- Email: [email protected]
Effect of pulmonary hypertension on transplant outcomes in patients with ventricular assist devices
Journal Pre-proof Effect of pulmonary hypertension on transplant outcomes in patients with ventricular assist devices Masahiko Ando, MD, PhD, MPH, Hiroo Takayama, MD, PhD, Paul A. Kurlansky, MD, Jiho Han, BS, Arthur R. Garan, MD, Veli K. Topkara, MD, Melana Yuzefpolskaya, MD, Paolo C. Colombo, MD, Maryjane Farr, MD, Yoshifumi Naka, MD, PhD, Koji Takeda, MD, PhD PII:
S0003-4975(19)31732-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.09.095
Reference:
ATS 33241
To appear in:
The Annals of Thoracic Surgery
Received Date: 10 January 2019 Revised Date:
7 September 2019
Accepted Date: 27 September 2019
Please cite this article as: Ando M, Takayama H, Kurlansky PA, Han J, Garan AR, Topkara VK, Yuzefpolskaya M, Colombo PC, Farr M, Naka Y, Takeda K, Effect of pulmonary hypertension on transplant outcomes in patients with ventricular assist devices, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.09.095. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Effect of pulmonary hypertension on transplant outcomes in patients with ventricular assist devices Running head: Effect of pulmonary hypertension
Masahiko Ando1, MD, PhD, MPH, Hiroo Takayama1, MD, PhD, Paul A Kurlansky1, MD, Jiho Han1, BS, Arthur R Garan2, MD, Veli K Topkara2, MD, Melana Yuzefpolskaya2, MD, Paolo C Colombo2, MD, Maryjane Farr2, MD, Yoshifumi Naka1, MD, PhD, Koji Takeda1, MD, PhD
1. Division of Cardiac Surgery, Columbia University Medical Center, New York, New York, U.S.A. 2. Division of Cardiology, Columbia University Medical Center, New York, New York, U.S.A.
Word count: 4500 Corresponding author: Masahiko Ando MD, PhD, MPH Address: Columbia University Medical Center, 177 Fort Washington Avenue, New York, NY 10032, U.S.A. Email: [email protected]
1
Abstract Background: Although extremely-high pulmonary vascular resistance (PVR) is a relative contraindication for heart transplantation (HTx), recent data with continuous-flow left ventricular assist devices (LVADs) indicate HTx outcomes may be different when high PVR is managed with LVAD. This study aims to clarify the contemporary association between PVR at HTx and post-transplant survival in LVAD vs. non-LVAD cohorts. Methods: We reviewed the United Network for Organ Sharing (UNOS) registry for adults transplanted from 2008 to 2015. In those with continuous-flow LVADs and those with no VADs at HTx, we grouped patients by low PVR (PVR<3), intermediate PVR (3<=PVR<6), and high PVR (PVR>=6) groups. Adjusted hazard ratios (aHRs) for death after HTx were calculated by Cox regression. Results: The non-LVAD cohort included 6270 patients (4385 in low, 1643 in intermediate, and 242 in high PVR), while the LVAD cohort included 4111 patients (3227 in low, 798 in intermediate, and 86 in high PVR). The high PVR LVAD group had the worst survival, which was not significant, likely to low power (p=0.300). In non-LVAD, the aHR for death was 1.047 (95%CI 1.010-1.088), while in LVAD, it was 1.063 (95%CI 1.010-1.119). Cubic spline analysis demonstrated non-linear associations between PVR and aHR, especially in the LVAD cohort. Conclusions: There was no significant evidence to conclude the effect of pre-transplant PVR on 2
post-transplant survival is higher in LVAD vs. non-LVAD patients, based on analysis of the UNOS database. However, further investigations are indicated to clarify heart transplant candidacy in those with extremely-high PVR even after LVAD.
Abstract word count: 250
3
Extremely high pulmonary vascular resistance (PVR) has been a relative contraindication for heart transplantation (HTx), given concerns for postoperative right heart failure (RHF) 1-4. Previous guidelines by the International Society for Heart and Lung Transplantation (ISHLT) recommended a preoperative PVR less than 5 wood unit (WU) as an acceptable eligibility criteria 5, based on relatively old data 2. In their renewed recommendation in 2016, there was no clear statement regarding an eligibility criterion for PVR 6. This is likely because expert consensus acknowledges recent advances in the prevention and management of RHF, or pulmonary hypertension (PH) 7-9, has enabled transplant programs to successfully transplant patients, previously considered ineligible for transplant on the basis of high PVR. Importantly, there remains a scarcity of contemporary analysis of large multi-center registries, focused on how pre-transplant PVR could affect HTx outcomes in patients with continuous-flow left ventricular assist device (LVAD) as bridge to transplant (BTT). Since bridging LVAD is known to be effective in decreasing PVR in candidates with reversible PH 10-13, those on LVAD with persistently high PVR could have worse outcomes due to irreversible PH, as compared to those not on LVADs and with the same PVR. Therefore, we hypothesized that we may need a different HTx eligibility criteria in PVR in those with LVADs and those without LVADs. In the present study, we aimed to clarify how pre-transplant PVR affects post-transplant survival differently in LVAD recipients vs. non-LVAD recipients, using the United Network for Organ Sharing (UNOS) registry.
4
Patients and Methods
The UNOS registry was queried for adult patients (age>18) listed for a single-organ primary HTx from January 1st 2008 to December 31st 2015 and subsequently undergoing HTx. Follow-up data were collected through December 2016. Patients who were on right ventricular assist device, extracorporeal membrane oxygenation, total artificial heart, nitric oxide, and ventilator at HTx were excluded. Those who did not have right heart catheter information were also excluded. We created the following three groups according to PVR value at HTx, those with low PVR (PVR<3 WU), intermediate PVR (3<=PVR<6), and high PVR (PVR>=6). Primary end point was death after HTx, and secondary endpoints were 30-day mortality and in-hospital comorbidities. We stratified the entire cohort by the existence of LVAD at HTx. In the LVAD cohort, we included those with Heartmate II (Abbott) or Heartware (Heartware), and in the non-LVAD cohort we included only those with no VAD at HTx. To evaluate heart-size matching, we calculated a heart mass ratio, by dividing predicted donor’s heart mass by recipient’s heart mass, based on a previous publication 14. The study was submitted to the Institutional Review Board of Columbia University Medical Center.
