Rescuing Patients With Severe Biventricular Failure in the Era of Continuous-Flow Left Ventricular Assist Device

Abstract

Background: We evaluated clinical outcomes of left ventricular assist device (LVAD) support in patients with or without severe right heart failure, in order to determine what kind of organ allocation system could help severe biventricular failure patients to be safely bridged to heart transplantation (HTx), even in Japan where the waiting time for HTx is extremely long.

Methods and Results: One hundred and seventy consecutive patients who were implanted with continuous-flow LVAD at the present institution were included in this study. The patients were divided into 2 groups: 158 patients with isolated LVAD (group-LVF) and 12 patients who required long-term mechanical or inotropic right heart support (group-BVF). Post-LVAD survival in group-BVF was significantly worse than in group-LVF (P<0.0001). Given that many patients in group-BVF died between 1 and 2 years after LVAD implantation, Kaplan-Meier survival curve simulation was carried out under the condition that all the patients in group-BVF who died on LVAD support >1 year after LVAD implantation had received HTx at 365 days after LVAD implantation and survived thereafter. In this simulation, no significant difference in survival was seen between the groups (P=0.2424).

Conclusions: A new allocation system that allows severe right heart failure patients to receive HTx at around 1 year would enable rescue of the patients with severe right heart failure.

Mechanical circulatory support with a continuous-flow left ventricular assist device (LVAD) is now considered a standard of care to bridge cardiac transplant eligible candidates until a suitable donor organ is obtained.^1–3 In patients with biventricular failure, however, outcomes continue to be poor.⁴ Regardless of the etiology, survival appears to be worse in patients requiring biventricular support compared with that in patients with isolated LVAD support. This has been attributed to the adverse hemodynamic effects of concomitant right ventricular (RV) dysfunction on global perfusion.

Heart transplantation, in contrast, is the gold standard treatment of end-stage heart failure. Despite the progress in heart failure treatment with continuous-flow LVAD, destination therapy using LVAD is still not approved in Japan, and heart transplantation remains the ultimate goal of heart failure treatment in this country. The number of heart transplant procedures increased from around 10 per year to 40–50 per year after a revision of the Japanese Organ Transplant Act in July 2010,² but the number is still very low in international terms and the mean waiting period was >1,150 days at the end of June 2016.² Because of this extremely long waiting time, it is almost impossible for patients with severe biventricular failure to be safely bridged to heart transplantation.

The aim of this retrospective study was to evaluate the historical improvement and limitations in the treatment of severe biventricular failure, and to provoke a discussion about heart allocation system in Japan.

Methods

Patients

Ethics committee approval was obtained for this retrospective study. Individual consent was waved. From October 2005 to August 2017, 170 patients had undergone 188 implantable continuous-flow LVAD implantations at the present institute. Of the 170 patients, 158 were supported with isolated LVAD, and this group of patients was named group-LVF. Those patients who initially required temporary mechanical right heart support but who later had removal of the RV assist device (RVAD) were also included in this group. The other 12 patients required long-term mechanical right heart support or continuous i.v. inotropic right heart support under continued hospitalization, and this group of patients was named group-BVF. Patient characteristics and clinical outcomes were compared between the 2 groups.

Device Selection for RVAD

The first choice of device as mechanical right heart support at the present institute was temporary extracorporeal centrifugal pumps such as Capiox (Terumo, Tokyo, Japan), Gyropump (Medtronic, Minneapolis, MN, USA), or Rotaflow (Maquet, Rastatt, Germany). After hemodynamic stabilization and the recovery of end-organ function, the patient was weaned off the temporary RVAD as far as possible, as described previously.⁵ If not possible, temporary RVAD was converted to durable RVAD such as Nipro paracorporeal pneumatic pump (Nipro, Osaka, Japan). Nipro pump was the only durable device approved in Japan to be used as RVAD.⁶ If right heart failure was so severe that the surgeon found that weaning from the temporary RVAD was not possible in 2 weeks, a durable pump was used instead of the temporary centrifugal pump from the beginning. Implantable continuous flow devices such as Jarvik2000 (Jarvik Heart, New York, NY, USA) and HVAD (Medtronic) were also used as durable RVAD. Such implantable devices were available only in a very limited number of patients as part of clinical investigations.^7,8

