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Impact of pre-transplant pulmonary hypertension on survival after heart transplantation: A UNOS registry analysis
International Journal of Cardiology 176 (2014) 595–599
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Impact of pre-transplant pulmonary hypertension on survival after heart transplantation: A UNOS registry analysis Kairav Vakil a,⁎, Sue Duval a, Alok Sharma a, Selcuk Adabag b, Kashan Syed Abidi a, Ziad Taimeh a, Monica Colvin-Adams a a b
Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA Division of Epidemiology and Community Health, School of Public Health, University of Minnesota and Veterans Affairs Medical Center, Minneapolis, MN, USA
a r t i c l e
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Article history: Received 22 March 2014 Received in revised form 29 July 2014 Accepted 11 August 2014 Available online 16 August 2014 Keywords: Pulmonary hypertension Heart transplantation Mortality
a b s t r a c t Introduction: Severe pre-transplant pulmonary hypertension (PH) has been associated with adverse short-term clinical outcomes after heart transplantation in relatively small single-center studies. The impact of pretransplant PH on long-term survival after heart transplantation has not been examined in a large, multi-center cohort. Methods: Adults (≥18 years) who underwent first time heart transplantation in the United States between 1987 and 2012 were retrospectively identified from the United Network for Organ Sharing registry. Pre-transplant PH was classified as mild, moderate, or severe based on pulmonary vascular resistance (PVR), trans-pulmonary gradient (TPG), and pulmonary artery (PA) mean pressure. Primary outcome was all-cause mortality. Results: Data from 26,649 heart transplant recipients (mean age 52 ± 12 years; 76% male; 76% Caucasian) were analyzed. During a mean follow-up of 5.7 ± 4.8 years, there were 10,334 (39%) deaths. Pre-transplant PH (PVR ≥ 2.5 WU) was a significant predictor of mortality (hazard ratio 1.10, 95% confidence interval 1.05–1.14, p b 0.0001) in multivariable analysis. However, the severity of pre-transplant PH (mild/moderate vs. severe) did not affect short or long-term survival. Similarly, even in patients who were supported with either a left ventricular assist device or a total artificial heart prior to transplant, severe pre-transplant PH was not associated with worse survival when compared to patients with mild/moderate pre-transplant PH. Conclusion: Pre-transplant PH (PVR ≥ 2.5 WU) is associated with a modest increase in mortality when compared to patients without pre-transplant PH. However, the severity of pre-transplant PH, assessed by PVR, TPG, or mean PA pressure, is not a discriminating factor for poor survival in patients listed for heart transplantation. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Heart transplantation is the mainstay of treatment for patients with end-stage heart failure. Pulmonary hypertension (PH) is commonly present in heart failure patients and portends adverse clinical outcomes irrespective of its etiology [1–3]. Presence of pre-transplant PH in heart organ recipients increases the risk of post-transplant PH and deterioration in right ventricular function in the donor heart. Cumulatively, these effects are associated with adverse post-operative outcomes [4,5]. As such, the International Society of Heart and Lung Transplantation (ISHLT) guidelines consider the presence of severe pre-transplant PH, defined as pulmonary vascular resistance (PVR) N5 Wood units (WU) or trans-pulmonary gradient (TPG) N 16–20 mm Hg, as a relative contraindication for heart transplantation [6]. Results from prior studies addressing the impact of pre-transplant PH on post-transplant survival have been inconsistent [4,7–14]. Further, ⁎ Corresponding author at: University of Minnesota, Mayo Mail Code 508, 420 Delaware Street SE, Minneapolis, MN 55455, USA. Tel.: +1 612 656 2451; fax: +1 612 626 4411. E-mail address: [email protected] (K. Vakil).
http://dx.doi.org/10.1016/j.ijcard.2014.08.072 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
relatively small single-center studies have shown that even milder degrees of pre-transplant PH may adversely influence survival after heart transplantation [4,8]. However, these studies were limited by relatively small sample size and short follow-up. Whether pre-transplant PH is associated with detrimental long-term survival in heart transplant recipients has not been examined in a large, multicenter cohort. As such, this study aims to examine the impact of pre-transplant PH on survival after heart transplantation in the largest multicenter prospective registry of heart transplant recipients in the United States (US).
Table 1 Classification of pulmonary hypertension severity based on different definitions. Definition
None
Mild
Moderate
Severe
Pulmonary vascular resistance (Wood units) Trans-pulmonary gradient (mm Hg) Mean pulmonary artery pressure (mm Hg)
b2.5
2.5–3.4
3.5–4.9
≥5.0
b13 b25
13–16 25–34
17–19 35–44
≥20 ≥45
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K. Vakil et al. / International Journal of Cardiology 176 (2014) 595–599 transplantation, and follow-up. For this study, ‘Standard Transplant Analysis and Research’ files with de-identified data for all heart transplant recipients were obtained from the UNOS [15]. Since no patient or center identifiers were used and the data are publicly available from the UNOS, this study was exempt from Institutional Review Board approval.
2.2. Study participants This analysis included all adults (≥18 years) who underwent first time heart transplantation in the US and were reported in the UNOS registry. Patients undergoing retransplantation, combined organ transplantations, transplantation for congenital heart disease, and those with missing information on pre-transplant PH or its severity, were excluded. Patients were also excluded if their pre-transplant cardiac hemodynamics were out of the following ranges: cardiac output (2 L/min–12 L/min), mean pulmonary artery (PA) pressure (10 mm Hg–80 mm Hg), and pulmonary capillary wedge pressure (5 mm Hg–50 mm Hg). Our final study cohort consisted of 26,649 patients.