Statistical Analysis Categorical variables, presented as frequencies and percentages, were compared using Chi-square test. Continuous variables, expressed as median and interquartile range, were compared using Kruskal-Wallis 5
Rank Sum Test. Kaplan-Meier and Cox regression analysis were performed to determine survival difference. Crude and adjusted hazard ratios (HRs) of death after HTx were calculated based on the PVR values at transplant. To adjust baseline profiles, we performed multivariable Cox regression including the following twelve baseline variables; PVR, age, gender, body mass index (BMI), diabetes, ethnicity (Hispanic/Latino), diagnosis of ischemic cardiomyopathy, cardiac index, creatinine, total bilirubin, inotropic support, and intra-aortic balloon pumping (IABP). Stepwise selection algorithm was used for model building to minimize Akaike’s Information Criterion. We also used a cubic spline model to clarify the possible non-linear association between PVR and hazard for death after HTx. Two-tailed p value <0.05 was considered to be statistically significant. All the analyses were performed with R statistical software, version 3.5.1.
Results Table 1 shows baseline profiles at HTx. In the non-LVAD cohort, 4385 patients had low PVR, 1643 intermediate PVR, and 242 high PVR. In the LVAD cohort, 3227 low PVR, 798 intermediate, and 86 high PVR. Interestingly, female were more frequent in higher PVR groups in both cohorts (p<0.001), and accordingly both BSA and BMI were lower in the higher PVR groups. There were no other clinically significant differences, but rate of Hispanic/Latino was higher in the higher PVR groups. As for hemodynamics and support, cardiac index tended to be lower (p<0.001), and inotropic supports were 6
more frequent in the higher PVR groups (p<0.001 for non-LVAD, p=0.004 for LVAD). Finally, higher PVR candidates tended to be in a higher acuity status at transplant (Table 1). In the non-LVAD cohort, waitlist time was shorter as compared to the low PVR group (p<0.001), but this tendency was not seen in the LVAD cohort. Supplementary Table 1 shows donor information. Both in the non-LVAD and LVAD cohorts, heart mass ratio (dividing donor’s predicted heart mass by recipient’s heart mass 14) was higher in the higher PVR groups. This indicates that higher PVR recipients were getting larger heart, as compared to lower PVR recipients. In the LVAD cohort, donor age was higher in the high PVR groups (p=0.008), but there were no differences in ischemic time or left ventricular ejection fraction in either cohort. Short-term outcomes are shown in Supplementary Table 2. In the non-LVAD cohort, there were no significant differences in 30-day mortality (2.6%, 2.7%, and 3.3% in low, intermediate, and high PVR groups, p=0.762). In the LVAD cohort, 30-day mortality was higher in the high PVR group but the result was not statistically significant (4.0%, 3.8%, and 8.1%, p=0.145). Figure 1A/1B show cubic spline curves for the association between PVR and adjusted HRs for death after HTx, with PVR=3 as the reference. In the non-LVAD cohort, there is no increase in the HR when PVR>3, while in the LVAD cohort, the HR continues to increase even when PVR>3. Importantly, there was no prominent slope increase (i.e. significant hazard change) that could indicate a potential cut-off PVR for HTx candidacy. Figure 2A/2B demonstrated Kaplan-Meier curves showing no significant differences 7
between the groups within each cohort. The results of Cox regression for hazard of death after HTx were shown in Supplementary Table 3 and 4.
Comment Since the early 1990s, eligibility criteria for heart transplantation have expanded with regard to increasing age, BMI, and other co-morbidities, likely as a result of improvements in peri-transplant managements, and also likely to reflect a changing demographic of candidates 15. Opportunities for transplant are offered to many recipients who historically would have been ineligible. With the expanding potential recipient pool, it is important to re-assess which ineligibility criteria should persist, especially as the donor pool remains inadequate. In the United States, the UNOS committee recently implemented a new heart allocation policy, designed to decrease waitlist mortality 16. Patients with higher acuity, and potentially more partially treated co-morbidities (e.g. high PVR), may be moving toward HTx. This fact, in the context of expanded recipient eligibility, indicates that understanding high risk features of a recipient is critically important, to maintain post-transplant survivals in the context of higher risk patients being transplanted 17. With regard to the present study, the cut-off of PVR (previously 5 WU) now disappeared in the updated criteria and is shown as “depending on severity” 5, 6. Such a change in PVR eligibility criteria would be associated with contemporary advances in medical treatments of PH 7, 8, and in continuous-flow LVADs 8
10-13, 18
, potentially improving high PVR risk by unloading the left ventricle. This indicates that those on
bridging LVADs with persistently high PVR should have worse outcomes due to irreversible PH, as compared to those not on LVADs and with the same PVR. Therefore, we hypothesized that we may need a different HTx eligibility criteria in PVR in those with LVADs at transplant and those without LVADs, which was a main focus of the present study. The major findings of the present study are summarized in the following three points: 1) In the non-LVAD cohort, the post-transplant survivals were similar between PVR groups (Figure 2A, p=0.400), and the cubic spline curve demonstrated that the hazard of post-transplant mortality was significantly lower when PVR<1, but the HRs remains flat when PVR>3 (Figure 1A). 2) In the LVAD cohort, there was no statistically significant survival differences between PVR groups (Figure 2B, p=0.300); however, the survival in the high PVR group tended to be lower than other two groups, indicating this analysis might have been underpowered due to the small number of patients in the high PVR group (n=86). 3) In the LVAD cohort, in contrast to the non-LVAD cohort, the cubic spline curve showed a gentle increase in the HRs, as PVR becomes >3 (Figure 1B). Despite our hypothesis, we did not find significant evidences to suggest a need for different eligibility criteria for HTx between LVAD and non-LVAD candidates. However, these results could become a springboard for discussion of HTx candidacy in the high PVR patients, especially in the LVAD cohorts. 9
Historically, there has been much discussion regarding the possible detrimental effects of high PVR on post-transplant outcomes 19, 20, or conversely there were some analysis reporting that PVR was not associated with worse outcomes 21-24. In either scenario, most of these studies were small studies based on a single-center experience, and the rest larger registry studies are outdated, failing to include recent HTx candidates optimized by contemporary continuous-flow LVADs or medical managements such as inhaled nitric oxide or pulmonary arterial dilators. We found one preceding study on UNOS registry by Vakil et al 25
, however, their study period was old (from 1987 to 2012) and the BTT-LVAD rate was only 10% 26.