Statistical Analysis

Continuous variables are presented as mean±SD, and categorical variables as numbers with or without proportions. All continuous variables were checked for normality using the Shapiro-Wilk test and normal probability plot. For univariate analysis, normally distributed variables were compared using Student’s t-test, non-normally distributed variables were compared using the Mann-Whitney U-test, and categorical variables were compared using chi-squared analysis or Fisher’s exact test, as appropriate. Survival curves for group-LVF, group-BVF and Nipro biventricular assist device (BiVAD) patients were prepared using the Kaplan-Meier method and were compared using the pairwise log-rank test. We also used the Kaplan-Meier method for the simulation of survival in group-BVF. Kaplan-Meier survival curve simulation was carried out under the condition that all the patients in group-BVF who died on LVAD support >1 year after LVAD implantation had received heart transplantation at 365 days after LVAD implantation and survived thereafter.

All P-values are 2-sided, and P<0.05 was considered to indicate statistical significance. Statistical analysis was performed using JMP Pro 13.0 (SAS Institute, Cary, NC, USA).

Results

Preoperative Characteristics and Clinical Outcomes

Table 1 lists the patient characteristics. Mean patient age tended to be younger in group-BVF (34.3±11.7 years) than in group-LVF (42.3±14.8 years, P=0.0670) and there were more female patients in group-BVF (58.3%) than in group-LVF (29.8%, P=0.0403). The main etiologies of heart failure in group-BVF were idiopathic cardiomyopathy and myocarditis, and no patients had ischemic cardiomyopathy in this group. The mean Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile number was smaller in group-BVF than in group-LVF (1.5±0.7 vs. 2.6±0.7, P<0.0001), suggesting more severe preoperative conditions in group-BVF than in group-LVF. LVAD type had no apparent impact on the requirement of right heart support.

Table 1. Patient Characteristics

	Group-LVF (n=158)	Group-BVF (n=12)	P-value
Age (years)	42.3±14.8	34.3±11.7	0.0670
Gender (female)	29.8	58.3	0.0403
Body surface area (m2)	1.60±0.22	1.53±0.20	0.2758
Diagnosis			<0.0001
DCM	84	1
dHCM	22	4
Myocarditis	5	4
ICM	23	0
Others	23	3
INTERMACS profile	2.6±0.7	1.5±0.7	<0.0001
Device (LVAD)			0.2682
HeartMate II	49	1
Jarvik2000	35	4
DuraHeart	33	5
EVAHEART	26	1
HeartWare	15	1

Data given as mean±SD, %, or n . BVF, patients who required long-term mechanical or inotropic right heart support; DCM, dilated cardiomyopathy; dHCM, dilated phase hypertrophic cardiomyopathy; ICM, ischemic cardiomyopathy; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; LVAD, left ventricular assist device; LVF, patients with isolated left ventricular assist device.

Table 2 lists the characteristics and the clinical outcomes of the 12 patients in group-BVF. Temporary RVAD with extracorporeal centrifugal pumps were used as initial RVAD in 4 patients (patients 5,6,9,11). After attempts to wean off RVAD had failed, the temporary RVAD was converted to Nipro RVAD in 2 patients and to Jarvik2000 RVAD in 1. The other patient was successfully bridged to heart transplantation with LVAD and temporary RVAD (patient 9). Two patients with fulminant myocarditis (patients 1,2), who were referred to the present institution under veno-arterial extracorporeal membrane oxygenation support with arrested heart, were implanted with Nipro BiVAD as the initial operation. No cardiac functional recovery was observed even after inflammation of the myocardium had resolved, and Nipro BiVAD was converted to implantable BiVAD with DuraHeart LVAD and Jarvik2000 RVAD.^7,9 Two patients with severe right heart failure: 1 due to arrhythmogenic RV cardiomyopathy (patient 3) and 1 due to secondary cardiomyopathy (Danon’s disease, patient 7) were implanted with implantable BiVAD (Jarvik2000 BiVAD and HVAD BiVAD, respectively) at the initial operation.^8,10,11 Four patients (patients 4,8,10,12) required continuous injection of inotropes although they were able to be separated from cardiopulmonary bypass during the initial operation. One of them later developed end-organ dysfunction and was implanted with the Nipro RVAD (patient 12). One patient with cardiac allograft vasculopathy (patient 4) underwent DuraHeart LVAD implantation, but heart failure remained because of low LVAD flow due to right heart failure and small LV chamber. LVAD inflow was changed from LV apex to left atrium, and the LVAD was exchanged to extracorporeal device. The patient could not be weaned off cardiopulmonary bypass without mechanical right heart support during this operation.

