Clinical Results, Adverse Events, and Change in End-Organ Function in Elderly Patients With HeartMateII Left Ventricular Assist Device　― Japanese Multicenter Study ―

Abstract

Background: Advanced age has an adverse impact on clinical results in left ventricular assist device (LVAD) patients. We compared the clinical results of patients aged >60 years with younger patients using a national Japanese database.

Methods and Results: Between April 2013 and December 2016, 300 patients underwent HeartMateII implantation. Of these, 37 patients were ≥60 years at LVAD implantation, and the clinical results of these patients were compared with the other younger 263 patients. At 1 and 3 years the on-device survival was 95%, 91% in younger patients, and 85%, 75% in older patients, respectively (P=0.016), although age was not a risk factor on the multivariate analysis. There was no significant difference between the groups in incidence of various adverse events except stroke. In the propensity-matching cohort, the incidence of stroke was significantly higher in patients aged >60 years (P=0.047). In patients aged >60 years, improvement of renal function was transient and there was no improvement later than 3 months, and recovery of serum albumin level to preoperative value was delayed.

Conclusions: There were significant differences in the stroke incidence and recovery of end-organ functions after LVAD implantation. This may have important implications for patient selection in future destination therapy in Japan, where quality of life is an important issue in LVAD support.

Use of a left ventricular assist device (LVAD) has become standard therapy for end-stage congestive heart failure.^1–6 Age has been shown to have an adverse impact on long-term clinical results for continuous-flow LVAD,^2,7,8 but the age at which the risk of an LVAD becomes unacceptable is undefined. Furthermore, studies on the risk factors for mortality after LVAD implantation specifically in elderly patients, are very limited.⁸

In Japan, destination therapy (DT) will be approved by the Ministry of Health, Labor and Welfare in the near future but, because of donor shortage and national transplantation rule, patients aged >60 years at the time of wait list entry are been being treated nominally with bridge-to-transplantation therapy (BTT) but practically with DT. To achieve better clinical results at introduction of DT in Japan, the clinical results and adverse events in these DT patients should be evaluated.

In the present study, we compared the clinical results of patients aged >60 years at LVAD implantation with younger patients, and analyzed the adverse events and change of end-organ function on long-term follow-up using a national database.

Methods

Patients

This study was a retrospective analysis of patients implanted with the HeartMateII LVAD as BTT at 30 institutions in Japan. The data represent the follow-up data in all patients who underwent HeartMateII implantation between April 2013 and December 2016. All data including baseline characteristics, laboratory values, echocardiographic parameters, surgical parameters, adverse events and mortality were extracted from the Japanese Registry for Mechanically Assisted Circulatory Support (J-MACS) database. Before LVAD implantation, all patients provided informed consent at each hospital.

In Japan, patients must be <65 years of age to be included on the national heart transplantation list. Because all patients who underwent continuous-flow implantable LVAD must be on the national heart transplantation list, all patients underwent HeartMateII LVAD implantation as BTT. The patients are divided into 2 categories according to the priority for heart transplantation depending on age at the time of listing. Briefly, patients aged <59 years have higher priority than patients aged >60 years at the time of waitlisting. The decision is made depending solely on the waiting period in all patients aged <59 years at the time of listing. If there is no suitable recipient in all patients aged <59 years, then the recipient is selected from patients aged >60 years at waitlisting, depending on the waiting period. In addition, the number of donors is very limited, therefore patients who are waitlisted at >60 years of age are treated with DT.

In the present study, because we could not collect data on the actual day of entry to the heart transplantation list, patients were divided into 2 groups based on age at LVAD implantation (>60 years, n=37; or <59 years, n=263). Baseline characteristics, duration of LVAD support, clinical outcomes, survival, and adverse events, and end-organ function at mid-term follow up were compared between the 2 groups. The primary endpoint was successful bridge to heart transplantation, death on device, LVAD removal for native heart recovery, or LVAD exchange for LVAD malfunction. Total follow-up period was 437.4 patient-years in the whole group; 401.0 patient-years in patients aged <59 years; and 36.4 patient-years in patients aged >60 years. Mean and median follow-up period was 1.46±1.05 years and 1.27 years (IQR, 0.58–2.40 years), respectively.