2.3. Definitions and outcomes Fig. 1. Prevalence of severity of pre-transplant pulmonary hypertension using PVR and TPG definitions. 2. Methods 2.1. Data source The United Network for Organ Sharing (UNOS) registry was used to retrospectively identify adult heart transplant recipients in the US from October 1, 1987 to December 31, 2012. The registry consists of data on pre- and post-transplant variables captured and entered by each transplant center into an online database at the time of listing,
Patients were classified as having PH based on their most recent cardiac hemodynamic assessment prior to heart transplantation. In the absence of a single uniform definition to classify the severity of PH, three different indices were used. For primary analyses, PVR and TPG were used; while mean pulmonary artery (PA) pressures were used for sensitivity analyses. TPG was calculated as the difference between mean PA pressures and pulmonary capillary wedge pressure. PVR was calculated as the ratio of TPG and cardiac output. Cut-off values for no PH (PVR b 2.5 WU or TPG b 13 mm Hg) and severe PH (PVR ≥ 5.0 WU or TPG ≥ 20 mm Hg) were based on the ISHLT definitions [6]. However, given the lack of a definite consensus for classification of PH severity, arbitrary intermediate cut-off values for mild and moderate PH were used for analysis. Classification of PH severity based on PVR, TPG, and mean PA pressures is shown in Table 1. The primary outcome was all-cause mortality.
Table 2 Clinical characteristics in relation to baseline severity of pulmonary hypertension defined by pulmonary vascular resistance. Characteristic
Available data (n)
All patients
PH group by severity
No PH n = 17,669
PH n = 8980
p-Value
Mild n = 4657
Moderate n = 2884
Severe n = 1439
p-Value for trenda
Demographics Age at HT, years Male sex Caucasian
26,649 26,649 26,649
52 ± 12 78% 79%
53 ± 11 73% 70%
b0.001 b0.0001 b0.0001
54 ± 11 73% 72%
53 ± 11 73% 68%
53 ± 11 70% 65%
b0.0001 b0.0001 b0.0001
Clinical variables BMI, kg/m2 Diabetes mellitus History of smoking Drug-treated COPD Pulmonary embolism Prior malignancy Cerebrovascular disease Prior cardiovascular surgery Serum creatinine, mg/dL Dialysis VO2 maximum, mL/kg/min
26,337 25,590 11,403 16,992 15,906 26,649 25,480 26,649 26,379 25,208 6341
27.0 ± 4.8 9.4% 49% 3.4% 1.3% 4.9% 4.1% 22.5% 1.3 ± 0.9 2.3% 11.8 ± 3.6
26.0 ± 4.7 9.8% 50% 3.6% 1.8% 5.1% 4.0% 19.1% 1.3 ± 1.1 2.5% 11.2 ± 3.4
b0.001 0.28 0.30 0.57 0.01 0.47 0.65 b0.001 0.26 0.37 b0.001
26.3 ± 4.7 10.2% 52% 3.8% 1.5% 5.2% 4.2% 20.4% 1.3 ± 0.9 2.5% 11.2 ± 3.4
25.8 ± 4.7 10.1% 50% 3.2% 2.2% 5.3% 3.6% 18.5% 1.3 ± 0.9 2.4% 11.2 ± 3.4
25.5 ± 4.7 7.9% 47% 3.8% 1.8% 4.5% 4.1% 15.8% 1.4 ± 1.6 2.6% 11.1 ± 3.4
b0.0001 0.87 0.99 0.76 0.004 0.78 0.46 b0.0001 0.071 0.45 b0.0001
Transplant-related variables Wait time, days Ischemic indication for HT Life support at HTb LVAD/TAH Donor age, years Donor:recipient weight ratio Ischemic time, hours
26,639 26,649 26,649 26,649 26,647 26,635 25,499
105 (32, 279) 48.3% 46.1% 11.2% 31 ± 12 1.00 ± 0.23 3.1 ± 1.1
80 (26, 214) 45.9% 53.8% 9.0% 31 ± 12 1.04 ± 0.24 3.1 ± 1.0
b0.001 b0.001 b0.001 b0.001 0.88 b0.0001 0.017
84 (27, 228) 46.3% 52.1% 9.6% 32 ± 12 1.03 ± 0.24 3.1 ± 1.0
77 (26, 202) 45.4% 54.2% 9.0% 31 ± 12 1.04 ± .025 3.1 ± 1.0
72 (25, 195) 45.5% 58.4% 6.8% 31 ± 12 1.06 ± 0.25 3.1 ± 1.0
b0.0001 b0.0001 b0.0001 b0.0001 0.65 b0.0001 0.004
Cardiac hemodynamics Cardiac output, L/min PA systolic pressure, mm Hg PA diastolic pressure, mm Hg PA mean pressure, mm Hg PCW pressure, mm Hg TPG, mm Hg PVR, Wood units
26,649 25,614 26,500 26,649 26,649 26,649 26,649
4.9 ± 1.5 38.7 ± 12.4 18.4 ± 7.6 25.1 ± 8.7 18.9 ± 8.4 6.7 ± 3.1 1.4 ± 0.6
3.7 ± 1.0 52.9 ± 14.5 26.1 ± 8.5 35.0 ± 9.8 21.7 ± 8.4 13.9 ± 5.3 3.9 ± 1.6
b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001
4.0 ± 1.0 48.4 ± 13.0 23.5 ± 7.7 31.8 ± 8.9 20.7 ± 8.5 11.5 ± 3.1 2.9 ± 0.3
3.6 ± 0.9 54.9 ± 13.2 27.3 ± 7.8 36.4 ± 8.8 22.5 ± 8.3 14.4 ± 3.8 4.1 ± 0.4
3.1 ± 0.8 63.7 ± 14.9 32.0 ± 8.5 42.5 ± 9.5 23.0 ± 7.9 20.4 ± 7.3 6.7 ± 2.1
b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001
Values are mean ± SD, median (IQR) or n (%). PH — pulmonary hypertension; HT — heart transplantation; BMI — body mass index; COPD — chronic obstructive pulmonary disease; LVAD — left ventricular assist device; PA — pulmonary artery; PCW — pulmonary capillary wedge; TAH — total artificial heart. a p for trend across all 4 categories: no PH, mild PH, moderate PH, and severe PH. b Includes ECMO, IABP, NO, ventilator, prostacyclin, or IV inotrope use.
