/dl)	1.28±0.83	1.22±1.00	1.32±0.72	0.605
Serum C-reactive protein (mg/dl)	8.6±8.6	8.6±7.9	8.6±9.1	0.994
Prothrombin time (international normalized ratio)	1.42±0.51	1.33±0.61	1.48±0.42	0.172
Plasma B-type natriuretic peptide (pg/ml)	1,263.8±1,254.5	1,451.8±1,329.9	1,150.2±1,206.7	0.310
Log10-BNP	2.93±0.41	3.00±0.41	2.88±0.41	0.228
Hemodynamic status
Mean pulmonary artery pressure (mmHg)	31.2±10.1	28.0±9.1	32.8±10.4	0.062
Pulmonary capillary wedge pressure (mmHg)	23.5±8.2	20.1±7.2	25.2±8.2	0.012*
Mean right atrial pressure (mmHg)	13.2±7.4	14.8±6.9	12.3±7.6	0.189
Cardiac index (L·min−1·m−2)	2.03±0.53	2.03±0.59	2.03±0.51	0.990
Echocardiographic parameters
Left ventricular diastolic dimension (mm)	64.2±14.8	55.8±11.5	69.3±14.3	<0.001*
Left ventricular ejection fraction (%)	21.5±12.6	25.1±16.4	19.3±9.1	0.078

*P<0.05 by unpaired t-test or Mann-Whitney’s test as appropriate. BNP, B-type natriuretic peptide. Other abbreviations as in Table 1.

Univariate Analysis for DTI and Selection of Factors for Multivariate Analysis

Among all baseline variables, 9 factors, comprising INTERMACS profile 1, past history of cardiac surgery, PCPS (+), CHDF (+), higher BMI, lower PCWP, smaller LVDd, lower hemoglobin and lower serum albumin, were significant predictors of DTI from the univariate logistic analysis.

Considering each OR and P value after correlation analysis, 6 factors (profile 1, past history of cardiac surgery, CHDF (+), LVDd <64 mm, hemoglobin <11 g/dl, and serum albumin <3.1 g/dl) were finally enrolled into the multivariate analysis (Table 3).

Table 3. Univariate Logistic Regression Analysis for DTI Among Study Patients With Extracorporeal LVAD

	P value	OR	95% CI
INTERMACS Profile 1	0.012*	4.587	1.406–14.925
Past history of cardiac surgery	0.013*	4.103	1.339–12.574
PCPS (+)	0.019*	2.973	1.194–7.401
CHDF (+)	0.013*	4.103	1.339–12.574
BMI (higher)	0.044*	1.108	1.003–1.223
PCWP (lower)	0.017*	1.091	1.015–1.172
LVDd (smaller)	<0.001*	1.092	1.043–1.143
Hemoglobin (lower)	0.020*	1.548	1.070–2.237
Serum albumin (lower)	0.006*	3.344	1.412–7.937
PCWP <22 mmHg	0.062	2.625	0.953–7.231
LVDd <64 mm	0.001*	5.087	1.967–13.156
Hemoglobin <11 g/dl	0.012*	5.402	1.451–20.112
Serum albumin <3.1 g/dl	<0.001*	8.259	2.969–22.970

*P<0.05 by logistic regression analysis. CI, confidence interval; LVDd, left ventricular diastolic dimension; OR, odds ratio; PCWP, pulmonary capillary wedge pressure. Other abbreviations as in Table 1.

Multivariate Analysis for DTI and New Scoring System

Multivariate analysis revealed that past history of cardiac surgery (OR 6.522), CHDF (+) (OR 4.862), LVDd <64 mm (OR 4.552) and serum albumin <3.1 g/dl (OR 10.064) (P<0.05, respectively) were independent predictors for DTI (Table 4).