They concluded that the presence of PH (PVR>=2.5) was an independent risk factor for mortality after HTx compared to normal PVR, with a similar tendency was found both in the LVAD and non-LVAD cohorts, but also reported that the severity of PH was not a discriminating factor for poor survival 25. Another large study of UNOS data by Tedford et al studied HTx recipients with mild PH, and investigated the prognostic value of PVR, transpulmonary gradient, and gradient between diastolic pulmonary artery pressure and wedge pressure, on post-transplant survival 27. Their conclusion was that all of these three indices had no effect on post-transplant survival 27. The main limitations of Tedford’s study was also that their inclusion period is outdated (from 1998 to 2011), where the BTT-LVAD rate was less than 15%, and also they did not adjust or stratify the effect of BTT-LVAD 27. In this sense, the present study is unique and worthwhile in that it included relatively recent recipients (from 2008 to 2015), and the multivariable analysis was stratified by presence or absense of BTT-LVAD. 10
Also, despite Vakil’s 25 and Tedford’s 27 reports, it would probably make more sense to most of us, that extremely high PVR patients should still have worse outcomes compared to normal PVR patients. Additionally, one of our interests is should there be any cut-off of pre-transplant PVR that would warrant transplant candidacy, and more importantly, should such cut-off values be different in the LVAD and non-LVAD recipients. In contrast to Vakil’s report 25, our updated survival curves (Figure 2A and 2B) may suggest, at least in the non-LVAD cohort, there could be no absolute contraindication in terms of high PVR in a current era with advanced PH treatments. However in the LVAD cohort, our data showed that we should carefully determine transplant eligibility, if pre-transplant PVR>6. There should be several explanations for why the associations between PVR and survival could be different in the non-LVAD and LVAD cohorts. PVR is generally determined by the combined effect of wedge pressure (i.e. LV unloading) and pulmonary vascular remodeling 28, frequently fixed and irreversible. Therefore, in the non-LVAD cohort, the contribution of high wedge pressure on PVR, which should resolve after HTx, could be relatively higher on average compared to those in the LVAD cohort. Additionally, although in the early 1990s pulmonary dilators such as sodium nitroprusside had already been considered to be effective in reducing pre-transplant PVR for HTx candidacy 3, since the 2000s, there have been dramatic developments in other pulmonary dilation therapies 7-9. We could speculate that recent post-HTx management with such highly-effective dilators might have mitigated a negative impact of PVR on HTx outcomes, especially in the non-LVAD cohort. However, in the LVAD cohort, such 11
dilator therapies might not be as effective as expected, because their high PVRs were already fixed, which were not reversible even with LV unloading by LVADs. This speculation would also support the reason why the prior studies including recipients before the year 2000, did not show such different effects of PVR on outcomes in the non-LVAD and LVAD cohorts, while the present study demonstrated less detrimental effects of PVR, especially in the non-LVAD cohort. Finally, the non-linear associations between PVR and the HRs of post-HTx mortality are of noteworthy. As shown in Figure 1A and 1B, both in the non-LVAD and LVAD cohort, the HRs of mortality were significantly lower when PVR<1, as compared to the reference PVR=3, compatible to the prior study 25. However, when PVR>3, the HR in the non-LVAD cohort was relatively flat (Figure 1A), and that in the LVAD cohort was gradually increasing as PVR goes up (Figure 1B). Besides, there were no significant risk change points in both cohorts. As described previously, these curves also support the idea that there should be no absolute PVR values that contraindicate the eligibility in the non-LVAD cohort, and in the LVAD cohort, higher PVR cautions against it, though we still do not have much evidence to conclude certain PVR value as an absolute contraindication for heart transplantation.
Limitations Our study has several limitations. First, the UNOS only gathers hemodynamic data closest to the day of transplantation, our PVR values might not reflect the actual PVRs at HTx and also it is difficult to adjust 12
the effect of LVAD support duration on the actual PVR values at HTx. Secondly, there was no additional information available regarding time gap between LVAD implantation, RHC, and HTx, which might have negatively biased the association between PVR and post-HTx survival. We did not investigate the effect of pulmonary vasodilator therapy at the time of RHC in detail. Thirdly, although a prior study reported the association between residual PH after HTx and worse survival 29, the UNOS registry does not include post-HTx hemodynamics and we were not able to address this association. Fourthly, centers may have accepted optimal donor hearts for higher PVR candidates, which might not be reflected in the UNOS registry, and as such, might confound the pure association between PVR and post-transplant survival. Finally, even if the present study did not show the significant association between intermediate PVR and post-transplant survival, hazard of RHF still might have been higher in higher PVR recipients, as reported previously 23.
Conclusions The current study clearly demonstrates that pre-transplant PVR was an independent predictor of post-transplant mortality both in LVAD and non-LVAD cohorts. However, while its adjusted effect in the non-LVAD cohort was not as high as expected when PVR>3, as compared to the reference PVR=3, its effect in the LVAD cohort was slightly higher when PVR>3, even if the analysis might have been underpowered due to the small number of patients in the high PVR group in the LVAD cohort. Further 13
prospective studies are indicated to clarify the heart transplant candidacy in this small population, who has an extremely-high PVR even after BTT-LVAD therapy.