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PH were less often Caucasian, more often female, and were more often on pre-transplant life support such as extracorporeal membrane oxygenation, intra-aortic balloon pump, nitric oxide inhalation, mechanical ventilation, prostacyclin, or inotrope use. Furthermore, the use of pretransplant life support was significantly higher in patients with severe PH as compared to patients with mild or moderate pre-transplant PH. Similarly, donor–recipient weight ratio was also significantly higher in patients with severe PH as compared to patients with mild or moderate pre-transplant PH. 3.2. Correlation between PVR, TPG, and mean PA pressure The Pearson's correlation coefficient between PVR and TPG was excellent (r = 0.85, p b 0.0001) (Fig. 2). However, the correlations between PVR and mean PA pressure (r = 0.53, p b 0.0001), and TPG and mean PA pressure (r = 0.5, p b 0.0001) were modest. 3.3. Pre-transplant PH and post-transplant survival Fig. 2. Scatterplot of pulmonary vascular resistance vs. trans-pulmonary gradient (r = 0.85; p b 0.0001). 2.4. Statistical analysis Continuous variables are summarized as mean ± standard deviation (SD) and categorical variables as frequency and percentage. Mann–Whitney tests or t-tests were used to compare continuous variables. Chi-square tests or Fisher's exact tests were used for categorical variables. Kaplan–Meier curves were constructed to assess survival of patients in relation to their pre-transplant PH severity and compared by the log-rank test. Cox proportional hazards regression analysis was used to assess the association between PH and mortality, with adjustment for confounders. Variables with a p-value b 0.05 for association with both mortality and PH in univariable analysis were eligible to be included in the multivariable model. The year of transplantation was forced as a covariate into the multivariable model. As such, the multivariable models were adjusted for sex, race, body mass index (BMI), ischemic etiology, pre-transplant life support, ischemic time, and year of transplantation. The proportional hazards assumption was tested in the fully adjusted model by adding an interaction term for each PH category with the natural log of follow-up time. If significant interaction was found, hazard ratios at various time points were calculated from this model. All comparisons were two-sided and a p-value b 0.05 was taken as statistically significant. Analyses were performed using Stata Version 13 (Stata Corp. 2013. Stata Statistical Software: Release 13. College Station, TX).
3. Results 3.1. Baseline characteristics The mean age of the 26,649 patients included in our analyses was 52 ± 12 years (76% male, 76% Caucasian). Pre-transplant PH was present in 34% patients using PVR (≥2.5 WU) and 21% patients using TPG (≥ 13 mm Hg). Prevalence of mild, moderate, and severe PH according to PVR and TPG is illustrated in Fig. 1. Baseline clinical and surgical characteristics of recipients with respect to presence of PH and its severity are displayed in Table 2. Patients with pre-transplant
During a mean follow-up of 5.7 ± 4.8 years, 10,334 (39%) deaths occurred. Using PVR, 3772 (42%) deaths occurred in patients with PH as compared to 6562 (37%) in patients without PH (p b 0.001). The presence of pre-transplant PH was a significant predictor of mortality (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.08–1.17), and remained a significant multivariable predictor of mortality (HR 1.10, 95% CI 1.05–1.14) after adjusting for confounders (age, sex, race, BMI, ischemic etiology, life support, ischemic time, and year of transplantation). Multivariable hazard ratios for mortality at 30-days, 6-months, 1-, 5-, and 10-years in relation to PH severity are shown in Table 3. While pre-transplant PH was a risk factor for early, but not longterm mortality, the severity of PH was not a discriminating factor for poor survival. Cumulative survival was similar when comparing patients with mild, moderate, and severe pre-transplant PH (Fig. 3A). Similar results were obtained when TPG (Fig. 3B), or mean PA pressure (Fig. 3C) was used for classifying PH severity. 3.4. Mechanical circulatory support and pre-transplant PH Mechanical circulatory support (MCS), such as left ventricular assist device (LVAD) or total artificial heart (TAH), was present in 2785 (10.5%) patients at the time of transplantation. Using PVR, patients with MCS were less likely to have pre-transplant PH. Further, patients with MCS who had pre-transplant PH, had milder degrees of PH (Table 2). Hazard ratios for mortality at specific time-points in relation to PH severity for patients in the MCS sub-group are reported in Table 3. Survival analysis assessing the impact of pretransplant PH severity among patient sub-groups with (Fig. 4A) and without (Fig. 4B) MCS revealed no difference in long-term survival between mild/moderate versus severe PH groups.