Device Implantation

Generally, because patients who undergo continuous-flow LVAD implantation must be on the national heart transplantation list in Japan, cardiogenic shock with unknown eligibility for heart transplantation is bridged with an paracorporeal ventricular assist device (VAD). These patients are initially hemodynamically stabilized with paracorporeal VAD,⁹ then converted to HeartMateII LVAD after confirmation and entry to the heart transplantation list.

The HeartMateII LVAD was mainly implanted by median sternotomy, except in some cases in which pump exchange from another type of VAD was performed via subcostal incision. Standard cardiopulmonary bypass was established by aortic perfusion with bicaval or single atrial drainage, according to whether the patient required additional procedures or institution policy. The majority of implants were performed under beating-heart conditions. The decision for additional concomitant valve surgery was performed at surgeon discretion in each hospital.

Postoperative anticoagulation depends mainly on cardiologist or cardiovascular surgeon discretion at each hospital. Briefly, antiplatelet therapy with 100 mg of aspirin daily and anticoagulation with warfarin is managed with a target prothrombin time-international normalized ratio (PT-INR) range of 2.0–2.5 according to manufacturer recommendation.

Data Collection

Patient data were obtained from the J-MACS database. Primary outcome variables included in-hospital mortality and overall survival. Preoperative variables that may affect the primary outcome were identified, including baseline demographics, medical history, laboratory values, and hemodynamics. Intraoperative variables, such as cardiopulmonary bypass time, amount of blood products used, and concomitant cardiac procedures, were also collected. Early post-implantation data included complications occurring between operation and hospital discharge. Major adverse events requiring readmission during LVAD support were also extracted. These included right heart failure, gastrointestinal tract bleeding, major cerebral events, driveline infection, and LVAD pocket infection. In the present study, cerebrovascular accident (CVA) was defined as cerebral infarction and/or intracranial hemorrhage. Transient ischemic attack and seizure without any corresponding lesion were excluded from CVA.

The modified Heart Mate II risk score (mHMRS) was calculated as follows: mHMRS=0.0274×age−0.723×serum albumin (mg/dL)−0.74×serum creatinine (mg/dL)+1.136×INR. The mHMRS constructed by excluding the number of LVAD implantations at each hospital from the HMRS,⁷ because we could not evaluate the number of LVAD implantations at each specific hospital in a specific year. Estimated glomerular filtration rate (eGFR) was calculated using the following formula: eGFR=186×(serum creatinine (mg/dL))^−1.154×(age)^−0.203×(0.742 if female).

Statistical Analysis

All data were analyzed using SPSS version 23.0 (SPSS, Chicago, IL, USA). Statistical significance was determined on the basis of a predetermined α=0.05. Categorical variables are expressed as frequencies and percentages and were compared across groups using chi-squared or Fisher’s exact tests. Continuous variables are expressed as mean±SD or median (IQR). Two-sample t-test, Mann-Whitney U-test or a paired t-test were used for comparisons across groups. Overall survival rate, and incidence of adverse events were estimated using Kaplan-Meier curves and compared across groups using log-rank test. Patients who underwent heart transplantation, HeartMateII removal for recovery, LVAD exchange for another LVAD were censored at each time. Cox regression hazard models for survival outcomes were used to adjust for the effects of preoperative variables on mid-term survival, and incidence of stroke. The factors in univariate analysis with P<0.10 were considered for Cox hazard modeling to identify the risk factors for overall mortality and incidence of stroke.

To compare the incidence of stroke and change in laboratory data between the 2 groups, the backgrounds of the 2 groups were adjusted using propensity score matching. Risk factors or trends in risk for stroke (left ventricular end-diastolic dimension (LVEDD), preoperative extracorporeal membranous oxygenation [ECMO] use) identified on univariate analysis or previously reported risk factors for stroke (female sex, body surface area [BSA], diabetes) were adjusted for the analysis of incidence of stroke.^10–12 For the analysis of change in renal function, preoperative eGFR, diabetes mellitus, ischemic etiology, and history of smoke were adjusted for the propensity matching. For the analysis of change in serum total bilirubin and albumin, preoperative central venous pressure, total bilirubin, serum albumin, platelet count, and body mass index were adjusted in the propensity matching. The propensity score was obtained by multivariate logistic regression. We performed a 1:2 nearest-available matching algorithm with a 0.1 caliper, then 68 patients aged <59 years and 34 patients aged >60-years were extracted depending on the propensity score matching model.