Table 2. Group-BVF: Patient Characteristics

Patient ID no.	Age (years)/ sex	Etiology	LVAD	Right heart support	Outcome
1	30/F	Fulminant myocarditis	Nipro → DuraHeart	Nipro → Jarvik2000 RVAD	Died on BiVAD (539 days)
2	35/F	Fulminant myocarditis	Nipro → DuraHeart	Nipro → Jarvik2000 RVAD	Discharged home → HTx (884 days)
3	27/F	ARVC	Jarvik2000	Jarvik2000 RVAD	Discharged home → HTx (1,245 days)
4	36/M	Post-HTx vasculopathy	DuraHeart → Nipro	Inotropes → EC-centrifugal RVAD → Nipro RVAD	Died on BiVAD (225 days)
5	24/M	dHCM	DuraHeart	EC-centrifugal RVAD → Nipro RVAD	Died on BiVAD (448 days)
6	32/M	Fulminant myocarditis	EVAHEART	EC-centrifugal RVAD → Jarvik2000 RVAD	Died on BiVAD (553 days)
7	13/F	Danon’s disease	HVAD	HVAD RVAD	Discharged home → HTx (826 days)
8	45/F	dHCM	Jarvik2000	Inotropes	HTx (801 days)
9	40/M	dHCM	Jarvik2000	EC-centrifugal RVAD	HTx (310 days)
10	59/F	DCM	Jarvik2000	Inotropes	Died on LVAD+inotropes (141 days)
11	42/F	Fulminant myocarditis	HeartMate II	EC-centrifugal → Nipro RVAD	Died on BiVAD (250 days)
12	28/M	dHCM	DuraHeart	Inotropes → Nipro RVAD	Died on BiVAD (1,407 days)

ARVC, arrhythmogenic right ventricular cardiomyopathy; BiVAD, biventricular assist device; EC, extracorporeal; HTx, heart transplantation; RVAD, right ventricular assist device. Other abbreviations as in Table 1.

Heart Transplantation

Of the 170 patients, 57 in group-LVF and 5 in group-BVF were successfully bridged to heart transplantation (Table 3). Mean waiting time at status 1 (active waiting duration on Japan Organ Transplantation Network waiting list under mechanical circulatory support or inotropic support) was significantly shorter in group-BVF than in group-LVF (703±397 days vs. 975±274 days, P=0.0441). Patients in group-BVF received heart transplantation when they were at a significantly lower rank on the waiting list (34.2±55.6 vs. 8.3±21.7, P=0.0325). This means that many patients in group-BVF received heart transplantation from more marginal donors who patients at the higher rank of the waiting list had rejected, compared with patients in group-LVF, and therefore waiting time was shorter. There was no significant difference in actuarial survival after heart transplantation between the groups (Figure 1).

Table 3. Successful Bridge to HTx

	Group-LVF (n=158)	Group-BVF (n=12)	P-value
Patients	57 (36.1)	5 (41.7)	0.6981
Waiting time at status 1 (days)	975±274	703±397	0.0441
Rank on the waiting list†	8.3±21.7	34.2±55.6	0.0325

Data given as mean±SD or n (%). ^†At the time of heart transplantation. Abbreviations as in Tables 1,2.

Figure 1.

Survival after heart transplantation (HTx) in patients with isolated left ventricular assist device (group-LVF) and in patients who required long-term mechanical or inotropic right heart support (group-BVF).

Biventricular Failure Patients

Improved Survival As a historical control, survival of patients who underwent Nipro BiVAD support from May 2000 to October 2010 (n=16) was compared with that of patients in group-BVF (Figure 2). One- and 2-year survival in the Nipro BiVAD group were 12.5% and 0%, respectively, whereas 1- and 2-year survival in group-BVF were 75.0% and 50.0%, respectively. Survival in group-BVF was significantly higher than that in the Nipro BiVAD group (P=0.0002).

Figure 2.

Survival after left ventricular assist device (LVAD) implantation in patients with Nipro biventricular assist device (BiVAD) and in patients who required long-term mechanical or inotropic right heart support (group-BVF).