Table 3 Multivariable hazard ratios for mortality at specific time points in relation to severity of pre-transplant pulmonary hypertension using pulmonary vascular resistance. 30-days (HR, 95% CI)
6-months (HR, 95% CI)
1-year (HR, 95% CI)
5-years (HR, 95% CI)
10-years (HR, 95% CI)
All patients Mild/moderate vs. no PH Severe vs. no PH Severe vs. mild/mod PH
1.21 (1.12, 1.30) 1.28 (1.12, 1.46) 1.06 (0.92, 1.22)
1.14 (1.09, 1.20) 1.14 (1.04, 1.25) 1.00 (0.91, 1.10)
1.12 (1.07, 1.17) 1.09 (1.00, 1.19) 0.98 (0.89, 1.07)
1.06 (1.01, 1.12) 0.98 (0.89, 1.08) 0.93 (0.84, 1.02)
1.04 (0.98, 1.10) 0.94 (0.84, 1.05) 0.91 (0.81, 1.02)
Patients with MCSa Mild/moderate vs. no PH Severe vs. no PH Severe vs. mild/mod PH
1.35 (1.06, 1.71) 1.17 (0.69, 1.99) 0.87 (0.51, 1.50)
1.33 (1.08, 1.62) 0.87 (0.52, 1.48) 0.66 (0.39, 1.13)
1.32 (1.06, 1.64) 0.78 (0.43, 1.41) 0.59 (0.32, 1.09)
1.30 (0.94, 1.79) 0.60 (0.26, 1.37) 0.46 (0.19, 1.08)
1.30 (0.89, 1.87) 0.54 (0.21, 1.38) 0.42 (0.16, 1.10)
PH — pre-transplant pulmonary hypertension; PVR — pulmonary vascular resistance; HR — hazard ratio; CI — confidence interval. Multivariable models adjusted for recipient age, sex, race, body mass index, ischemic etiology for transplantation, pre-transplant life support, ischemic time, and year of transplantation. a MCS — mechanical circulatory support (includes patients with either left ventricular assist device or total artificial heart).
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Fig. 4. Kaplan–Meier survival curves in relation to severity of pre-transplant PH defined by PVR in patients (A) with mechanical circulatory support (log-rank p = 0.003) and (B) without mechanical circulatory support (log-rank p b 0.0001).
Fig. 3. Kaplan–Meier survival curves in relation to severity of pre-transplant PH: (A) PH defined by pulmonary vascular resistance (overall log-rank p b 0.0001; and log-rank p = 0.8 when comparing mild/moderate/severe groups only); (B) PH defined by transpulmonary gradient (overall log-rank p b 0.0001; and log-rank p = 0.44 when comparing mild/moderate/severe groups only); and (C) PH defined by mean pulmonary artery pressure (overall log-rank p = 0.0001; and log-rank p = 0.52 when comparing mild/ moderate/severe groups only).
4. Discussion This study, which represents the real-world experience from the largest multi-center registry of heart transplant recipients in the US, highlights several important findings. First, our analyses show that pre-transplant PH was a modest, although significant, risk factor for early but not long-term post-transplant mortality. Second, the presence of severe PH as classified by PVR, TPG, or mean PA pressure was not
associated with an increased risk for mortality when compared to patients with mild/moderate PH. Finally, although the incidence and severity of pre-transplant PH was lesser in patients who were bridged to transplant with MCS, we found no difference in survival among patients with mild/moderate PH vs. severe PH in this sub-group either. These findings have important clinical implications in patient selection for heart transplantation. Since ~20% of deaths early after transplantation are attributed to allograft right ventricular failure, the current ISHLT guidelines consider the presence of severe pre-transplant PH as a relative contraindication for heart transplantation [6]. However, a recent study by Chang et al. that reported increased mortality in patients with elevated pre-transplant PVR [4] showed that greater than 50% of the deaths in the 1st year were attributable to cellular rejection, rather than allograft dysfunction. While multiple studies have shown an adverse association between severe pre-transplant PH and post-transplant mortality [16–20], others have yielded conflicting results [4,7–14,21]. Studies supporting the current practice guidelines have either been limited by short follow-up duration or lacked sufficient statistical power to examine the effect of pre-transplant PH on longterm post-transplant survival. In the current study, PVR ≥ 5 WU was associated with a 28%, 14%, and 9% increased risk of 30-day, 6-month, and 1-year mortality respectively, but not of 10-year mortality when compared to patients without PH (PVR b 2.5 WU). Furthermore, the impact of milder degrees of pre-transplant PH on post-transplant survival has not been well studied. While some studies have reported a ~2.5-fold increase in short-term mortality [8,22], others have failed to show such a differential effect on early compared to late mortality following transplantation [4,11]. Our results suggest that
K. Vakil et al. / International Journal of Cardiology 176 (2014) 595–599
mild/moderate PH is a significant predictor of 30-day, 6-month, 1-, and 5-year mortality, but not 10-year mortality. Most importantly, our analyses show that early- or long-term survival after heart transplantation did not differ significantly between patients with mild/moderate versus severe pre-transplant PH irrespective of the presence of pretransplant MCS. As such, although pre-transplant PH is a risk factor for mortality, its severity does not seem to be a discriminating factor for poor survival following heart transplantation. To validate our results further, we used other hemodynamic indices such as mean PA pressure and TPG to classify PH severity. While mean PA pressure has been traditionally used to define PH, unlike PVR and TPG, it fails to provide accurate information on the degree of intrinsic resistance in the pulmonary vasculature. As expected, we found excellent correlation between distributions of PVR and TPG in our cohort, whereas the correlation of PVR or TPG with mean PA pressure, was modest. Despite the sub-optimal correlation between mean PA pressure and other indices of PH, our results were consistent irrespective of the definition used to classify PH severity. Our study has a few limitations. First, given that UNOS gathers data only on the hemodynamics closest to the time of transplantation, information