Results

Preoperative patient characteristics are listed in Table 1. Mean age was 41.4±11.8 years in the <59-years age group, and 62.4±1.6 years in the >60-years age group. Male sex was more prevalent in patients aged <59 years, and BSA was significantly smaller in patients aged >60 years. There was no statistical difference in blood type, etiology, or Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile. Thirty-five (13%) of the patients aged <59 years had other VAD before HeartMateII implantation, whereas 11 (30%) of the patients aged >60 years had other VAD (P=0.015). As for laboratory data, hemoglobin, platelet count, and serum cholinesterase were significantly lower in the patients aged >60 years. As for renal function, serum blood urea nitrogen (BUN) and creatinine were significantly higher, and eGFR was significantly lower in the >60-years age group. There was no significant difference in the echocardiographic data and right heart catheter parameters. Calculated mHMRS was significantly higher in patients aged >60 years (1.22±1.12 vs. 2.33±1.73, P<0.001).

Table 1. Baseline Patient Characteristics

	Age <59 years (n=263)	Age ≥60 years (n=37)	P-value
Baseline characteristics
Age (years)	41.4±11.8	62.4±1.6	<0.001
Male	207 (79)	21 (57)	0.007
BSA (m2)	1.64±0.16	1.58±0.14	0.022
BMI (kg/m2)	20.6±3.2	20.1±2.7	0.331
Blood type			0.138
Type A	89 (34)	17 (46)
Type B	57 (22)	11 (30)
Type O	94 (36)	7 (19)
Type AB	23 (9)	2 (5)
Etiology
Non-ischemic DCM	183 (70)	26 (70)	1.000
Ischemic CM	27 (10)	7 (19)	0.161
HCM or RCM	29 (11)	3 (8)	0.779
INTERMACS profile			0.283
Profile I	21 (8)	3 (8)
Profile II	94 (36)	19 (51)
Profile III	134 (51)	14 (38)
Profile IV	10 (4)	0 (0)
Profile ≥V	4 (2)	1 (3)
Mechanical support before LVAD
IABP	52 (20)	8 (22)	0.827
ECMO	4 (2)	1 (3)	0.486
CVVHD	2 (1)	1 (3)	0.328
Ventilator	9 (3)	3 (8)	0.175
Other VAD	35 (13)	11 (30)	0.015
Laboratory variables
WBC count (×1,000/μL)	6.44±2.26	6.37±2.40	0.866
Hemoglobin (g/dL)	11.7±2.0	10.9±2.1	0.040
Platelets (×1,000/μL)	203±77	167±74	0.006
CRP (mg/dL)	0.3 (0.1–1.3)	0.5 (0.1–3.0)	0.318
Total protein (mg/dL)	6.60±0.74	6.46±0.74	0.302
Albumin (mg/dL)	3.73±0.55	3.51±0.67	0.028
ChE (IU/L)	234±77	185±68	0.010
LDH (IU/L)	251 (199–347)	261 (231–319)	0.253
AST (IU/L)	26 (20–34)	23 (18–34)	0.411
ALT (IU/L)	24 (15–37)	16 (12–25)	0.012
Total bilirubin (mg/dL)	0.9 (0.7–1.3)	1.0 (0.6–1.8)	0.697
BUN (mg/dL)	19.0±10.8	24.9±13.9	0.003
Creatinine(mg/dL)	0.98±0.37	1.12±0.37	0.030
eGFR (mL/min/1.73 m2)	102±59	74±42	0.005
Echocardiographic parameters
LVEDD (mm)	70±13	66±14	0.085
LVESD (mm)	63±13	60±14	0.144
Right heart catheter parameters
Systolic PAP (mmHg)	42±17	41±13	0.721
Diastolic PAP (mmHg)	21±10	20±7	0.484
RAP (mmHg)	9.2±5.9	9.0±5.6	0.876
Cardiac index (L/min/m2)	2.1±0.6	2.0±0.5	0.261
mHMRS	1.22±1.12	2.33±1.73	<0.001

Data given as n (%), mean±SD or median (IQR). ALT, alanine transaminase; AST, aspartate transaminase; BMI, body mass index; BSA, body surface area; BUN, blood urea nitrogen; ChE, choline esterase; CM, cardiomyopathy; CRP, C-reactive protein; CVVHD, continuous veno-venous hemodialysis; DCM, dilated cardiomyopathy; ECMO, extracorporeal membranous oxygenation; eGFR, estimated glomerular filtration rate; HCM, hypertrophic cardiomyopathy; IABP, intra-aortic balloon pumping; LDH, lactate dehydrogenase; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; mHMRS, modified Heart Mate risk score; PAP, pulmonary artery pressure; RAP, right atrial pressure; RCM, restrictive cardiomyopathy; VAD, ventricular assist device; WBC, white blood cell.