14
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19
Figure legends
Figure 1. Cubic spline curves for the association between PVR at transplant and adjusted hazard ratio for death after transplant
1A: Non-LVAD, 1B: LVAD, PVR: Pulmonary vascular resistance
Figure 2. Kaplan-Meier survivals after heart transplantation
1A: Non-LVAD, 1B: LVAD, PVR: Pulmonary vascular resistance, Low PVR: PVR<3, Intermediate PVR: 3<=PVR<6, High PVR, PVR>=6
20
Tables Non LVAD
LVAD
PVR<3
3<=PVR<6
PVR>=6
P-value
Patient number
4385
1643
242
Age
57.0 [48.0, 63.0]
57.0 [48.0, 63.0]
56.0 [47.2, 62.0]
Female (%)
1198 (27.3)
666 (40.5)
99 (40.9)
Blood type (%)
PVR<3
3<=PVR<6
PVR>=6
3227
798
86
0.324
56.0 [48.0, 63.0]
57.0 [48.0, 63.0]
55.5 [44.2, 61.8]
0.366
<0.001
545 (16.9)
224 (28.1)
25 (29.1)
<0.001
0.016
P-value
0.734
A
1944 (44.3)
695 (42.3)
96 (39.7)
1249 (38.7)
289 (36.2)
30 (34.9)
AB
353 (8.1)
122 (7.4)
16 (6.6)
111 (3.4)
33 (4.1)
2 (2.3)
B
654 (14.9)
295 (18.0)
53 (21.9)
452 (14.0)
116 (14.5)
15 (17.4)
O
1434 (32.7)
531 (32.3)
77 (31.8)
1415 (43.8)
360 (45.1)
39 (45.3)
Height (cm)
175.0 [167.6, 180.3]
170.2 [162.6, 177.8]
167.6 [162.6, 175.3]
<0.001
177.8 [170.2, 182.9]
172.7 [165.6, 180.3]
172.7 [167.6, 180.0]
<0.001
Weight (kg)
80.4 [69.4, 93.0]
74.8 [63.5, 86.2]
72.8 [60.2, 86.2]
<0.001
88.0 [75.0, 99.8]
81.6 [70.9, 94.4]
80.2 [69.2, 95.2]
<0.001
Body surface area (m2)
1.96 [1.79, 2.10]
1.86 [1.70, 2.02]
1.83 [1.63, 1.99]
<0.001
2.06 [1.90, 2.20]
1.98 [1.82, 2.12]
1.95 [1.82, 2.11]
<0.001
Body mass index (kg/m2)
26.6 [23.4, 30.0]
25.5 [22.5, 29.1]
25.1 [22.2, 29.5]
<0.001
28.5 [25.1, 32.0]
27.7 [24.8, 31.4]
27.3 [24.4, 31.4]
0.004
Diagnosis (%)
0.012
0.344
Dilated Cardiomyopathy
2065 (47.1)
839 (51.1)
138 (57.0)
1786 (55.3)
460 (57.6)
52 (60.5)
Ischemic Cardiomyopathy
1615 (36.8)
553 (33.7)
77 (31.8)
1318 (40.8)
298 (37.3)
30 (34.9)
Restrictive Cardiomyopathy
203 (4.6)
87 (5.3)
8 (3.3)
26 (0.8)
8 (1.0)
0 (0.0)
Congenital Heart Disease
130 (3.0)
37 (2.3)
5 (2.1)
11 (0.3)
6 (0.8)
1 (1.2)
Others
372 (8.5)
127 (7.7)
14 (5.8)
86 (2.7)
26 (3.3)
3 (3.5)
Diabetes (%)
1113 (25.4)
476 (29.0)
68 (28.1)
0.016
1020 (31.6)
254 (31.8)
20 (23.3)
0.251
Hispanic/Latino (%)
330 (7.5)
160 (9.7)
24 (9.9)
0.012
188 (5.8)
75 (9.4)
7 (8.1)
0.001
Creatinine (mg/dl)
1.2 [0.9, 1.4]
1.2 [0.9, 1.4]
1.2 [0.9, 1.5]
0.609
1.2 [1.0, 1.4]
1.2 [0.9, 1.4]
1.1 [0.9, 1.3]
0.095
Total bilirubin (mg/dl)
0.7 [0.5, 1.1]
0.8 [0.5, 1.3]
0.9 [0.6, 1.4]
<0.001
0.7 [0.5, 1.0]
0.7 [0.5, 1.0]
0.7 [0.5, 1.2]
0.548
21
Hemodynamics and support PVR (wood unit)
1.7 [1.1, 2.3]
3.8 [3.3, 4.5]
6.9 [6.3, 8.4]
<0.001
1.7 [1.2, 2.2]
3.7 [3.2, 4.3]
7.0 [6.3, 8.0]
<0.001
Cardiac Index (L/min/m2)
2.3 [1.9, 2.8]
1.9 [1.6, 2.2]
1.5 [1.2, 1.7]
<0.001
2.4 [2.1, 2.8]
1.9 [1.6, 2.2]
1.4 [1.1, 1.8]
<0.001
PAP systolic (mmHg)
38.0 [30.0, 47.0]
50.0 [41.0, 59.0]
60.0 [51.2, 69.8]
<0.001
34.0 [27.0, 42.0]
48.0 [37.0, 58.0]
61.0 [51.0, 66.8]
<0.001
PAP diastolic (mmHg)
18.0 [13.0, 23.0]
24.0 [19.0, 29.0]
30.0 [24.0, 35.0]
<0.001
15.0 [11.0, 21.0]
24.0 [16.0, 30.0]
30.0 [25.0, 35.0]
<0.001
PAP mean (mmHg)
25.0 [19.7, 32.0]
34.0 [28.0, 40.0]
42.0 [36.0, 48.0]
<0.001
23.0 [17.0, 29.0]
33.0 [25.0, 41.0]
44.0 [37.5, 49.8]
<0.001
PCWP (mmHg)
18.0 [12.0, 24.0]
21.0 [15.0, 26.0]
23.0 [17.0, 28.0]
<0.001
15.0 [9.0, 20.0]
19.0 [10.0, 27.0]
23.0 [16.2, 27.0]
<0.001
Inotropes (%)
2573 (58.7)
1078 (65.6)
172 (71.1)
<0.001
169 (5.2)
62 (7.8)
9 (10.5)
0.004
IABP (%)
344 (7.8)
171 (10.4)
35 (14.5)
<0.001
16 (0.5)
5 (0.6)
0 (0.0)
0.717
Heartmate II
-
-
-
-
2648 (82.1)
635 (79.6)
65 (75.6)
0.100
Heartware
-
-
-
-
579 (17.9)
163 (20.4)
21 (24.4)
-
LVAD type
Status at transplant (%)
<0.001
0.042
Status IA
1973 (45.0)
813 (49.5)
134 (55.4)
2239 (69.4)
552 (69.2)
70 (81.4)
Status IB
1967 (44.9)
705 (42.9)
100 (41.3)
988 (30.6)
246 (30.8)
16 (18.6)
Status II
445 (10.1)
125 (7.6)
8 (3.3)
0 (0.0)
0 (0.0)
0 (0.0)
61 [21, 171]
51 [17, 137]
41 [15, 110]
199 [79, 416]
167 [81, 344]
178 [88, 375]
Days on waiting list (days)
<0.001
0.032
Table 1. Baseline Characteristics
PVR: Pulmonary Vascular Resistance, PAP: Pulmonary Artery Pressure, PCWP: Pulmonary Capillary Wedge Pressure, IABP: Intra-aortic Balloon Pumping, LVAD: Left Ventricular Assist
Device
22
S0003-4975(19)31732-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.09.095
Reference:
ATS 33241
To appear in:
The Annals of Thoracic Surgery
Received Date: 10 January 2019 Revised Date:
7 September 2019
Accepted Date: 27 September 2019
Please cite this article as: Ando M, Takayama H, Kurlansky PA, Han J, Garan AR, Topkara VK, Yuzefpolskaya M, Colombo PC, Farr M, Naka Y, Takeda K, Effect of pulmonary hypertension on transplant outcomes in patients with ventricular assist devices, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.09.095. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
Effect of pulmonary hypertension on transplant outcomes in patients with ventricular assist devices Running head: Effect of pulmonary hypertension
Masahiko Ando1, MD, PhD, MPH, Hiroo Takayama1, MD, PhD, Paul A Kurlansky1, MD, Jiho Han1, BS, Arthur R Garan2, MD, Veli K Topkara2, MD, Melana Yuzefpolskaya2, MD, Paolo C Colombo2, MD, Maryjane Farr2, MD, Yoshifumi Naka1, MD, PhD, Koji Takeda1, MD, PhD
1. Division of Cardiac Surgery, Columbia University Medical Center, New York, New York, U.S.A. 2. Division of Cardiology, Columbia University Medical Center, New York, New York, U.S.A.