Poor Outcome Compared With LVAD Patients Figure 3 compares the survival of patients in group-LVF and group-BVF. One-, 2- and 3-year survival were 90.1%, 85.5%, and 84.8%, respectively, in group-LVF, and 75.0%, 50.0%, and 50.0% years, respectively, in group-BVF. Survival in group-BVF was significantly worse than in group-LVF (P=0.0080). Most of the deaths in group-BVF occurred ≤2 years after LVAD implantation.

Figure 3.

Survival after left ventricular assist device (LVAD) implantation in patients with isolated LVAD (group-LVF) and in patients who required long-term mechanical or inotropic right heart support (group-BVF). Green circle, heart transplantation; red circle, death after heart transplantation.

Survival Simulation

Based on the fact that most of the deaths in group-BVF occurred in the first 2 years and that patients who die ≤1 year after LVAD implantation are often too sick to receive heart transplantation, we carried out survival simulation for group-BVF under the condition that all patients who died after 1 year in group-BVF received heart transplantation at 365 days after LVAD implantation and survived thereafter (Figure 4). Death after heart transplantation was counted as it was. There was no significant difference in survival between the groups (P=0.2424).

Figure 4.

Survival in patients with isolated left ventricular assist device (LVAD; group-LVF) and survival simulation in patients who required long-term mechanical or inotropic right heart support (group-BVF) under the condition that all patients in group-BVF who died on LVAD support >1 year after LVAD implantation had received heart transplantation (HTx) at 365 days after LVAD implantation and survived thereafter. Green circles, HTx; red circle, death after HTx.

Discussion

In the present study we found that the survival of the patients who underwent BiVAD implantation significantly improved in the era of implantable continuous-flow devices compared with that in the era of paracorporeal pulsatile device. The survival of BiVAD patients, however, was still significantly worse than that of isolated LVAD patients. Waiting time for heart transplantation was significantly shorter for BiVAD patients than for isolated LVAD patients because BiVAD patients accepted more marginal donors than LVAD patients. Nevertheless, survival after heart transplantation was equivalent in the 2 groups.

There are several reasons for the improvement in survival of the patients who underwent BiVAD implantation. One of the reasons is obviously the improvement in device technology. In the 6th annual report of INTERMACS published in 2014, Kirklin et al reported significantly improved survival in patients who were implanted with continuous-flow device compared with patients who were implanted with pulsatile device, both as LVAD and BiVAD.¹² In the present study, clinical outcomes of Nipro BiVAD implantation were devastating. No patient survived >2 years even though the average waiting time for heart transplantation in Japan was longer than 2 years,^2,13 and therefore, no patient was successfully bridged to heart transplantation with the Nipro BiVAD. Although the right heart supports used in patients in group-BVF varied, consisting of the Nipro pump, continuous-flow pumps, extracorporeal centrifugal pumps, and inotropes (Table 2), all the patients in group-BVF were implanted with implantable continuous-flow pumps as LVAD, and this was a great advantage over the Nipro BiVAD.

Another reason is the utilization of continuous-flow implantable pumps as RVAD. Five of 12 patients in group-BVF were implanted with continuous-flow BiVAD as part of clinical investigations. All 5 patients survived longer than 1 year, and 3 of them survived longer than 2 years and were successfully bridged to heart transplantation. The clinical use of continuous-flow implantable BiVAD was first reported by Frazier et al in 2004;¹⁴ they used the Jarvik2000 in a salvage procedure for acute postoperative right-sided heart failure. Although the patient died 12 days after BiVAD implantation because of sepsis and hepatic failure, they suggested that timelier implantation of the BiVAD might be lifesaving. Since then, other investigators, including us, have reported success with short- and long-term implantable BiVAD support.^{7–11,15–17} Widespread use of continuous-flow implantable BiVAD, however, is limited because of technical and logistic challenges that add to the complexity of device management. One of these challenges is the anatomic limitation. The difficulty of accommodating 2 pump housings and opposing outflow conduits has traditionally discouraged the use of BiVAD therapy. Another substantial limitation of BiVAD therapy is the need for duplicate equipment: 2 controllers, 4 active batteries, and an additional backup power supply, all of which constitute a physical and operational burden. Likewise, the need to manage and manipulate multiple controllers increases the complexity of dual-device training. Additionally, and the most importantly, there also exists the reimbursement issues of the second pump. The use of implantable continuous-flow device as an RVAD is not approved in Japan nor in the USA, or in other European countries.