Operation results are listed in Table 2. Concomitant aortic valve surgery was done in 19 (7%) of the patients aged <59 years and in 6 (16%) of the patients aged >60 years. Two (1%) of the patients aged <59 years required postoperative right ventricular assist device implantation (RVAD), and none of the patients aged >60 years required RVAD. Patients aged >60 years required significantly more blood transfusion, and longer intensive care unit stay. One patient in each group died during 30 days after surgery.

Table 2. Results of Surgery

	Age <59 years (n=263)	Age >60 years (n=37)	P-value
Concomitant surgery
Aortic valve procedure	19 (7)	6 (16)	0.102
Mitral valve procedure	22 (8)	4 (11)	0.543
Tricuspid valve procedure	77 (29)	13 (35)	0.451
RVAD implantation	2 (1)	0 (0)	>0.999
Aortic cross-clamp	29 (11)	10 (27)	0.016
Operation time and transfusion
Total operation time (min)	481±182	494±174	0.697
CPB time (min)	139±60	150±67	0.301
Total amount of blood transfusion (L)	2.08 (1.30–3.51)	2.73 (1.66–5.53)	0.028
Re-exploration for bleeding	21 (8)	2 (5)	0.751
Intensive care unit stay (days)	6 (4–11)	13 (7–27)	0.026
30-day mortality	1 (0.4)	1 (3)	0.193
Adverse events during LVAD support
CVA (events/patient-year)	0.115	0.330	0.015
Driveline infection (events/patient-year)	0.277	0.330	0.783
LVAD pocket infection (events/patient-year)	0.047	0.028	0.920
Right heart failure (events/patient-year)	0.007	0.055	0.912
GI bleeding (events/patient-year)	0.027	0.055	0.861

Data given as n (%), mean±SD or median (IQR). CPB, cardiopulmonary bypass; CVA, cerebrovascular accident; GI, gastrointestinal; LVAD, left ventricular assist device; RVAD, right ventricular assist device.

The outcome of the whole group of 300 patients and the 37 patients aged >60 years is shown in Figure 1A,B. The on-device survival was 95%, 94%, 91% in patients aged <59 years, and 85%, 75%, 75% in patients aged >60 years, at 1, 2, and 3 years, respectively (P=0.016; Figure 1C). We further analyzed the risk factors for overall mortality in the entire cohort (Table 3). On univariate analysis, older age, absence of idiopathic dilated cardiomyopathy, higher serum C-reactive protein (CRP), and higher serum BUN were preoperative risk factors for overall mortality. On multivariate analysis, only higher CRP was a risk factor for overall mortality.

Figure 1.

Outcome of HeartMateII left ventricular assist device (LVAD) implantation in (A) the whole group (n=300) and (B) patients aged >60 years (n=37). (C) Kaplan-Meier on-device survival in patients aged (red line) >60 years and (blue line) <59 years. OHT, orthotopic heart transplantation.

