Journal of Artificial Organs

, Volume 17, Issue 1, pp 16–22

Paracorporeal ventricular assist device as a bridge to transplant candidacy in the era of implantable continuous-flow ventricular assist device

Authors

    • Department of Cardiovascular MedicineNational Cerebral and Cardiovascular Center
    • Department of TransplantationNational Cerebral and Cardiovascular Center
  • Tomoyuki Fujita
    • Department of Adult Cardiac SurgeryNational Cerebral and Cardiovascular Center
  • Yoshihiro Murata
    • Department of TransplantationNational Cerebral and Cardiovascular Center
  • Michinari Hieda
    • Department of TransplantationNational Cerebral and Cardiovascular Center
  • Takuya Watanabe
    • Department of TransplantationNational Cerebral and Cardiovascular Center
  • Takuma Sato
    • Department of TransplantationNational Cerebral and Cardiovascular Center
  • Haruki Sunami
    • Department of TransplantationNational Cerebral and Cardiovascular Center
  • Masanobu Yanase
    • Department of TransplantationNational Cerebral and Cardiovascular Center
  • Hiroki Hata
    • Department of Adult Cardiac SurgeryNational Cerebral and Cardiovascular Center
  • Takeshi Nakatani
    • Department of TransplantationNational Cerebral and Cardiovascular Center
Original Article Artificial Heart (Clinical)

DOI: 10.1007/s10047-013-0731-3

Cite this article as:
Suwa, H., Seguchi, O., Fujita, T. et al. J Artif Organs (2014) 17: 16. doi:10.1007/s10047-013-0731-3

Abstract

Ventricular assist devices (VADs) have long been used as bridge to transplant therapy (BTT). Nipro-Toyobo paracorporeal pulsatile-flow VAD (nt-VAD) was the only device available until April 2011, when implantable continuous-flow VADs (cf-VADs) became available. Although cf-VADs are central to BTT, nt-VAD remains a necessary option. We aimed to clarify the role of nt-VAD in an era of increasing cf-VAD use. We retrospectively reviewed patients who underwent VAD implantation at the National Cerebral and Cardiovascular Center from May 2011 to March 2013. Characteristics were compared between the nt-VAD and cf-VAD groups. Twenty-nine patients (mean age 37.7 ± 11.1 years, 23 males) underwent VAD implantation. Fifteen patients initially received nt-VADs, although 4 were converted to cf-VADs. Of these 15 patients, 3 were too small for cf-VADs and 2 needed bilateral ventricular support. The remaining 10 patients received nt-VADs (7 patients at INTERMACS level 1 and 3 at level 2). The nt-VAD group patients had significantly more preoperative mechanical circulatory support and were in a more critical condition before VAD implantation than the cf-VAD group. The 2-year survival rate was not significantly different. Despite the critical conditions of nt-VAD patients, their overall survival is not statistically inferior to that of cf-VAD patients. nt-VAD is a good option as a BTC for the patient with urgent and critical condition.

Keywords

Ventricular assist deviceBridge to transplant candidacyImplantable continuous-flow ventricular assist deviceParacorporeal pulsatile-flow ventricular assist device

Introduction

The ventricular assist device (VAD) is an alternative therapy for the patient with advanced heart failure who does not respond to conventional pharmacological and non-pharmacological treatments, whereas VAD was basically allowed to use only for patients deemed eligible for candidates of heart transplant in Japan [13]. Until April 2011, Nipro-Toyobo-paracorporeal pulsatile-flow ventricular assist device (nt-VAD, Nipro, Osaka, Japan) has been long used as only device for bridge to transplant therapy (BTT) in Japan and almost 90 % of the candidates for heart transplant received VAD. Therefore, over 90 % of heart transplant candidate had to wait at least for a couple of years with nt-VAD under hospitalization before receiving heart transplant so far [4]. On the other hand, 2 implantable continuous-flow ventricular assist device [cf-VAD, EVAHEART (Sun Medical, Nagano, Japan) and DuraHeart (Terumo Heart, Ann Arbor, MI, USA)] which has been long awaited was approved for health insurance coverage from April 2011 and it has become a central player in BTT since then [5]. cf-VAD has been expected to bring in more safe and fulfilling lives for heart transplant candidates at their home. With these circumstances, demands for nt-VAD, a former central player of BTT in Japan, has reduced and its role in clinical practice has changed.