Another possible explanation for improved survival in BiVAD patients is the strategy in heart transplantation. The mean waiting time for donor heart in group-BVF was 703±397 days, which was significantly shorter than that in group-LVF (975±274 days, P=0.0441; Table 3). In Japan, all the patients who are waiting for heart transplantation with inotropic support, LVAD support or BiVAD support are listed as “status 1” and are not distinguished by more precise clinical conditions. All the patients in status 1 are sorted only by the time on the list. Therefore, the only possible way to make the waiting time shorter than for other patients is to accept the marginal donor heart that is refused by the patients at a higher rank on the waiting list. The mean rank on the waiting list at the time of heart transplantation in group-BVF and LVF was 34.2±55.6 and 8.3±21.7, respectively, and the difference was significant (P=0.0325). This means that patients in group-BVF underwent heart transplantation when they were at a significantly lower rank on the waiting list than patients in group-LVF. The use of so-called marginal donors is now generally accepted and widespread. Historically, the upper age limit for heart donation was 40–45 years, but there is no definitive reason why selected older donor hearts cannot be used if structurally normal.¹⁸ Prieto et al reported that there was no difference in long-term survival between recipients of older hearts and those who received hearts from younger donors and suggested that donors should not be excluded based solely on age.¹⁸ Also in the present study, the post-transplant survival in group-BVF was not significantly inferior to that of group-LVF, although the patients in group-BVF were considered to have received hearts from more marginal donors than in group-LVF. It is also true, however, that when utilizing marginal donor hearts, we must carefully consider donor and recipient characteristics to minimize deaths on the waiting list and to maximize graft survival outcomes. Fudim et al reported worse graft survival with utilization of marginal donor organs compared with utilization of standard organs.¹⁹ Nevertheless, when these transplant recipients were compared with patients who remained on optimal medical therapy, survival and quality of life were significantly improved.^20,21

The fact that the survival of patients with biventricular failure might be improved (at least partly) by shortening the waiting time for heart transplantation prompted the next clinical question: what if these patients could receive heart transplantation even earlier? Considering that the patients with biventricular failure who die ≤1 year after LVAD implantation may be too sick to undergo heart transplantation, we carried out Kaplan-Meier survival curve simulation under the condition that all the patients in group-BVF who died on LVAD support >1 year after LVAD implantation had received heart transplantation at 365 days after LVAD implantation and survived thereafter. On this survival curve simulation, no significant difference was seen in survival between the 2 groups. This suggests that if the patients with severe biventricular failure could receive heart transplantation 1 year after LVAD implantation (not from marginal donors but from standard donors), survival in biventricular failure patients would be as good as that in isolated LVAD patients. There are a few options to enable biventricular failure patients to receive heart transplantation at 1 year. For example, the simplest way is to set a new status over “status 1” that gives priority to BiVAD patients who are waiting for >1 year. Patients in this new status have top priority to receive heart transplantation, and heart transplantation may be available for them around 1 year after BiVAD implantation. Another option is to give triplicate waiting points for BiVAD patients. Given that the average waiting time in status 1 was 1,157 days in 2016 in Japan,² a patient with BiVAD could expect a donor heart in approximately 385 days under this system.

Study Limitations

We recognize several limitations in the present study, including those related to a single-center retrospective analysis. The number of patients in this study was relatively low, limiting statistical power. Because of the small number, we needed to analyze patients on different types of right heart support in the same cohort. Although it is difficult to conduct this kind of study in a prospective way, it is necessary to re-evaluate these data in a multicenter study. The setting of heart transplantation in Japan, especially the waiting time, is totally different from that in other countries. Therefore, the suggestion of the new allocation system could be applied only in Japan. We recognize that the simulation method we used in this study is too simple, and that the simulation does not precisely predict the survival of patients in the real world. More precise simulation requires large-scale data on patient survival after heart transplantation, which we do not have. Moreover, in the suggestion of the new allocation system, we did not consider the negative impact on the survival of isolated LVAD patients if we give the priority for heart transplantation to the BiVAD patients. We believe, however, that such data as presented in this study could trigger a discussion about the heart allocation system in this country.

Conclusions

Survival of those with severe right heart failure after LVAD implantation was still very poor compared with that of isolated LVAD patients, although it significantly improved compared with that of paracorporeal pulsatile BiVAD patients. A new heart allocation system that allows severe right heart failure patients to receive heart transplantation at around 1 year would enable rescue of the patients with severe right heart failure.

Disclosures

The authors declare no conflicts of interest.

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