Table 4. Multivariate Logistic Regression Analysis for DTI Among Study Patients With Extracorporeal LVAD

	Univariate analysis			Multivariate analysis
	P value	OR	95% CI	P value	OR	95% CI
INTERMACS Profile 1	0.012*	4.587	1.406–14.925
Past history of cardiac surgery	0.013*	4.103	1.339–12.574	0.011*	6.522	1.534–27.739
CHDF (+)	0.013*	4.103	1.339–12.574	0.033*	4.862	1.132–20.877
LVDd <64 mm	0.001*	5.087	1.967–13.156	0.01*	4.552	1.437–14.420
Hemoglobin <11 g/dl	0.012*	5.402	1.451–20.112
Serum albumin <3.1 g/dl	<0.001*	8.259	2.969–22.970	<0.001*	10.064	2.864–35.368

*P<0.05 by logistic regression analysis. Abbreviations as in Tables 1,3.

Subsequently, we constructed a new scoring system for DTI. According to each OR in the multivariate analysis, we gave 2 points to LVDd <64 mm, 2 points to CHDF (+), 3 points to past history of cardiac surgery, and 4 points to serum albumin <3.1 g/dl. The DTI score was calculated out of a total 11 points and it had high predictive value for DTI (area under the curve 0.864). Moreover, we classified the subjects into 3 categories according to DTI score: low-risk group (0–3 points), medium-risk group (4–6 points) and high-risk group (7–11 points). With a cutoff of 3 points, the sensitivity and specificity were 0.906 and 0.623, respectively. With a cutoff of 7 points, sensitivity and specificity were 0.406 and 0.981, respectively (Figure 2).

Figure 2.

Receiver-operating characteristic curve of the score for predicting ineligibility for destination therapy (DT). AUC, area under the curve; pts, points.

The incidence of DTI was 8% (3/36) in the low-risk group, 46% (16/35) in the medium-risk group and 93% (13/14) in the high-risk group. The number of deaths was 1, 6 and 8 in each group respectively. Kaplan-Meier analysis showed significantly poor survival among those in the high DTI score group within 6 months after extracorporeal VAD implantation (Figure 3).

Figure 3.

Kaplan-Meier survival curves according to DTI score classification during the 6 months after extracorporeal VAD implantation. *Log-rank test. DTI, destination therapy ineligibility; pts, points; VAD, ventricular assist device.

Discussion

Our study demonstrated that LVDd <64 mm, CHDF (+), past history of cardiac surgery and serum albumin <3.1 g/dl were independent predictors for DTI. The DTI score, which was calculated by the existence/absence of these 4 factors, was useful for stratifying patients receiving extracorporeal VAD from the viewpoint of the probability of DTI.

Reason for Stratifying High-Risk Patients for DT Among Extracorporeal VAD Patients

Because prospective trials for DT have not been performed in Japan to date, we retrospectively investigated patients who had received extracorporeal VAD implantation for screening those at high risk for bridge to I-LVAD as DT. Owing to its high cost and limited sources of I-LVAD,¹⁶ it will be necessary to select patients who can receive optimal benefit from DT.

On the other hand, the prognosis and quality of life are extremely poor for those who are destined to live with extracorporeal VAD implantation indefinitely. Therefore, it will also be important to ascertain those who cannot be bridged to heart transplantation or I-LVAD (ie, DTI). In such a population, extracorporeal VAD implantation itself may be potentially contraindicated. Especially in aged (>65 years) patients with INTERMACS profile 1, extracorporeal VAD implantation as a bridge to DT should be cautiously indicated. Because the age is absolutely unmodifiable, there is no chance of using VAD for BTT under the current policy for Japanese heart transplantation listing.

Evaluation for DTI

Because of the high incidence of device-related complications during extracorporeal VAD support,¹¹ bridge to I-LVAD is generally recommended within several months before complications such as infection, thrombosis and bleeding emerge. For the present study, we set the time limit of bridge to I-LVAD for DT at 6 months, and needless to say patients must be alive during this observational period.