This study aimed to clarify renewed roles of nt-VAD in the era of cf-VAD and to review the underlying problems of current VAD therapy by analyzing the 2-year experience of VAD usage in National Cerebral and Cardiovascular Center.

Methods

Patient population

We retrospectively analyzed 29 consecutive patients with advanced heart failure who received VADs from May 2011 to March 2013 at the National Cerebral and Cardiovascular Center. Although cf-VAD was approved for health insurance coverage in April 2011 in Japan, our institute only employed it from May 2011, after 1 month preparation. All patients received VAD implantation for BTT or bridge to transplant candidacy (BTC) after approval for transplant candidates by institutional committee. Patients’ characteristics were compared between nt-VAD group and cf-VAD group. VAD implantation was performed as previously reported [6]. Administration of heart failure medications such as angiotensin-converting enzyme inhibitors and β-adrenergic blockades after device implantation was encouraged same as patients with heart failure without mechanical supports. All subjects enrolled in this research have given their informed consent. Data collection, analysis, and reporting were approved by the National Cerebral and Cardiovascular Center Institutional Review Board.

Clinical parameters

We retrospectively obtained baseline clinical parameters from patients’ medical records, including demographics, blood examinations, and echocardiographic parameters [left ventricular diastolic dimension (LVDd), left ventricular systolic dimension (LVDs), ejection fraction (EF), left atrial dimension (LAD), interventricular septal thickness (IVST), posterior wall thickness (PWT)]. Severity of each patient was stratified based on The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) patient profile [7].

Clinical events

VAD-related cerebrovascular events included transient ischemic attack (TIA) and clinical strokes (ischemic or hemorrhagic) including subarachnoid hemorrhage. A TIA was defined as an episode of neurological disorder (lasting < 24 h) resulting from focal cerebral ischemia and not associated with evidence of cerebral infarction on imaging. Clinical strokes were defined as acute neurological disorder that lasted more than 24 h with evidence of infarction or hemorrhage on computed tomography. Event of VAD-related infection included infection caused by drive-line of cf-VAD or inflow and outflow cannulas of nt-VAD requiring hospitalization for receiving intravenous antibiotics. Drive-line and cannula infection was defined as the presence of purulent discharge from exit-site of drive-line and cannula. Administration of oral antibiotics at outpatient clinic was not considered an event of VAD-related infection.

Statistical analysis

Statistical analysis was performed using JMP software (version 9, SAS institute Inc. USA). Continuous variables with normal distribution are expressed as mean ± standard deviation (SD). The Chi square test was used for categorical variables, and analysis of variance (ANOVA) test was used for continuous variables. A values of P < 0.05 was considered significant. Kaplan–Meier analysis was used to evaluate overall survival and event-free survival for device-related cerebrovascular disease and infection of nt-VAD and cf-VAD group.

Results

Preoperative patient characteristics

The preoperative characteristics of both nt-VAD and cf-VAD group are listed in Table 1. A total of 29 patients underwent VAD implantation from May 2011 to March 2013 at our institute. Of these, 14 patients (48.2 %) initially received cf-VAD, while 15 patients (51.8 %) initially received nt-VAD. Comparison between the 2 groups revealed that female sex, patients with small BSA, and patients with critical conditions including more severe INTERMACS levels requiring more temporary mechanical circulatory support prior to VAD implantation were found in nt-VAD group. Lower rate of β-adrenergic blockades and angiotensin-converting enzyme inhibitors administration were also demonstrated. There were no differences in the baseline data of blood examinations and echocardiographic findings.
Table 1

Baseline characteristics of the patients according to the types of ventricular assist device implanted

 

cf-VAD (n = 14)

nt-VAD (n = 15)

P value

Age at VAD implantation, years

42.4 ± 7.4

35.1 ± 9.9

0.05

Male sex, n (%)

14 (100)

9 (60)