Word count: 4500 Corresponding author: Masahiko Ando MD, PhD, MPH Address: Columbia University Medical Center, 177 Fort Washington Avenue, New York, NY 10032, U.S.A. Email: [email protected]
1
Abstract Background: Although extremely-high pulmonary vascular resistance (PVR) is a relative contraindication for heart transplantation (HTx), recent data with continuous-flow left ventricular assist devices (LVADs) indicate HTx outcomes may be different when high PVR is managed with LVAD. This study aims to clarify the contemporary association between PVR at HTx and post-transplant survival in LVAD vs. non-LVAD cohorts. Methods: We reviewed the United Network for Organ Sharing (UNOS) registry for adults transplanted from 2008 to 2015. In those with continuous-flow LVADs and those with no VADs at HTx, we grouped patients by low PVR (PVR<3), intermediate PVR (3<=PVR<6), and high PVR (PVR>=6) groups. Adjusted hazard ratios (aHRs) for death after HTx were calculated by Cox regression. Results: The non-LVAD cohort included 6270 patients (4385 in low, 1643 in intermediate, and 242 in high PVR), while the LVAD cohort included 4111 patients (3227 in low, 798 in intermediate, and 86 in high PVR). The high PVR LVAD group had the worst survival, which was not significant, likely to low power (p=0.300). In non-LVAD, the aHR for death was 1.047 (95%CI 1.010-1.088), while in LVAD, it was 1.063 (95%CI 1.010-1.119). Cubic spline analysis demonstrated non-linear associations between PVR and aHR, especially in the LVAD cohort. Conclusions: There was no significant evidence to conclude the effect of pre-transplant PVR on 2
post-transplant survival is higher in LVAD vs. non-LVAD patients, based on analysis of the UNOS database. However, further investigations are indicated to clarify heart transplant candidacy in those with extremely-high PVR even after LVAD.
Abstract word count: 250
3
Extremely high pulmonary vascular resistance (PVR) has been a relative contraindication for heart transplantation (HTx), given concerns for postoperative right heart failure (RHF) 1-4. Previous guidelines by the International Society for Heart and Lung Transplantation (ISHLT) recommended a preoperative PVR less than 5 wood unit (WU) as an acceptable eligibility criteria 5, based on relatively old data 2. In their renewed recommendation in 2016, there was no clear statement regarding an eligibility criterion for PVR 6. This is likely because expert consensus acknowledges recent advances in the prevention and management of RHF, or pulmonary hypertension (PH) 7-9, has enabled transplant programs to successfully transplant patients, previously considered ineligible for transplant on the basis of high PVR. Importantly, there remains a scarcity of contemporary analysis of large multi-center registries, focused on how pre-transplant PVR could affect HTx outcomes in patients with continuous-flow left ventricular assist device (LVAD) as bridge to transplant (BTT). Since bridging LVAD is known to be effective in decreasing PVR in candidates with reversible PH 10-13, those on LVAD with persistently high PVR could have worse outcomes due to irreversible PH, as compared to those not on LVADs and with the same PVR. Therefore, we hypothesized that we may need a different HTx eligibility criteria in PVR in those with LVADs and those without LVADs. In the present study, we aimed to clarify how pre-transplant PVR affects post-transplant survival differently in LVAD recipients vs. non-LVAD recipients, using the United Network for Organ Sharing (UNOS) registry.
4
Patients and Methods
The UNOS registry was queried for adult patients (age>18) listed for a single-organ primary HTx from January 1st 2008 to December 31st 2015 and subsequently undergoing HTx. Follow-up data were collected through December 2016. Patients who were on right ventricular assist device, extracorporeal membrane oxygenation, total artificial heart, nitric oxide, and ventilator at HTx were excluded. Those who did not have right heart catheter information were also excluded. We created the following three groups according to PVR value at HTx, those with low PVR (PVR<3 WU), intermediate PVR (3<=PVR<6), and high PVR (PVR>=6). Primary end point was death after HTx, and secondary endpoints were 30-day mortality and in-hospital comorbidities. We stratified the entire cohort by the existence of LVAD at HTx. In the LVAD cohort, we included those with Heartmate II (Abbott) or Heartware (Heartware), and in the non-LVAD cohort we included only those with no VAD at HTx. To evaluate heart-size matching, we calculated a heart mass ratio, by dividing predicted donor’s heart mass by recipient’s heart mass, based on a previous publication 14. The study was submitted to the Institutional Review Board of Columbia University Medical Center.