Next, persistent systemic organ dysfunction is a substantial barrier for DT. Although there are criteria for DT LVAD eligibility in the CMS criteria, no statements have been made about evaluation for organ dysfunction when selecting DT patients.¹⁰ This is not surprising because DT in origin is a therapeutic option for advanced heart failure with irreversible end-organ dysfunction. However, the academic consensus statement for DT eligibility in Japan includes the J-VAD risk score to secure good prognosis of DT, and therefore we applied this score to evaluate patients’ end-organ dysfunction.¹³

Moreover, we defined those who received BiVAD support as ineligible for DT. There is not a systematic tool available for predicting the probability of weaning from RVAD before surgery. Long-term support by RVAD was reported to have a high occurrence of multi-organ failure, sepsis, and thrombosis,¹⁷ and was associated with poor prognosis.¹⁸ Currently, there is no insurance coverage for implantable RVAD or total artificial heart in Japan, and indefinite support by extracorporeal RVAD is unbearable for anybody.

Significance of Each Parameter of DTI Score

First of all, it is important to determine the characteristics of those who die early (within 6 months in this study) after extracorporeal VAD implantation. The factors for early death after VAD implantation have been reported in several papers, although “early” was variably defined among the studies. We previously reported the TVAD score, which efficiently predicts 1-year survival with LVAD support.¹⁹ Our new DTI score included same factors of the TVAD score: lower albumin level and smaller LVDd, indicating that these 2 parameters play a key role in post-LVAD survival.

Preoperative low serum albumin level is known as an independent risk factor for mortality after cardiac surgery.^20,21 It was also reported that a low level of serum albumin was associated with postoperative acute renal failure and prolonged hospitalization after LVAD implantation.²² We reported that a perioperative low serum albumin level predicted the recovery of exercise tolerance,²³ and was a risk for driveline infection after I-LVAD surgery.²⁴ Low serum albumin may be a mixed consequence of malnutrition,²⁵ congestive hepatopathy,²⁶ or prolonged systemic inflammation.^23,27 The causal relationship between albumin level and clinical outcome has long been a matter of debate, but the above-referenced results suggest that low serum albumin is clearly associated with the mortality and morbidity of patients with LVAD implantation. Consequently, most of the scoring systems, including the J-VAD score, to predict post-LVAD survival adopted serum albumin level as a crucial surrogate marker. We have previously reported that postoperative albumin levels significantly correlated with preoperative levels 1 month after VAD implantation.²³ Similarly, there was also a significant correlation between preoperative albumin levels and those at 6 months after operation (r=0.261, P=0.036) in the present study. As a result, those who had a lower serum albumin before surgery were likely to have a higher J-VAD score after VAD implantation in this study (r=−0.441, P<0.01).

We previously reported that a smaller LVDd was a risk factor for BiVAD requirement.²⁸ Smaller LVDd was also associated with late-onset RV failure after I-LVAD implantation.²⁹ Because perioperative as well as postoperative RV failure is accompanied by poor prognosis.^18,30 our result that smaller LVDd is a risk factor for post-LVAD survival and is a barrier for bridge to DT among patients with extracorporeal VAD is reasonable.

Renal failure and elevated right atrial pressure are known as significant risk factors for mortality after VAD implantation.^19,31 Elevated right atrial pressure itself is reported as a risk factor for renal failure.³² Those who needed CHDF must have had both renal failure and high right atrial pressure, but CHDF by itself was not a risk factor for survival after VAD implantation in our hands.¹⁹ However, we reported that CHDF was a significant predictor of BiVAD necessity probably because of the severe RV dysfunction.²⁸ Also, it is not surprising that patients who require CHDF preoperatively are at high risk of post-LVAD prolonged renal dysfunction. Therefore, it is pertinent that CHDF is one of the DTI parameters. We previously demonstrated that post-LVAD recovery of end-organ function was strongly dependent on the patient’s age, although the data were from relatively younger patients.³³ Preoperative renal dysfunction may be more difficult to recover in the aged population that would be the main target for DT.

Past history of cardiac surgery has been generally considered as a risk factor for postoperative wound infection or bleeding.³⁴ The 6th INTERMACS annual report stated that a history of cardiac surgery was a significant risk factor for early death after VAD implantation.⁴ Patients undergoing cardiac reoperation sometimes have complications directly related to sternal reentry, including delayed wound healing, surgical site infection, and sepsis. Besides, past cardiac reoperation is reported as a risk factor for RVAD requirement during LVAD implantation,³⁵ probably because of pericardial constriction, which may result in a high risk for DT.