Table 3. Indicators of Overall Mortality

	Univariate		Multivariate
	HR (95% CI)	P-value	HR (95% CI)	P-value
Age (years)	1.05 (1.01–1.09)	0.015	1.03 (0.99–1.07)	0.131
Male	0.44 (0.19–1.22)	0.083	0.82 (0.26–2.74)	0.747
BSA (m2)	0.07 (0.01–1.11)	0.059	0.19 (0.01–2.83)	0.227
BMI (kg/m2)	0.93 (0.80–1.06)	0.281
Idiopathic DCM	0.37 (0.16–0.89)	0.027	0.42 (0.16–1.09)	0.090
Ischemic CM	1.28 (0.30–3.78)	0.702
HCM	1.43 (0.33–4.24)	0.582
Diabetes mellitus	1.20 (0.35–3.26)	0.743
Past smoker	0.69 (0.27–1.63)	0.397
Concomitant aortic valve surgery	0.76 (0.04–3.65)	0.778
Concomitant mitral valve surgery	0.51 (0.03–2.24)	0.464
Mechanical support
IABP	1.55 (0.55–3.82)	0.380
ECMO	7.88 (0.43–41.5)	0.129
Ventilator	3.43 (0.55–11.9)	0.158
Other VAD	2.11 (0.75–5.19)	0.148
Preoperative laboratory variables
WBC count (×1,000/μL)	1.09 (0.90–1.28)	0.355
Hemoglobin (g/dL)	0.90 (0.73–1.12)	0.334
Platelets (×1,000/μL)	1.00 (0.94–1.05)	0.964
CRP (mg/dL)	1.09 (1.02–1.16)	0.024	1.23 (1.11–1.36)	0.001
Total protein (mg/dL)	0.69 (0.38–1.30)	0.255
Albumin (mg/dL)	0.48 (0.22–1.05)	0.067
Total bilirubin (mg/dL)	1.14 (0.86–1.37)	0.285
BUN (mg/dL)	1.05 (1.01–1.07)	0.006	1.03 (1.00–1.06)	0.070
Creatinine(mg/dL)	1.29 (0.36–3.95)	0.676
eGFR (mL/min/1.73 m2)	1.00 (0.99–1.01)	0.738
Echocardiographic parameters
LVEDD (cm)	0.80 (0.58–1.11)	0.185
LVESD (cm)	0.83 (0.59–1.15)	0.268
Right heart catheter parameters
Systolic PAP (mmHg)	0.99 (0.96–1.02)	0.567
Diastolic PAP (mmHg)	0.97 (0.92–1.02)	0.306
RAP (mmHg)	1.04 (0.96–1.10)	0.312
Cardiac index (L/min/m2)	1.33 (0.53–3.10)	0.531

Abbreviations as in Table 1.

Incidence of adverse events is listed in Table 2, Figures 2,S1. The incidence of CVA was significantly prevalent in patients aged >60 years (Figure 2A). In order to evaluate the risk factor for CVA in Japanese HeartMateII patients, we further analyzed the baseline characteristics, preoperative parameters, and intraoperative parameters. On multivariate analysis, older age (hazard ratio [HR], 1.03; 95% CI: 1.01–1.06, P=0.017) and small LVEDD (HR, 0.77; 95% CI: 0.60–0.97, P=0.001) were identified as independent risk factors for stroke during HeartMateII support (Table 4). To evaluate the impact of age on the incidence of stroke, the incidence of stroke in the propensity-matched cohort was compared between the 2 groups (Figure 2B). In the propensity-matched cohort, the incidence of CVA was significantly higher in patients aged >60 years (P=0.047). The HR for age>60 years for stroke in the propensity cohort was 2.49 (95% CI: 0.96–6.34, P=0.063). There was no significant difference in incidence of right heart failure, driveline infection, or gastrointestinal bleeding (Figure S1A–C). The incidence of LVAD thrombosis was higher in patients aged >60 years (Figure S1D).

Figure 2.

Incidence of stroke in (A) the whole group, and (B) the propensity-matched cohort after HeartMateII left ventricular assist device implantation in patients aged (red line) >60 years and (blue line) <59 years.