Statistical Analysis Categorical variables, presented as frequencies and percentages, were compared using Chi-square test. Continuous variables, expressed as median and interquartile range, were compared using Kruskal-Wallis 5
Rank Sum Test. Kaplan-Meier and Cox regression analysis were performed to determine survival difference. Crude and adjusted hazard ratios (HRs) of death after HTx were calculated based on the PVR values at transplant. To adjust baseline profiles, we performed multivariable Cox regression including the following twelve baseline variables; PVR, age, gender, body mass index (BMI), diabetes, ethnicity (Hispanic/Latino), diagnosis of ischemic cardiomyopathy, cardiac index, creatinine, total bilirubin, inotropic support, and intra-aortic balloon pumping (IABP). Stepwise selection algorithm was used for model building to minimize Akaike’s Information Criterion. We also used a cubic spline model to clarify the possible non-linear association between PVR and hazard for death after HTx. Two-tailed p value <0.05 was considered to be statistically significant. All the analyses were performed with R statistical software, version 3.5.1.
Results Table 1 shows baseline profiles at HTx. In the non-LVAD cohort, 4385 patients had low PVR, 1643 intermediate PVR, and 242 high PVR. In the LVAD cohort, 3227 low PVR, 798 intermediate, and 86 high PVR. Interestingly, female were more frequent in higher PVR groups in both cohorts (p<0.001), and accordingly both BSA and BMI were lower in the higher PVR groups. There were no other clinically significant differences, but rate of Hispanic/Latino was higher in the higher PVR groups. As for hemodynamics and support, cardiac index tended to be lower (p<0.001), and inotropic supports were 6
more frequent in the higher PVR groups (p<0.001 for non-LVAD, p=0.004 for LVAD). Finally, higher PVR candidates tended to be in a higher acuity status at transplant (Table 1). In the non-LVAD cohort, waitlist time was shorter as compared to the low PVR group (p<0.001), but this tendency was not seen in the LVAD cohort. Supplementary Table 1 shows donor information. Both in the non-LVAD and LVAD cohorts, heart mass ratio (dividing donor’s predicted heart mass by recipient’s heart mass 14) was higher in the higher PVR groups. This indicates that higher PVR recipients were getting larger heart, as compared to lower PVR recipients. In the LVAD cohort, donor age was higher in the high PVR groups (p=0.008), but there were no differences in ischemic time or left ventricular ejection fraction in either cohort. Short-term outcomes are shown in Supplementary Table 2. In the non-LVAD cohort, there were no significant differences in 30-day mortality (2.6%, 2.7%, and 3.3% in low, intermediate, and high PVR groups, p=0.762). In the LVAD cohort, 30-day mortality was higher in the high PVR group but the result was not statistically significant (4.0%, 3.8%, and 8.1%, p=0.145). Figure 1A/1B show cubic spline curves for the association between PVR and adjusted HRs for death after HTx, with PVR=3 as the reference. In the non-LVAD cohort, there is no increase in the HR when PVR>3, while in the LVAD cohort, the HR continues to increase even when PVR>3. Importantly, there was no prominent slope increase (i.e. significant hazard change) that could indicate a potential cut-off PVR for HTx candidacy. Figure 2A/2B demonstrated Kaplan-Meier curves showing no significant differences 7
between the groups within each cohort. The results of Cox regression for hazard of death after HTx were shown in Supplementary Table 3 and 4.
Comment Since the early 1990s, eligibility criteria for heart transplantation have expanded with regard to increasing age, BMI, and other co-morbidities, likely as a result of improvements in peri-transplant managements, and also likely to reflect a changing demographic of candidates 15. Opportunities for transplant are offered to many recipients who historically would have been ineligible. With the expanding potential recipient pool, it is important to re-assess which ineligibility criteria should persist, especially as the donor pool remains inadequate. In the United States, the UNOS committee recently implemented a new heart allocation policy, designed to decrease waitlist mortality 16. Patients with higher acuity, and potentially more partially treated co-morbidities (e.g. high PVR), may be moving toward HTx. This fact, in the context of expanded recipient eligibility, indicates that understanding high risk features of a recipient is critically important, to maintain post-transplant survivals in the context of higher risk patients being transplanted 17. With regard to the present study, the cut-off of PVR (previously 5 WU) now disappeared in the updated criteria and is shown as “depending on severity” 5, 6. Such a change in PVR eligibility criteria would be associated with contemporary advances in medical treatments of PH 7, 8, and in continuous-flow LVADs 8
10-13, 18
, potentially improving high PVR risk by unloading the left ventricle. This indicates that those on
bridging LVADs with persistently high PVR should have worse outcomes due to irreversible PH, as compared to those not on LVADs and with the same PVR. Therefore, we hypothesized that we may need a different HTx eligibility criteria in PVR in those with LVADs at transplant and those without LVADs, which was a main focus of the present study. The major findings of the present study are summarized in the following three points: 1) In the non-LVAD cohort, the post-transplant survivals were similar between PVR groups (Figure 2A, p=0.400), and the cubic spline curve demonstrated that the hazard of post-transplant mortality was significantly lower when PVR<1, but the HRs remains flat when PVR>3 (Figure 1A). 2) In the LVAD cohort, there was no statistically significant survival differences between PVR groups (Figure 2B, p=0.300); however, the survival in the high PVR group tended to be lower than other two groups, indicating this analysis might have been underpowered due to the small number of patients in the high PVR group (n=86). 3) In the LVAD cohort, in contrast to the non-LVAD cohort, the cubic spline curve showed a gentle increase in the HRs, as PVR becomes >3 (Figure 1B). Despite our hypothesis, we did not find significant evidences to suggest a need for different eligibility criteria for HTx between LVAD and non-LVAD candidates. However, these results could become a springboard for discussion of HTx candidacy in the high PVR patients, especially in the LVAD cohorts. 9
Historically, there has been much discussion regarding the possible detrimental effects of high PVR on post-transplant outcomes 19, 20, or conversely there were some analysis reporting that PVR was not associated with worse outcomes 21-24. In either scenario, most of these studies were small studies based on a single-center experience, and the rest larger registry studies are outdated, failing to include recent HTx candidates optimized by contemporary continuous-flow LVADs or medical managements such as inhaled nitric oxide or pulmonary arterial dilators. We found one preceding study on UNOS registry by Vakil et al 25
, however, their study period was old (from 1987 to 2012) and the BTT-LVAD rate was only 10% 26.