There have been several scoring systems for assessing postoperative mortality and complications, including the HeartMate II risk score,¹⁴ DT risk score,³⁶ the Seattle Heart Failure Model³⁷ or the Model for End Stage Liver Disease score.³⁸ All these scoring systems are for patients with de novo I-LVAD implantation for DT, and there is no scoring system for assessing ineligibility for DT among patients with extracorporeal VAD. Considering that 93% of the high-risk group were classified as DTI, extracorporeal VAD implantation itself may not be indicated in such a population because there is little chance of providing any further treatment. In this regard, the DTI score, which consists of objective parameters that can be obtained noninvasively, is useful for screening those high-risk patients. Especially among the aged population with cardiogenic shock, extracorporeal VAD implantation may not be indicated for those with a high DTI score.

Study Limitations

The present study had a small number of subjects at a single center, and may have a potential selection bias. The definitions of DTI we described in the present study are the most essential conditions for DT. Practically, there are other ineligibility factors such as device infection, physical frailty or stroke at a time of bridge to I-LVAD. We could not assess these factors minutely in the present study because they are difficult to quantify appropriately and there would be many confounding factors. In the future, it will be necessary to inspect these factors thoroughly. Perioperative BiVAD implantation would not necessarily be a contraindication for DT. If a patient is over 65 years, there is no chance of using VAD as BTT under the current policy for Japanese heart transplantation listing. In contrast to organ failure, age is absolutely unmodifiable. Of course there may be a chance for RVAD removal in such cases, but as mentioned we do not know yet how to predict the possibility of RVAD removal. We consider it too risky to put BiVAD in older patients who have no likelihood of receiving a transplant in the future, and it is also miserable that older patients with extracorporeal RVAD are destined to stay in hospital indefinitely.

If a patient with multiple organ failure is under the age of 65 years, there may be a chance for BTT after extracorporeal VAD implantation because organ failure is by itself a modifiable issue for transplant listing. That is the usual policy known as “bridge to decision”, and there is nothing new to be discussed. So let us discuss a patient with a recent (<5 years of complete remission) history of cancer going into cardiogenic shock. It may be justified to use extracorporeal VAD (or even BiVAD) in this patient. If the patient is weaned from RVAD support after a certain period of extracorporeal BiVAD treatment, then we will consider bridge for DT. In this context, BiVAD implantation is reasonable as the initial therapy.

Even if RVAD cannot be weaned, the patient can possibly be listed for transplant after keeping the person in the hospital for a couple of years to confirm that cancer does not recur. Therefore, we may not exclude the BiVAD strategy in younger patients, and DT eligibility may be harder to define. However, the story is not easy after successful listing. We have to keep in mind that the patient could wait another 3 years or more after listing before receiving a transplant under the current Japanese policy that does not give a priority for BiVAD patients. In total, the patient will have to wait on BiVAD for 5–6 years. It is definitely a tough decision. We consider the BiVAD option is still challenging, even for younger patients, when they have a recent history of cancer. Finally, although we defined the time limit of conversion to implantable LVAD at 6 months, there may be some cases when the patient can be converted to I-LVAD more than 6 months from extracorporeal VAD implantation.

Conclusions

Our novel DTI score was useful for stratifying the possibility of bridge to I-LVAD for DT among patients with extracorporeal VAD. In aged patients who have high DTI scores with cardiogenic shock, the indication for extracorporeal VAD implantation itself should be estimated with caution.

Disclosures

None.