of ‘reversibility’ of PH was not available. Thus, it is likely that patients with severe PH with potentially reversible disease may indeed have milder degrees of PH at the time of transplant due to optimization of their pre-transplant hemodynamics. Alternatively, there could be a selection bias that patients with truly severe disease may have been denied heart transplantation. However, to minimize the impact of this on our findings, we validated our results using PVR and TPG for PH classification, which are less likely to be affected by alterations in left heart function than are mean PA pressures. Further, given that having pre-transplant MCS is likely to near-optimize reversible PH [23], we performed sub-group analyses in patients with LVAD or TAH that yielded similar results. Secondly, the retrospective nature of this study relies on individual transplant centers for the quality of data reporting. Third, since post-transplant management is likely to be influenced by center-dependent practices, we cannot account for institutional factors that may have impacted post-transplant survival. Lastly, prior studies have reported adverse association between recurrence of PH after transplantation and survival [24]. Since UNOS does not have data on posttransplant hemodynamic indices or allograft right ventricular function, we were unable to investigate this association. In conclusion, pre-transplant PH (PVR ≥ 2.5 WU) is associated with a modestly increased risk of early, but not long-term mortality when compared to patients without pre-transplant PH. Importantly, the severity of pre-transplant PH, as assessed by PVR, TPG, or mean PA pressure, does not appear to be a discriminating factor for poor survival in patients listed for heart transplantation. Studies to assess strategies for managing pre-transplant PH and their impact on post-transplant outcomes are warranted. Financial disclosures and conflicts of interest This work was supported in part by Health Resources and Services Administration contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. None of the authors have any financial disclosures or other conflicts of interests to disclose.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Impact of pre-transplant pulmonary hypertension on survival after heart transplantation: A UNOS registry analysis Kairav Vakil a,⁎, Sue Duval a, Alok Sharma a, Selcuk Adabag b, Kashan Syed Abidi a, Ziad Taimeh a, Monica Colvin-Adams a a b
Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA Division of Epidemiology and Community Health, School of Public Health, University of Minnesota and Veterans Affairs Medical Center, Minneapolis, MN, USA
a r t i c l e
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Article history: Received 22 March 2014 Received in revised form 29 July 2014 Accepted 11 August 2014 Available online 16 August 2014 Keywords: Pulmonary hypertension Heart transplantation Mortality
a b s t r a c t Introduction: Severe pre-transplant pulmonary hypertension (PH) has been associated with adverse short-term clinical outcomes after heart transplantation in relatively small single-center studies. The impact of pretransplant PH on long-term survival after heart transplantation has not been examined in a large, multi-center cohort. Methods: Adults (≥18 years) who underwent first time heart transplantation in the United States between 1987 and 2012 were retrospectively identified from the United Network for Organ Sharing registry. Pre-transplant PH was classified as mild, moderate, or severe based on pulmonary vascular resistance (PVR), trans-pulmonary gradient (TPG), and pulmonary artery (PA) mean pressure. Primary outcome was all-cause mortality. Results: Data from 26,649 heart transplant recipients (mean age 52 ± 12 years; 76% male; 76% Caucasian) were analyzed. During a mean follow-up of 5.7 ± 4.8 years, there were 10,334 (39%) deaths. Pre-transplant PH (PVR ≥ 2.5 WU) was a significant predictor of mortality (hazard ratio 1.10, 95% confidence interval 1.05–1.14, p b 0.0001) in multivariable analysis. However, the severity of pre-transplant PH (mild/moderate vs. severe) did not affect short or long-term survival. Similarly, even in patients who were supported with either a left ventricular assist device or a total artificial heart prior to transplant, severe pre-transplant PH was not associated with worse survival when compared to patients with mild/moderate pre-transplant PH. Conclusion: Pre-transplant PH (PVR ≥ 2.5 WU) is associated with a modest increase in mortality when compared to patients without pre-transplant PH. However, the severity of pre-transplant PH, assessed by PVR, TPG, or mean PA pressure, is not a discriminating factor for poor survival in patients listed for heart transplantation. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Heart transplantation is the mainstay of treatment for patients with end-stage heart failure. Pulmonary hypertension (PH) is commonly present in heart failure patients and portends adverse clinical outcomes irrespective of its etiology [1–3]. Presence of pre-transplant PH in heart organ recipients increases the risk of post-transplant PH and deterioration in right ventricular function in the donor heart. Cumulatively, these effects are associated with adverse post-operative outcomes [4,5]. As such, the International Society of Heart and Lung Transplantation (ISHLT) guidelines consider the presence of severe pre-transplant PH, defined as pulmonary vascular resistance (PVR) N5 Wood units (WU) or trans-pulmonary gradient (TPG) N 16–20 mm Hg, as a relative contraindication for heart transplantation [6]. Results from prior studies addressing the impact of pre-transplant PH on post-transplant survival have been inconsistent [4,7–14]. Further, ⁎ Corresponding author at: University of Minnesota, Mayo Mail Code 508, 420 Delaware Street SE, Minneapolis, MN 55455, USA. Tel.: +1 612 656 2451; fax: +1 612 626 4411. E-mail address: [email protected] (K. Vakil).