They concluded that the presence of PH (PVR>=2.5) was an independent risk factor for mortality after HTx compared to normal PVR, with a similar tendency was found both in the LVAD and non-LVAD cohorts, but also reported that the severity of PH was not a discriminating factor for poor survival 25. Another large study of UNOS data by Tedford et al studied HTx recipients with mild PH, and investigated the prognostic value of PVR, transpulmonary gradient, and gradient between diastolic pulmonary artery pressure and wedge pressure, on post-transplant survival 27. Their conclusion was that all of these three indices had no effect on post-transplant survival 27. The main limitations of Tedford’s study was also that their inclusion period is outdated (from 1998 to 2011), where the BTT-LVAD rate was less than 15%, and also they did not adjust or stratify the effect of BTT-LVAD 27. In this sense, the present study is unique and worthwhile in that it included relatively recent recipients (from 2008 to 2015), and the multivariable analysis was stratified by presence or absense of BTT-LVAD. 10
Also, despite Vakil’s 25 and Tedford’s 27 reports, it would probably make more sense to most of us, that extremely high PVR patients should still have worse outcomes compared to normal PVR patients. Additionally, one of our interests is should there be any cut-off of pre-transplant PVR that would warrant transplant candidacy, and more importantly, should such cut-off values be different in the LVAD and non-LVAD recipients. In contrast to Vakil’s report 25, our updated survival curves (Figure 2A and 2B) may suggest, at least in the non-LVAD cohort, there could be no absolute contraindication in terms of high PVR in a current era with advanced PH treatments. However in the LVAD cohort, our data showed that we should carefully determine transplant eligibility, if pre-transplant PVR>6. There should be several explanations for why the associations between PVR and survival could be different in the non-LVAD and LVAD cohorts. PVR is generally determined by the combined effect of wedge pressure (i.e. LV unloading) and pulmonary vascular remodeling 28, frequently fixed and irreversible. Therefore, in the non-LVAD cohort, the contribution of high wedge pressure on PVR, which should resolve after HTx, could be relatively higher on average compared to those in the LVAD cohort. Additionally, although in the early 1990s pulmonary dilators such as sodium nitroprusside had already been considered to be effective in reducing pre-transplant PVR for HTx candidacy 3, since the 2000s, there have been dramatic developments in other pulmonary dilation therapies 7-9. We could speculate that recent post-HTx management with such highly-effective dilators might have mitigated a negative impact of PVR on HTx outcomes, especially in the non-LVAD cohort. However, in the LVAD cohort, such 11
dilator therapies might not be as effective as expected, because their high PVRs were already fixed, which were not reversible even with LV unloading by LVADs. This speculation would also support the reason why the prior studies including recipients before the year 2000, did not show such different effects of PVR on outcomes in the non-LVAD and LVAD cohorts, while the present study demonstrated less detrimental effects of PVR, especially in the non-LVAD cohort. Finally, the non-linear associations between PVR and the HRs of post-HTx mortality are of noteworthy. As shown in Figure 1A and 1B, both in the non-LVAD and LVAD cohort, the HRs of mortality were significantly lower when PVR<1, as compared to the reference PVR=3, compatible to the prior study 25. However, when PVR>3, the HR in the non-LVAD cohort was relatively flat (Figure 1A), and that in the LVAD cohort was gradually increasing as PVR goes up (Figure 1B). Besides, there were no significant risk change points in both cohorts. As described previously, these curves also support the idea that there should be no absolute PVR values that contraindicate the eligibility in the non-LVAD cohort, and in the LVAD cohort, higher PVR cautions against it, though we still do not have much evidence to conclude certain PVR value as an absolute contraindication for heart transplantation.
Limitations Our study has several limitations. First, the UNOS only gathers hemodynamic data closest to the day of transplantation, our PVR values might not reflect the actual PVRs at HTx and also it is difficult to adjust 12
the effect of LVAD support duration on the actual PVR values at HTx. Secondly, there was no additional information available regarding time gap between LVAD implantation, RHC, and HTx, which might have negatively biased the association between PVR and post-HTx survival. We did not investigate the effect of pulmonary vasodilator therapy at the time of RHC in detail. Thirdly, although a prior study reported the association between residual PH after HTx and worse survival 29, the UNOS registry does not include post-HTx hemodynamics and we were not able to address this association. Fourthly, centers may have accepted optimal donor hearts for higher PVR candidates, which might not be reflected in the UNOS registry, and as such, might confound the pure association between PVR and post-transplant survival. Finally, even if the present study did not show the significant association between intermediate PVR and post-transplant survival, hazard of RHF still might have been higher in higher PVR recipients, as reported previously 23.
Conclusions The current study clearly demonstrates that pre-transplant PVR was an independent predictor of post-transplant mortality both in LVAD and non-LVAD cohorts. However, while its adjusted effect in the non-LVAD cohort was not as high as expected when PVR>3, as compared to the reference PVR=3, its effect in the LVAD cohort was slightly higher when PVR>3, even if the analysis might have been underpowered due to the small number of patients in the high PVR group in the LVAD cohort. Further 13
prospective studies are indicated to clarify the heart transplant candidacy in this small population, who has an extremely-high PVR even after BTT-LVAD therapy.