Table 4. Indicators of Stroke

	Univariate		Multivariate
	HR (95% CI)	P-value	HR (95% CI)	P-value
Age (years)	1.03 (1.01–1.06)	0.014	1.03 (1.01–1.06)	0.017
Male	1.10 (0.55–2.45)	0.790
BSA (m2)	0.50 (0.08–3.35)	0.477
BMI (kg/m2)	0.99 (0.90–1.08)	0.815
Idiopathic DCM	0.69 (0.38–1.31)	0.253
Ischemic CM	0.83 (0.25–2.07)	0.719
HCM	0.88 (0.26–2.19)	0.808
Diabetes mellitus	1.39 (0.63–2.78)	0.398
Past smoker	1.09 (0.59–1.98)	0.787
Mechanical support
IABP	1.17 (0.54–2.28)	0.676
ECMO	4.70 (0.76–15.7)	0.086	4.79 (0.67–19.2)	0.107
Ventilator	1.42 (0.23–4.62)	0.647
Other VAD	1.24 (0.53–2.55)	0.591
Laboratory variables
WBC count (×1,000/μL)	1.00 (0.87–1.14)	0.952
Hemoglobin (g/dL)	0.92 (0.80–1.07)	0.263
Platelets (×1,000/μL)	1.00 (0.96–1.04)	0.986
CRP (mg/dL)	1.04 (0.95–1.10)	0.354
Total protein (mg/dL)	1.09 (0.71–1.70)	0.688
Albumin (mg/dL)	0.90 (0.52–1.57)	0.699
Total bilirubin (mg/dL)	1.07 (0.87–1.23)	0.445
BUN (mg/dL)	1.02 (0.99–1.04)	0.158
Creatinine(mg/dL)	0.82 (0.32–1.89)	0.653
eGFR (mL/min/1.73 m2)	1.00 (1.00–1.01)	0.130
Echocardiographic parameters
LVEDD (cm)	0.77 (0.61–0.97)	0.025	0.77 (0.60–0.97)	0.001
LVESD (cm)	0.78 (0.62–0.98)	0.030
Right heart catheter parameters
Systolic PAP (mmHg)	1.00 (0.97–1.02)	0.700
Diastolic PAP (mmHg)	1.00 (0.96–1.03)	0.956
RAP (mmHg)	0.96 (0.89–1.05)	0.165
Cardiac index (L/min/m2)	1.14 (0.61–2.05)	0.669
Concomitant aortic valve surgery	0.67 (0.11–2.16)	0.546
Concomitant mitral valve surgery	0.51 (0.08–1.65)	0.299
Operation time (min)	1.00 (0.99–1.00)	0.995
CPB time (min)	1.00 (0.99–1.00)	0.521

Abbreviations as in Tables 1,2.

We focused on change in end-organ function in patients aged >60 years. With regard to renal function, eGFR was significantly improved at 1 week and 1 month after LVAD implantation in both groups. In the longer term, however, whereas eGFR improvement compared with baseline was maintained in patients aged <59 years until 1 year, in patients aged >60 years eGFR improvement was transient, and there was no significant improvement after 3 months after LVAD implantation (Figure 3A). Because preoperative eGFR was significantly different in both groups, we evaluated the change in eGFR in the propensity-matched cohort. eGFR was improved and maintained during the first year in patients aged <59 years. In contrast, in patients aged >60 years, eGFR immediately returned to baseline after 3 months, and was significantly worse than in the <59-years age group (Figure 3B). With regard to serum total bilirubin level, in the overall cohort, serum total bilirubin was significantly higher in patients aged >60 years at 1 week and 1 month postoperatively (Figure S2A). After propensity matching, in patients aged >60 years, serum bilirubin was significantly higher at 1 week, but there was no difference at 1 month (Figure S2B). With regard to serum albumin, in patients aged <59 years, serum albumin was significantly lower at 1 week and 1 month after LVAD implantation, but was significantly higher at 3 months after implantation (Figure 4A). In contrast, in patients aged >60 years, there was no difference at 3 months compared with baseline, but at 6 months serum albumin was higher than the baseline level. After propensity matching, serum albumin in patients aged >60 years was significantly lower than in patients aged <59 years at 3, 6 months and 1 year, even though baseline albumin level was the same in the 2 groups (Figure 4B).

Figure 3.

Change in estimated glomerular filtration rate (eGFR) after HeartMateII left ventricular assist device implantation in (A) the whole group and (B) the propensity-matched group after adjusting for preoperative eGFR, diabetes mellitus, ischemic etiology, and history of smoke, in patients aged (red line) >60 years and (blue line) <59 years.

Figure 4.

Change in serum albumin after HeartMateII left ventricular assist device implantation in (A) the whole group and (B) the propensity-matched cohort in patients aged (red line) >60 years and (blue line) <59 years.

Discussion

Primary findings of the present national database study are (1) although the overall survival of patients aged >60 years was lower than that of patients aged <59 years, the clinical results were favorable, with a 3-year survival rate of 75%; (2) with regard to adverse events, CVA and LVAD thrombosis events were significantly more prevalent in patients aged >60 years, and age was associated with increased incidence of CVA after propensity matching; (3) improvement of eGFR in patients aged >60 years was transient and disappeared 3 months after LVAD implantation; and (4) although serum total bilirubin was maintained within normal limits in both groups except in the acute phase, it took significantly longer for patients aged >60 years to recover baseline serum albumin level.