http://dx.doi.org/10.1016/j.ijcard.2014.08.072 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
relatively small single-center studies have shown that even milder degrees of pre-transplant PH may adversely influence survival after heart transplantation [4,8]. However, these studies were limited by relatively small sample size and short follow-up. Whether pre-transplant PH is associated with detrimental long-term survival in heart transplant recipients has not been examined in a large, multicenter cohort. As such, this study aims to examine the impact of pre-transplant PH on survival after heart transplantation in the largest multicenter prospective registry of heart transplant recipients in the United States (US).
Table 1 Classification of pulmonary hypertension severity based on different definitions. Definition
None
Mild
Moderate
Severe
Pulmonary vascular resistance (Wood units) Trans-pulmonary gradient (mm Hg) Mean pulmonary artery pressure (mm Hg)
b2.5
2.5–3.4
3.5–4.9
≥5.0
b13 b25
13–16 25–34
17–19 35–44
≥20 ≥45
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K. Vakil et al. / International Journal of Cardiology 176 (2014) 595–599 transplantation, and follow-up. For this study, ‘Standard Transplant Analysis and Research’ files with de-identified data for all heart transplant recipients were obtained from the UNOS [15]. Since no patient or center identifiers were used and the data are publicly available from the UNOS, this study was exempt from Institutional Review Board approval.
2.2. Study participants This analysis included all adults (≥18 years) who underwent first time heart transplantation in the US and were reported in the UNOS registry. Patients undergoing retransplantation, combined organ transplantations, transplantation for congenital heart disease, and those with missing information on pre-transplant PH or its severity, were excluded. Patients were also excluded if their pre-transplant cardiac hemodynamics were out of the following ranges: cardiac output (2 L/min–12 L/min), mean pulmonary artery (PA) pressure (10 mm Hg–80 mm Hg), and pulmonary capillary wedge pressure (5 mm Hg–50 mm Hg). Our final study cohort consisted of 26,649 patients.
2.3. Definitions and outcomes Fig. 1. Prevalence of severity of pre-transplant pulmonary hypertension using PVR and TPG definitions. 2. Methods 2.1. Data source The United Network for Organ Sharing (UNOS) registry was used to retrospectively identify adult heart transplant recipients in the US from October 1, 1987 to December 31, 2012. The registry consists of data on pre- and post-transplant variables captured and entered by each transplant center into an online database at the time of listing,
Patients were classified as having PH based on their most recent cardiac hemodynamic assessment prior to heart transplantation. In the absence of a single uniform definition to classify the severity of PH, three different indices were used. For primary analyses, PVR and TPG were used; while mean pulmonary artery (PA) pressures were used for sensitivity analyses. TPG was calculated as the difference between mean PA pressures and pulmonary capillary wedge pressure. PVR was calculated as the ratio of TPG and cardiac output. Cut-off values for no PH (PVR b 2.5 WU or TPG b 13 mm Hg) and severe PH (PVR ≥ 5.0 WU or TPG ≥ 20 mm Hg) were based on the ISHLT definitions [6]. However, given the lack of a definite consensus for classification of PH severity, arbitrary intermediate cut-off values for mild and moderate PH were used for analysis. Classification of PH severity based on PVR, TPG, and mean PA pressures is shown in Table 1. The primary outcome was all-cause mortality.