14
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19
Figure legends
Figure 1. Cubic spline curves for the association between PVR at transplant and adjusted hazard ratio for death after transplant
1A: Non-LVAD, 1B: LVAD, PVR: Pulmonary vascular resistance
Figure 2. Kaplan-Meier survivals after heart transplantation
1A: Non-LVAD, 1B: LVAD, PVR: Pulmonary vascular resistance, Low PVR: PVR<3, Intermediate PVR: 3<=PVR<6, High PVR, PVR>=6
20
Tables Non LVAD
LVAD
PVR<3
3<=PVR<6
PVR>=6
P-value
Patient number
4385
1643
242
Age
57.0 [48.0, 63.0]
57.0 [48.0, 63.0]
56.0 [47.2, 62.0]
Female (%)
1198 (27.3)
666 (40.5)
99 (40.9)
Blood type (%)
PVR<3
3<=PVR<6
PVR>=6
3227
798
86
0.324
56.0 [48.0, 63.0]
57.0 [48.0, 63.0]
55.5 [44.2, 61.8]
0.366
<0.001
545 (16.9)
224 (28.1)
25 (29.1)
<0.001
0.016
P-value
0.734
A
1944 (44.3)
695 (42.3)
96 (39.7)
1249 (38.7)
289 (36.2)
30 (34.9)
AB
353 (8.1)
122 (7.4)
16 (6.6)
111 (3.4)
33 (4.1)
2 (2.3)
B
654 (14.9)
295 (18.0)
53 (21.9)
452 (14.0)
116 (14.5)
15 (17.4)
O
1434 (32.7)
531 (32.3)
77 (31.8)
1415 (43.8)
360 (45.1)
39 (45.3)
Height (cm)
175.0 [167.6, 180.3]
170.2 [162.6, 177.8]
167.6 [162.6, 175.3]
<0.001
177.8 [170.2, 182.9]
172.7 [165.6, 180.3]
172.7 [167.6, 180.0]
<0.001
Weight (kg)
80.4 [69.4, 93.0]
74.8 [63.5, 86.2]
72.8 [60.2, 86.2]
<0.001
88.0 [75.0, 99.8]
81.6 [70.9, 94.4]
80.2 [69.2, 95.2]
<0.001
Body surface area (m2)
1.96 [1.79, 2.10]
1.86 [1.70, 2.02]
1.83 [1.63, 1.99]
<0.001
2.06 [1.90, 2.20]
1.98 [1.82, 2.12]
1.95 [1.82, 2.11]
<0.001
Body mass index (kg/m2)
26.6 [23.4, 30.0]
25.5 [22.5, 29.1]
25.1 [22.2, 29.5]
<0.001
28.5 [25.1, 32.0]
27.7 [24.8, 31.4]
27.3 [24.4, 31.4]
0.004
Diagnosis (%)
0.012
0.344
Dilated Cardiomyopathy
2065 (47.1)
839 (51.1)
138 (57.0)
1786 (55.3)
460 (57.6)
52 (60.5)
Ischemic Cardiomyopathy
1615 (36.8)
553 (33.7)
77 (31.8)
1318 (40.8)
298 (37.3)
30 (34.9)
Restrictive Cardiomyopathy
203 (4.6)
87 (5.3)
8 (3.3)
26 (0.8)
8 (1.0)
0 (0.0)
Congenital Heart Disease
130 (3.0)
37 (2.3)
5 (2.1)
11 (0.3)
6 (0.8)
1 (1.2)
Others
372 (8.5)
127 (7.7)
14 (5.8)
86 (2.7)
26 (3.3)
3 (3.5)
Diabetes (%)
1113 (25.4)
476 (29.0)
68 (28.1)
0.016
1020 (31.6)
254 (31.8)
20 (23.3)
0.251
Hispanic/Latino (%)
330 (7.5)
160 (9.7)
24 (9.9)
0.012
188 (5.8)
75 (9.4)
7 (8.1)
0.001
Creatinine (mg/dl)
1.2 [0.9, 1.4]
1.2 [0.9, 1.4]
1.2 [0.9, 1.5]
0.609
1.2 [1.0, 1.4]
1.2 [0.9, 1.4]
1.1 [0.9, 1.3]
0.095
Total bilirubin (mg/dl)
0.7 [0.5, 1.1]
0.8 [0.5, 1.3]
0.9 [0.6, 1.4]
<0.001
0.7 [0.5, 1.0]
0.7 [0.5, 1.0]
0.7 [0.5, 1.2]
0.548
21
Hemodynamics and support PVR (wood unit)
1.7 [1.1, 2.3]
3.8 [3.3, 4.5]
6.9 [6.3, 8.4]
<0.001
1.7 [1.2, 2.2]
3.7 [3.2, 4.3]
7.0 [6.3, 8.0]
<0.001
Cardiac Index (L/min/m2)
2.3 [1.9, 2.8]
1.9 [1.6, 2.2]
1.5 [1.2, 1.7]
<0.001
2.4 [2.1, 2.8]
1.9 [1.6, 2.2]
1.4 [1.1, 1.8]
<0.001
PAP systolic (mmHg)
38.0 [30.0, 47.0]
50.0 [41.0, 59.0]
60.0 [51.2, 69.8]
<0.001
34.0 [27.0, 42.0]
48.0 [37.0, 58.0]
61.0 [51.0, 66.8]
<0.001
PAP diastolic (mmHg)
18.0 [13.0, 23.0]
24.0 [19.0, 29.0]
30.0 [24.0, 35.0]
<0.001
15.0 [11.0, 21.0]
24.0 [16.0, 30.0]
30.0 [25.0, 35.0]
<0.001
PAP mean (mmHg)
25.0 [19.7, 32.0]
34.0 [28.0, 40.0]
42.0 [36.0, 48.0]
<0.001
23.0 [17.0, 29.0]
33.0 [25.0, 41.0]
44.0 [37.5, 49.8]
<0.001
PCWP (mmHg)
18.0 [12.0, 24.0]
21.0 [15.0, 26.0]
23.0 [17.0, 28.0]
<0.001
15.0 [9.0, 20.0]
19.0 [10.0, 27.0]
23.0 [16.2, 27.0]
<0.001
Inotropes (%)
2573 (58.7)
1078 (65.6)
172 (71.1)
<0.001
169 (5.2)
62 (7.8)
9 (10.5)
0.004
IABP (%)
344 (7.8)
171 (10.4)
35 (14.5)
<0.001
16 (0.5)
5 (0.6)
0 (0.0)
0.717
Heartmate II
-
-
-
-
2648 (82.1)
635 (79.6)
65 (75.6)
0.100
Heartware
-
-
-
-
579 (17.9)
163 (20.4)
21 (24.4)
-
LVAD type
Status at transplant (%)
<0.001
0.042
Status IA
1973 (45.0)
813 (49.5)
134 (55.4)
2239 (69.4)
552 (69.2)
70 (81.4)
Status IB
1967 (44.9)
705 (42.9)
100 (41.3)
988 (30.6)
246 (30.8)
16 (18.6)
Status II
445 (10.1)
125 (7.6)
8 (3.3)
0 (0.0)
0 (0.0)
0 (0.0)
61 [21, 171]
51 [17, 137]
41 [15, 110]
199 [79, 416]
167 [81, 344]
178 [88, 375]
Days on waiting list (days)
<0.001
0.032
Table 1. Baseline Characteristics
PVR: Pulmonary Vascular Resistance, PAP: Pulmonary Artery Pressure, PCWP: Pulmonary Capillary Wedge Pressure, IABP: Intra-aortic Balloon Pumping, LVAD: Left Ventricular Assist
Device
22