References

• 1.    Gorodeski  EZ,  Chu  EC,  Reese  JR,  Shishehbor  MH,  Hsich  E,  Starling  RC. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Heart Fail 2009; 2: 320–324.
• 2.    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.
• 3.    Yancy  CW,  Jessup  M,  Bozkurt  B,  Butler  J,  Casey  DE Jr,  Drazner  MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128: e240–e327, doi:10.1161/CIR.0b013e31829e8776.
• 4.    Kirklin  JK,  Naftel  DC,  Pagani  FD,  Kormos  RL,  Stevenson  LW,  Blume  ED, et al. Sixth INTERMACS annual report: A 10,000-patient database. J Heart Lung Transplant 2014; 33: 555–564.
• 5.    Teuteberg  JJ,  Stewart  GC,  Jessup  M,  Kormos  RL,  Sun  B,  Frazier  OH, et al. Implant strategies change over time and impact outcomes: Insights from the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). JACC Heart Fail 2013; 1: 369–378.
• 6.    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.
• 7.    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.
• 8.    Fang  JC. Rise of the machines: Left ventricular assist devices as permanent therapy for advanced heart failure. N Engl J Med 2009; 361: 2282–2285.
• 9.    McIlvennan  CK,  Magid  KH,  Ambardekar  AV,  Thompson  JS,  Matlock  DD,  Allen  LA. Clinical outcomes after continuous-flow left ventricular assist device: A systematic review. Circ Heart Fail 2014; 7: 1003–1013.
• 10.   Centers for Medicare & Medicaid Services Online Manual System, section 20.9: Artificial heart and related devices. https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=246&ncdver=5&NCAId=211&ver=20&NcaName=Artificial+Hearts&bc=ACAAAAAAIAAA&; (accessed September 20, 2015).
• 11.    Sasaoka  T,  Kato  TS,  Komamura  K,  Takahashi  A,  Nakajima  I,  Oda  N, et al. Improved long-term performance of pulsatile extracorporeal left ventricular assist device. J Cardiol 2010; 56: 220–228.
• 12.    Kirklin  JK,  Naftel  DC,  Kormos  RL,  Stevenson  LW,  Pagani  FD,  Miller  MA, et al. Third INTERMACS Annual Report: The evolution of destination therapy in the United States. J Heart Lung Transplant 2011; 30: 115–123.
• 13.   Japanese Association for Clinical Ventricular Assist Systems (JACVAS). The academic consensus statement for DT in Japan. http://www.jacvas.com/view_dt.html (in Japanese) (accessed September 20, 2015).
• 14.    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.
• 15.    Cleveland  JC Jr,  Naftel  DC,  Reece  TB,  Murray  M,  Antaki  J,  Pagani  FD, et al. Survival after biventricular assist device implantation: An analysis of the Interagency Registry for Mechanically Assisted Circulatory Support database. J Heart Lung Transplant 2011; 30: 862–869.
• 16.    Moreno  SG,  Novielli  N,  Cooper  NJ. Cost-effectiveness of the implantable HeartMate II left ventricular assist device for patients awaiting heart transplantation. J Heart Lung Transplant 2012; 31: 450–458.
• 17.    Lang  SA,  O’Neill  B,  Waterworth  P,  Bilal  H. Can the temporary use of right ventricular assist devices bridge patients with acute right ventricular failure after cardiac surgery to recovery? Interact Cardiovasc Thorac Surg 2014; 18: 499–510.
• 18.    Takeda  K,  Naka  Y,  Yang  JA,  Uriel  N,  Colombo  PC,  Jorde  UP, et al. Outcome of unplanned right ventricular assist device support for severe right heart failure after implantable left ventricular assist device insertion. J Heart Lung Transplant 2014; 33: 141–148.
• 19.    Imamura  T,  Kinugawa  K,  Shiga  T,  Endo  M,  Kato  N,  Inaba  T, et al. Novel risk scoring system with preoperative objective parameters gives a good prediction of 1-year mortality in patients with a left ventricular assist device. Circ J 2012; 76: 1895–1903.
• 20.    Bhamidipati  CM,  LaPar  DJ,  Mehta  GS,  Kern  JA,  Upchurch  GR Jr,  Kron  IL, et al. Albumin is a better predictor of outcomes than body mass index following coronary artery bypass grafting. Surgery 2011; 150: 626–634.