0.01

BSA at the time of VAD surgery, m2

1.73 ± 0.08

1.56 ± 0.18

0.02

Duration of heart failure, day

2892 ± 1404

2283 ± 2175

0.3

Etiology, n (%)

 DCM

11 (78.7)

10 (66.8)

 d-HCM

1 (7.1)

2 (13.4)

 ICM

1 (7.1)

1 (6.6)

 PPCM

0 (0)

1 (6.6)

 Others

1 (7.1)

1 (6.6)

INTERMACS patient profile, n (%)

 Level 1

0 (0)

9 (60)

 Level 2

3 (21.4)

6 (40)

 Level 3

11 (78.6)

0 (0)

Pre-VAD MCS, n (%)

 ECMO

0 (0)

6 (40)

0.01

 IABP

3 (21.4)

13 (86.6)

0.001

Intravenous inotropic agents, μg/kg/min

 (DOA, μg/kg/min + DOB, μg/kg/min)

5.04 ± 1.04

7.39 ± 2.63

0.04

Medication, n (%)

 β-blocker

14 (100)

9 (60)

0.01

 ACE inhibitor or Ang-II antagonist

13 (76.9)

7 (46.6)

0.01

 Aldosterone antagonist

13 (76.9)

6 (40)

0.05

Laboratory examinations

 WBC, /μL

6321.4 ± 1144.8

7586.7 ± 2079.1

0.21

 Hb, mg/dL

12.3 ± 1.2

11.4 ± 1.6

0.14

 T-Bil, mg/dL

1.29 ± 0.43

2.07 ± 1.18

0.08

 Cre, mg/dL

1.17 ± 0.34

1.01 ± 0.36

0.51

 Na, mEq/L

136.4 ± 2.6

135.2 ± 5.2

0.53

 CRP

1.49 ± 1.38

5.25 ± 5.02

0.08

 BNP, pg/dL

812.6 ± 458.2

933.9 ± 494.2

0.1

Echocardiographic parameters

 LVEDD, mm

74.6 ± 7.7

71.7 ± 9.7

0.77

 LVESD, mm

67.4 ± 9.9

65.8 ± 10.5

0.95

 LVEF, %

16.5 ± 6.9

16.8 ± 7.4

0.76

AR, grade 1–4

 1

1

1

0.87

 2–4

0

0

cf-VAD implantable continuous-flow ventricular assist device, nt-VAD Nipro-Toyobo paracorporeal pulsatile-flow ventricular assist device, VAD ventricular assist device, BSA body surface area, DCM dilated cardiomyopathy, d-HCM dilated-phase hypertrophic cardiomyopathy, ICM ischemic cardiomyopathy, PPCM peripartum cardiomyopathy, INTERMACS the interagency Registry for Mechanical Assisted Circulatory Support, Pre VAD MCS mechanical circulatory support prior to VAD implantation, ECMO extracorporeal membrane oxygenation, IABP intra-aortic balloon pump, DOA dopamine, DOB dobutamine, ACE angiotensin converting enzyme, Ang-II angiotensin II, WBC white blood cell, Hb hemoglobin, T-Bil total bilirubin, Cre creatinine, Na sodium, CRP C-reactive protein, BNP brain natriuretic peptide, LVEDD left ventricular end-diastolic dimension, LVESD left ventricular systolic dimension, LVEF left ventricular ejection fraction, AR aortic regurgitation