Table 2 Clinical characteristics in relation to baseline severity of pulmonary hypertension defined by pulmonary vascular resistance. Characteristic
Available data (n)
All patients
PH group by severity
No PH n = 17,669
PH n = 8980
p-Value
Mild n = 4657
Moderate n = 2884
Severe n = 1439
p-Value for trenda
Demographics Age at HT, years Male sex Caucasian
26,649 26,649 26,649
52 ± 12 78% 79%
53 ± 11 73% 70%
b0.001 b0.0001 b0.0001
54 ± 11 73% 72%
53 ± 11 73% 68%
53 ± 11 70% 65%
b0.0001 b0.0001 b0.0001
Clinical variables BMI, kg/m2 Diabetes mellitus History of smoking Drug-treated COPD Pulmonary embolism Prior malignancy Cerebrovascular disease Prior cardiovascular surgery Serum creatinine, mg/dL Dialysis VO2 maximum, mL/kg/min
26,337 25,590 11,403 16,992 15,906 26,649 25,480 26,649 26,379 25,208 6341
27.0 ± 4.8 9.4% 49% 3.4% 1.3% 4.9% 4.1% 22.5% 1.3 ± 0.9 2.3% 11.8 ± 3.6
26.0 ± 4.7 9.8% 50% 3.6% 1.8% 5.1% 4.0% 19.1% 1.3 ± 1.1 2.5% 11.2 ± 3.4
b0.001 0.28 0.30 0.57 0.01 0.47 0.65 b0.001 0.26 0.37 b0.001
26.3 ± 4.7 10.2% 52% 3.8% 1.5% 5.2% 4.2% 20.4% 1.3 ± 0.9 2.5% 11.2 ± 3.4
25.8 ± 4.7 10.1% 50% 3.2% 2.2% 5.3% 3.6% 18.5% 1.3 ± 0.9 2.4% 11.2 ± 3.4
25.5 ± 4.7 7.9% 47% 3.8% 1.8% 4.5% 4.1% 15.8% 1.4 ± 1.6 2.6% 11.1 ± 3.4
b0.0001 0.87 0.99 0.76 0.004 0.78 0.46 b0.0001 0.071 0.45 b0.0001
Transplant-related variables Wait time, days Ischemic indication for HT Life support at HTb LVAD/TAH Donor age, years Donor:recipient weight ratio Ischemic time, hours
26,639 26,649 26,649 26,649 26,647 26,635 25,499
105 (32, 279) 48.3% 46.1% 11.2% 31 ± 12 1.00 ± 0.23 3.1 ± 1.1
80 (26, 214) 45.9% 53.8% 9.0% 31 ± 12 1.04 ± 0.24 3.1 ± 1.0
b0.001 b0.001 b0.001 b0.001 0.88 b0.0001 0.017
84 (27, 228) 46.3% 52.1% 9.6% 32 ± 12 1.03 ± 0.24 3.1 ± 1.0
77 (26, 202) 45.4% 54.2% 9.0% 31 ± 12 1.04 ± .025 3.1 ± 1.0
72 (25, 195) 45.5% 58.4% 6.8% 31 ± 12 1.06 ± 0.25 3.1 ± 1.0
b0.0001 b0.0001 b0.0001 b0.0001 0.65 b0.0001 0.004
Cardiac hemodynamics Cardiac output, L/min PA systolic pressure, mm Hg PA diastolic pressure, mm Hg PA mean pressure, mm Hg PCW pressure, mm Hg TPG, mm Hg PVR, Wood units
26,649 25,614 26,500 26,649 26,649 26,649 26,649
4.9 ± 1.5 38.7 ± 12.4 18.4 ± 7.6 25.1 ± 8.7 18.9 ± 8.4 6.7 ± 3.1 1.4 ± 0.6
3.7 ± 1.0 52.9 ± 14.5 26.1 ± 8.5 35.0 ± 9.8 21.7 ± 8.4 13.9 ± 5.3 3.9 ± 1.6
b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001
4.0 ± 1.0 48.4 ± 13.0 23.5 ± 7.7 31.8 ± 8.9 20.7 ± 8.5 11.5 ± 3.1 2.9 ± 0.3
3.6 ± 0.9 54.9 ± 13.2 27.3 ± 7.8 36.4 ± 8.8 22.5 ± 8.3 14.4 ± 3.8 4.1 ± 0.4
3.1 ± 0.8 63.7 ± 14.9 32.0 ± 8.5 42.5 ± 9.5 23.0 ± 7.9 20.4 ± 7.3 6.7 ± 2.1
b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b0.0001
Values are mean ± SD, median (IQR) or n (%). PH — pulmonary hypertension; HT — heart transplantation; BMI — body mass index; COPD — chronic obstructive pulmonary disease; LVAD — left ventricular assist device; PA — pulmonary artery; PCW — pulmonary capillary wedge; TAH — total artificial heart. a p for trend across all 4 categories: no PH, mild PH, moderate PH, and severe PH. b Includes ECMO, IABP, NO, ventilator, prostacyclin, or IV inotrope use.
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PH were less often Caucasian, more often female, and were more often on pre-transplant life support such as extracorporeal membrane oxygenation, intra-aortic balloon pump, nitric oxide inhalation, mechanical ventilation, prostacyclin, or inotrope use. Furthermore, the use of pretransplant life support was significantly higher in patients with severe PH as compared to patients with mild or moderate pre-transplant PH. Similarly, donor–recipient weight ratio was also significantly higher in patients with severe PH as compared to patients with mild or moderate pre-transplant PH. 3.2. Correlation between PVR, TPG, and mean PA pressure The Pearson's correlation coefficient between PVR and TPG was excellent (r = 0.85, p b 0.0001) (Fig. 2). However, the correlations between PVR and mean PA pressure (r = 0.53, p b 0.0001), and TPG and mean PA pressure (r = 0.5, p b 0.0001) were modest. 3.3. Pre-transplant PH and post-transplant survival Fig. 2. Scatterplot of pulmonary vascular resistance vs. trans-pulmonary gradient (r = 0.85; p b 0.0001). 2.4. Statistical analysis Continuous variables are summarized as mean ± standard deviation (SD) and categorical variables as frequency and percentage. Mann–Whitney tests or t-tests were used to compare continuous variables. Chi-square tests or Fisher's exact tests were used for categorical variables. Kaplan–Meier curves were constructed to assess survival of patients in relation to their pre-transplant PH severity and compared by the log-rank test. Cox proportional hazards regression analysis was used to assess the association between PH and mortality, with adjustment for confounders. Variables with a p-value b 0.05 for association with both mortality and PH in univariable analysis were eligible to be included in the multivariable model. The year of transplantation was forced as a covariate into the multivariable model. As such, the multivariable models were adjusted for sex, race, body mass index (BMI), ischemic etiology, pre-transplant life support, ischemic time, and year of transplantation. The proportional hazards assumption was tested in the fully adjusted model by adding an interaction term for each PH category with the natural log of follow-up time. If significant interaction was found, hazard ratios at various time points were calculated from this model. All comparisons were two-sided and a p-value b 0.05 was taken as statistically significant. Analyses were performed using Stata Version 13 (Stata Corp. 2013. Stata Statistical Software: Release 13. College Station, TX).