In the present study, the on-device survival in the patients aged >60 years was 85%, 75% and 75% at 1, 2 and 3 years, respectively. Slaughter et al first reported that overall survival rate for DT in HeartMateII patients with mean age 62±12 years was 68% and 58% at 1 and 2 years.⁵ In the recent INTERMACS annual report, survival with DT at 1 and 3 years was 76% and 57%, although the patient background was not given in detail.² The present clinical results in patients aged >60 years was better than or equivalent to these previous reports, probably because the present patients were nominally eligible for heart transplantation. Furthermore, on multivariate analysis age was not a risk factor for overall mortality, and this might mean that appropriate selection of candidates for LVAD therapy would provide satisfactory clinical results in an aged population. Given, however, that the number of patients aged >60 years is still limited even in the national database, further studies on the risk in elderly LVAD patients in Japanese cohorts are needed.

Stroke, which severely worsens quality of life, is a major adverse event during LVAD support,^13–16 and risk analysis of stroke is essential to achieve better quality of life in DT patients. In the present study, age was one of the independent predictors of stroke during LVAD support. Furthermore, age approximately doubled the incidence of stroke even after adjusting for other independent risk factors (LVEDD, preoperative ECMO use) in the multivariate analysis, and after adjusting for sex, BSA and diabetes, which have been reported as risk factors of stroke.^10–12 Several studies have concluded that there is no significant association between age and incidence of stroke.^12,17,18 In contrast, Coffin et al reported that age was the only significant risk factor for all neurologic events after adjusting device.¹⁹ Careful attention should be paid, however, to the interpretation of these previous reports that evaluated the risk factors of stroke, because almost all these studies consisted only of Caucasian and/or African-American patients. In addition, only 1 study has compared the incidence of stroke between Caucasian and African-American LVAD patients,²⁰ and no previous studies on Asian patients have been reported. The incidence of CVAs in the general population differs according to ethnicity,^21,22 therefore, it would be reasonable that the prevalence of stroke would differ as well. Although the incidence of stroke in younger patients in the present study was similar to that in previous reports that consisted mainly of Caucasian and/or African-American subjects,^12,17,18 further studies are needed to evaluate the risk factors and etiologies of stroke in elderly Asian patients.

In several reports, continuous-flow LVAD implantation was found to temporarily improve renal function, but this improvement was transient and declined after 1 month.^23–26 In the present study, at 3 months after LVAD implantation, renal function in patients aged >60 years was similar to the baseline level, and was significantly worse compared with that in patients aged <59 years even after propensity matching. Sharma et al reported that baseline GFR remained normal over a long duration due to renal functional reserve (RFR) utilization.²⁷ The present results may indicate that younger patients might have better RFR than older patients, even when baseline eGFR is the same. Impairment of renal function, which can require hemodialysis and/or diet restriction, can affect the quality of life, which should be particularly emphasized in the DT population. Thus, early LVAD implantation may be warranted for elderly patients before RFR becomes limited.

In the present study, it took longer for serum albumin to normalize in patients aged >60 years than in those aged <59 years. In patients with heart failure, the prevalence of hypoalbuminemia is approximately 20–30%, and it has emerged as an independent risk factor for mortality.^28,29 The normalization of serum albumin after LVAD implantation has an impact on long-term survival and exercise capacity.^30,31 These previous results and the present ones imply that it takes longer for patients aged >60 years to recover functional and nutritional status and exercise capacity. Therefore, LVAD implantation should not be delayed until the appearance of cardiac cachexia, particularly in elderly patients.

The present study has several limitations. First, the number of patients aged >60 years was limited. Therefore, we could not perform subset analysis in elderly patients. Second, because of the multicenter study design, adverse events, especially stroke events, could not be categorized, and hemorrhagic stroke could not be distinguished from ischemic stroke.

Conclusions

Although older age was not a significant risk factor of survival after LVAD implantation as BTT, there were significant differences in the incidence of stroke and recovery of end-organ function after LVAD implantation between patients aged ≥60 years and <60 years. This may have important implications for patient selection for future DT in Japan, where quality of life is an important issue in LVAD support.

Supplementary Files

Supplementary File 1

Figure S1. Incidence of (A) right heart failure (B) driveline infection (C) gastrointestinal bleeding (D) left ventricular assist device (LVAD) thrombus after HeartMateII LVAD implantation in patients aged (red line) >60 years and (blue line) <59 years.

Figure S2. Change in serum total bilirubin level after HeartMateII left ventricular assist device implantation in (A) the whole group and (B) the propensity-matched group in patients aged (red) >60 years and (blue) <59 years.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-17-0881

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