Clinical course

The clinical course of enrolled patient is summarized in Fig. 1. The cf-VAD group consist of 12 EVAHEARTs and 2 DuraHearts. In the nt-VAD group, 2 patients needed biventricular support and 4 were converted to cf-VADs. In the 2 cases needing biventricular support, both nt-VAD and extracorporeal membrane oxygenation (ECMO) were used for right ventricular support, respectively. In the 4 conversion cases, 2 EVAHEARTs and 2 DureHearts were used. One patient receiving cf-VAD and 2 patients receiving nt-VAD died due to cerebrovascular disease and sepsis, respectively. Furthermore, 3 patients implanted with nt-VAD were weaned from VAD because of recovery of native cardiac function, while no patient with cf-VAD demonstrated sufficient recovery of native cardiac function enough to be weaned from VAD. By the end of the study period, 17 of original patients were supported by cf-VAD and 6 were supported by nt-VAD. The overall survival curves of both cf-VAD and nt-VAD were shown in Fig. 2. Whereas, the cf-VAD and nt-VAD group demonstrated comparatively favorable 2-year survival rates of 92.8 and 86.6 %, respectively; there was no statistically significant difference in survival between them. The event-free curves for VAD-related complications such as VAD-related infection and VAD-related cerebrovascular disease are displayed in Fig. 2. There were no statistically significant differences between the patient who initially received cf-VAD and nt-VAD in terms of either VAD-related infection or VAD-related cerebrovascular disease.
https://static-content.springer.com/image/art%3A10.1007%2Fs10047-013-0731-3/MediaObjects/10047_2013_731_Fig1_HTML.gif
Fig. 1

Clinical course of all study patients. This flowchart shows the clinical course of patients who initially received nt-VAD or cf-VAD

https://static-content.springer.com/image/art%3A10.1007%2Fs10047-013-0731-3/MediaObjects/10047_2013_731_Fig2_HTML.gif
Fig. 2

Kaplan–Meier curves for overall survival and freedom from device-related complications. There were no significant differences between patients who initially received cf-VAD or nt-VAD in terms of overall survival, VAD-related infection, or VAD-related cerebrovascular disease (CVD) (P = 0.5, P = 0.4, and P = 0.1, respectively)

Individual demographics of the patient receiving nt-VADs

The individual demographics for patients who initially received nt-VADs are shown in Table 2. nt-VADs were implanted in 3 patients (1 male and 2 females) because of their less body surface area (BSA; lower than 1.4 m2) and in 2 patients because of severe heart failure requiring a biventricular assist device (BiVAD). One case requiring BiVAD was diagnosed as peripartum cardiomyopathy and was weaned from VAD when native cardiac function was recovered, whereas the other BiVAD case had a diagnosis of d-HCM with hypoplastic right ventricle and died due to sepsis. BTC was the main indication for nt-VAD implantation in 10 patients (7 patients were INTERMACS level 1 while 3 patients were INTERMACS levels 2). Preoperatively, of 7 INTERMACS level 1 patients, 4 were supported by both ECMO and the intra-aortic balloon pump (IABP) and 3 were supported with IABP alone. Two patients with INTERMACS level 2 were also supported with IABP before surgery. Among the 10 BTC patients, 4 were converted to cf-VAD and of these 4 patients, case 1 who had been converted to cf-VAD 108 days after nt-VAD implantation suffered from VAD pocket infection requiring repetitive lavage of infected pocket with long-term administration of antibiotics after conversion. Remaining 3 patients were converted within 15 days after nt-VAD implantation and they had uneventful postoperative outcome. In total, 5 patients were now on nt-VAD support for BTT and 1 patient who had complicated by repetitive cerebrovascular disease following nt-VAD implantation still on nt-VAD support for BTC.
Table 2

Patient demographics for the Nipro-Toyobo ventricular assist device

Patient number

Sex

Age (y. o)

BSA (m2)

Etiology

pre VAD MCS

INTERMACS profile

Reason for nt-VAD

Conversion or weaning of VAD

Duration of nt-VAD (days)

VAD-related complications

Current status

Case 1

M

28

1.63

DCM

IABP

1

BTC

Conversion to cf-VAD

108

Pocket and drive-line infection

BTT at outpatient

Case 2

M

16

1.6

DCM

IABP

1

BTC

Conversion to cf-VAD

15

Drive-line infection

BTT at outpatient

Case 3

M

26

1.87

DCM

IABP, ECMO

1

BTC

Conversion to cf-VAD

15

CVD and drive-line infection

BTT at outpatient

Case 4

M

55

1.73

ICM

IABP

1

BTC

Conversion to cf-VAD

7

CVD

BTT at outpatient

Case 5

M

43

1.85

DCM

None

2

BTC

Weaned from VAD

136

 

Stable at outpatient

Case 6

M

33

1.69

DCM

IABP

2

BTC

Weaned from VAD

104

 