• 21.    Montazerghaem  H,  Safaie  N,  Samiei Nezhad  V. Body mass index or serum albumin levels: Which is further prognostic following cardiac surgery? J Cardiovasc Thorac Res 2014; 6: 123–126.
• 22.    Go  PH,  Hodari  A,  Nemeh  HW,  Borgi  J,  Lanfear  DE,  Williams  CT, et al. Effect of preoperative albumin levels on outcomes in patients undergoing left ventricular device implantation. ASAIO J 2015; 61: 734–737.
• 23.    Imamura  T,  Kinugawa  K,  Nitta  D,  Hatano  M,  Kinoshita  O,  Nawata  K, et al. Perioperative hypoalbuminemia affects improvement in exercise tolerance after left ventricular assist device implantation. Circ J 2015; 79: 1970–1975.
• 24.    Imamura  T,  Kinugawa  K,  Nitta  D,  Inaba  T,  Maki  H,  Hatano  M, et al. Readmission due to driveline infection can be predicted by new score by using serum albumin and body mass index during long-term left ventricular assist device support. J Artif Organs 2015; 18: 120–127.
• 25.    Arques  S,  Ambrosi  P. Human serum albumin in the clinical syndrome of heart failure. J Card Fail 2011; 17: 451–458.
• 26.    Samsky  MD,  Patel  CB,  DeWald  TA,  Smith  AD,  Felker  GM,  Rogers  JG, et al. Cardiohepatic interactions in heart failure: An overview and clinical implications. J Am Coll Cardiol 2013; 61: 2397–2405.
• 27.    Bouras  G,  Giannopoulos  G,  Hatzis  G,  Alexopoulos  D,  Leventopoulos  G,  Deftereos  S. Inflammation and chronic heart failure: From biomarkers to novel anti-inflammatory therapeutic strategies. Med Chem 2014; 10: 682–699.
• 28.    Shiga  T,  Kinugawa  K,  Imamura  T,  Kato  N,  Endo  M,  Inaba  T, et al. Combination evaluation of preoperative risk indices predicts requirement of biventricular assist device. Circ J 2012; 76: 2785–2791.
• 29.    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.
• 30.    Takeda  K,  Takayama  H,  Colombo  PC,  Yuzefpolskaya  M,  Fukuhara  S,  Han  J, et al. Incidence and clinical significance of late right heart failure during continuous-flow left ventricular assist device support. J Heart Lung Transplant 2015; 34: 1024–1032.
• 31.    Yoshioka  D,  Sakaguchi  T,  Saito  S,  Miyagawa  S,  Nishi  H,  Yoshikawa  Y, et al. Predictor of early mortality for severe heart failure patients with left ventricular assist device implantation: Significance of INTERMACS level and renal function. Circ J 2012; 76: 1631–1638.
• 32.    Damman  K,  van Deursen  VM,  Navis  G,  Voors  AA,  van Veldhuisen  DJ,  Hillege  HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53: 582–588.
• 33.    Imamura  T,  Kinugawa  K,  Shiga  T,  Endo  M,  Kato  N,  Inaba  T, et al. Preoperative levels of bilirubin or creatinine adjusted by age can predict their reversibility after implantation of left ventricular assist device. Circ J 2013; 77: 96–104.
• 34.    Milano  CA,  Kesler  K,  Archibald  N,  Sexton  DJ,  Jones  RH. Mediastinitis after coronary artery bypass graft surgery: Risk factors and long-term survival. Circulation 1995; 92: 2245–2251.
• 35.    Meineri  M,  Van Rensburg  AE,  Vegas  A. Right ventricular failure after LVAD implantation: Prevention and treatment. Best Pract Res Clin Anaesthesiol 2012; 26: 217–229.
• 36.    Lietz  K,  Long  JW,  Kfoury  AG,  Slaughter  MS,  Silver  MA,  Milano  CA, et al. Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era: Implications for patient selection. Circulation 2007; 116: 497–505.
• 37.    Ketchum  ES,  Moorman  AJ,  Fishbein  DP,  Mokadam  NA,  Verrier  ED,  Aldea  GS, et al. Predictive value of the Seattle Heart Failure Model in patients undergoing left ventricular assist device placement. J Heart Lung Transplant 2010; 29: 1021–1025.
• 38.    Matthews  JC,  Pagani  FD,  Haft  JW,  Koelling  TM,  Naftel  DC,  Aaronson  KD. Model for end-stage liver disease score predicts left ventricular assist device operative transfusion requirements, morbidity, and mortality. Circulation 2010; 121: 214–220.