Stable

Case 7

F

22

1.41

d-HCM

IABP, ECMO

1

BTC

 

16

 

Death (sepsis)

Case 8

F

21

1.44

DCM

IABP, ECMO

1

BTC

 

262

Cannula infection

BTT with nt-VAD

Case 9

M

38

1.83

DCM

IABP

2

BTC

 

226

CVD and cannula infection

BTT with nt-VAD

Case 10

M

37

1.67

DCM

IABP, ECMO

1

BTC

 

206

CVD and cannula infection

BTT with nt-VAD

Case 11

F

27

1.31

d-HCM

None

2

BSA < 1.4 m2

 

625

CVD

BTT with nt-VAD

Case 12

M

26

1.34

DCM

IABP

2

BSA < 1.4 m2

 

470

Cannula infection

BTT with nt-VAD

Case 13

F

57

1.33

DCM

IABP

3

BSA < 1.4 m2

 

115

CVD

BTC with nt-VAD

Case 14

F

31

1.33

PPCM

IABP, ECMO

1

BiVAD

Weaned from VAD

25

 

Stable at outpatient

Case 15

F

49

1.4

Others

IABP, ECMO

1

BiVAD

 

42

 

Death (sepsis)

BSA body surface area, pre VAD MCS mechanical circulatory support prior to VAD implantation, INTERMACS the interagency Registry for Mechanical Assisted Circulatory Support, DCM dilated cardiomyopathy, IABP intra-aortic balloon pump, BTC bridge to candidacy, cf-VAD implantable continuous-flow ventricular assist device, BTT bridge to transplant, ECMO extracorporeal cardiopulmonary membrane oxygenation, CVD cerebrovascular disease, ICM ischemic cardiomyopathy, d-HCM dilated-phase hypertrophic cardiomyopathy, nt-VAD Nipro-Toyobo extracorporeal pulsatile-flow ventricular assist device, PPCM peripartum cardiomyopathy, BiVAD biventricular assist device

Discussion

VAD therapy is currently the most established therapy for advanced heart failure that is unresponsive to conventional treatments, and its use is increasing annually. For a long time, nt-VAD was the only consistently used device approved for use in BTT in Japan. However, in April 2011, the EVAHEART and DuraHeart cf-VADs were introduced and approved for health insurance coverage for BTT [810], with the expectation that patients would have an improved quality of life in their homes and that nt-VAD would be used in fewer cases. However, after analyzing the 2-year experience of VAD therapy in the National Cerebral and Cardiovascular Center, we found that since the introduction of cf-VAD, nt-VADs were still initially implanted in 15 (51.7 %) of the 29 patients studied. The indications for nt-VAD implantation were the necessity of bilateral ventricular support (2 cases), less BSA for cf-VAD (3 cases), and BTC (10 cases) in patients at lower INTERMACS patient profiles (levels 1 and 2).

The INTERMACS annual report recently revealed that VAD implantation was associated with a poor prognosis in patients at INTERMACS levels 1 and 2. As a result, the proportion of patients at INTERMACS level 1 undergoing VAD implantation gradually decreased from 44.2 % in the first annual report to 19.7 % in the fifth annual report [7, 1114]. In response to these reports, use of nt-VADs has become a reasonable strategy for INTERMACS level 1 patients as BTC in order to avoid use of expensive implantable devices in high-risk patients and to allow more time to assess their transplant candidacy. Our study further disclosed that there were no statistically significant difference between nt-VAD and cf-VAD in terms of their overall survival and VAD-related complications such as drive-line or cannula infection, and cerebrovascular disease despite much sicker patients were included for nt-VAD patients. Furthermore, there was always the possibility of these nt-VAD patients converting to cf-VAD later if they stabilized and were deemed eligible for heart transplant. In our patient series, 4 cases of nt-VAD were converted to cf-VAD, and all continue to be well in outpatient clinic reviews.

Of course, there still remain several problems in operating nt-VAD for BTC device. First, not all the patients can afford to be converted from nt-VAD to cf-VAD. Continuous infection associated with both surgical procedure of nt-VAD implantation and nt-VAD itself (e.g., cannulas infection) are potential obstacles to VAD conversion. Indeed, nt-VAD has been reported to be an independent risk factor for VAD-related infection over time; therefore, conversion of nt-VAD to cf-VAD always carries a risk of post-conversion infection such as pump pocket infection [15]. In fact, case 1 of our series, who had been converted to cf-VAD over 3 months after initial nt-VAD implantation, developed pocket infection from the cannula exit-site infection of nt-VAD. Furthermore, case 8, 9 and 10 could not be converted to cf-VAD because of clinically evident cannula exit-site infection of nt-VAD. Yoshioka et al. [16] also reported their experience of 8 conversions from nt-VAD to DureHeart in which 3 cases were complicated by pocket infection. Considering that the incidence of device-related infection is known to increase over time, VAD conversion was performed as soon as possible after the patients’ condition stabilized and their suitability for transplant was determined [15]. In fact, Case 2, 3 and 4 received VAD conversion within 15 days after nt-VAD implantation, and they did not develop pocket infections. The second problem is that use of nt-VADs for BTC may force patients with critical conditions to undergo a second invasive surgical procedure in a relatively short period of time when they undergo VAD conversion. The third problem is that if candidacy for transplant is not approved, since nt-VAD has been shown to be a durable device, patients receiving nt-VADs have to be hospitalized for the rest of their lives with nt-VAD support and no hope for heart transplant. In fact, our case 13 who had repeated cerebrovascular events after nt-VAD implantation still could not apply for the transplant waiting list due to residual neurological defects.

To resolve these issues, we propose the followings. Both approval of destination therapy (DT) for health insurance coverage and introduction of other easy-to-use and short-term devices that can be implanted by low-invasive procedures may be helpful. However, DT is currently under consideration in Japan and it should be considered carefully in terms of both ethical perspective and its cost effectiveness. Short-term VADs have been used as BTC so far [17, 18]. John et al. [19] reported their experience with the Levitronix CentriMag circulatory support system as bridge to decision in patient with refractory acute cardiogenic shock with multi-system organ failure. In this study, 12 critical patients were enrolled for analysis, of whom 8 were successfully bridged to implantable VAD (HeartMate XVE); 5 were successfully bridged to heart transplant and only 1 died before heart transplant despite extreme critical conditions of the patient (1-month survival of 75 % and 1-year survival of 62.5 %). Therefore, temporary devices such as the Levitronix CentriMag circulatory support system may play a role in BTC. However, since there is no big difference in terms of invasiveness between nt-VAD and Levitronix CentriMag circulatory support system, development and introduction of less-invasive, short-term VADs are essential for improvement of current VAD therapy.

In addition, it would be useful to encourage close communication with primary care physicians and general cardiologists of other facility with no VAD programs about the importance of VAD therapy for advance heart failure patients before they deteriorate to lower INTERMACS level.

Conclusion

At present, cf-VADs are the first-line mechanical circulatory device for patients with advanced heart failure who meet the indications for both heart transplant and VAD implantation. However, not all patients are suitable for cf-VAD, and a prominent reason for nt-VAD implantation is use as BTC in critically ill INTERMACS level 1 or 2 patients. In our case series, nt-VAD could be subsequently converted to cf-VAD and there were no significant differences in overall survival or the development of VAD-related complications. Therefore, nt-VAD is potentially a good option for BTC in critically ill patients even in the era of cf-VAD. However, VAD therapy is still in transition, and we are currently seeking better ways to use VADs in advanced heart failure patients. Other new VADs are scheduled to be available in the near future, and they will further impact the current role of the nt-VAD.

Study limitations

This study had several limitations. First, this study was a retrospective study in a single center with a relatively small sample size. Second, device strategy of VAD differs somewhat by each institution. Nevertheless, our device strategy in this study basically stands on current health insurance regulation so that we believe that our report can be a general applicable reference for current device strategy.

Acknowledgments

We thank Hiroshi Nishioka, Akira Hatanaka, Rieko Sakai, Emiko Fujiwara and Yumiko Hori for patient care and management of VADs.

Conflict of interest

All the authors have declared no conflict of interests.

Copyright information

© The Japanese Society for Artificial Organs 2013