3. Results 3.1. Baseline characteristics The mean age of the 26,649 patients included in our analyses was 52 ± 12 years (76% male, 76% Caucasian). Pre-transplant PH was present in 34% patients using PVR (≥2.5 WU) and 21% patients using TPG (≥ 13 mm Hg). Prevalence of mild, moderate, and severe PH according to PVR and TPG is illustrated in Fig. 1. Baseline clinical and surgical characteristics of recipients with respect to presence of PH and its severity are displayed in Table 2. Patients with pre-transplant
During a mean follow-up of 5.7 ± 4.8 years, 10,334 (39%) deaths occurred. Using PVR, 3772 (42%) deaths occurred in patients with PH as compared to 6562 (37%) in patients without PH (p b 0.001). The presence of pre-transplant PH was a significant predictor of mortality (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.08–1.17), and remained a significant multivariable predictor of mortality (HR 1.10, 95% CI 1.05–1.14) after adjusting for confounders (age, sex, race, BMI, ischemic etiology, life support, ischemic time, and year of transplantation). Multivariable hazard ratios for mortality at 30-days, 6-months, 1-, 5-, and 10-years in relation to PH severity are shown in Table 3. While pre-transplant PH was a risk factor for early, but not longterm mortality, the severity of PH was not a discriminating factor for poor survival. Cumulative survival was similar when comparing patients with mild, moderate, and severe pre-transplant PH (Fig. 3A). Similar results were obtained when TPG (Fig. 3B), or mean PA pressure (Fig. 3C) was used for classifying PH severity. 3.4. Mechanical circulatory support and pre-transplant PH Mechanical circulatory support (MCS), such as left ventricular assist device (LVAD) or total artificial heart (TAH), was present in 2785 (10.5%) patients at the time of transplantation. Using PVR, patients with MCS were less likely to have pre-transplant PH. Further, patients with MCS who had pre-transplant PH, had milder degrees of PH (Table 2). Hazard ratios for mortality at specific time-points in relation to PH severity for patients in the MCS sub-group are reported in Table 3. Survival analysis assessing the impact of pretransplant PH severity among patient sub-groups with (Fig. 4A) and without (Fig. 4B) MCS revealed no difference in long-term survival between mild/moderate versus severe PH groups.
Table 3 Multivariable hazard ratios for mortality at specific time points in relation to severity of pre-transplant pulmonary hypertension using pulmonary vascular resistance. 30-days (HR, 95% CI)
6-months (HR, 95% CI)
1-year (HR, 95% CI)
5-years (HR, 95% CI)
10-years (HR, 95% CI)
All patients Mild/moderate vs. no PH Severe vs. no PH Severe vs. mild/mod PH
1.21 (1.12, 1.30) 1.28 (1.12, 1.46) 1.06 (0.92, 1.22)
1.14 (1.09, 1.20) 1.14 (1.04, 1.25) 1.00 (0.91, 1.10)
1.12 (1.07, 1.17) 1.09 (1.00, 1.19) 0.98 (0.89, 1.07)
1.06 (1.01, 1.12) 0.98 (0.89, 1.08) 0.93 (0.84, 1.02)
1.04 (0.98, 1.10) 0.94 (0.84, 1.05) 0.91 (0.81, 1.02)
Patients with MCSa Mild/moderate vs. no PH Severe vs. no PH Severe vs. mild/mod PH
1.35 (1.06, 1.71) 1.17 (0.69, 1.99) 0.87 (0.51, 1.50)
1.33 (1.08, 1.62) 0.87 (0.52, 1.48) 0.66 (0.39, 1.13)
1.32 (1.06, 1.64) 0.78 (0.43, 1.41) 0.59 (0.32, 1.09)
1.30 (0.94, 1.79) 0.60 (0.26, 1.37) 0.46 (0.19, 1.08)
1.30 (0.89, 1.87) 0.54 (0.21, 1.38) 0.42 (0.16, 1.10)
PH — pre-transplant pulmonary hypertension; PVR — pulmonary vascular resistance; HR — hazard ratio; CI — confidence interval. Multivariable models adjusted for recipient age, sex, race, body mass index, ischemic etiology for transplantation, pre-transplant life support, ischemic time, and year of transplantation. a MCS — mechanical circulatory support (includes patients with either left ventricular assist device or total artificial heart).
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Fig. 4. Kaplan–Meier survival curves in relation to severity of pre-transplant PH defined by PVR in patients (A) with mechanical circulatory support (log-rank p = 0.003) and (B) without mechanical circulatory support (log-rank p b 0.0001).
Fig. 3. Kaplan–Meier survival curves in relation to severity of pre-transplant PH: (A) PH defined by pulmonary vascular resistance (overall log-rank p b 0.0001; and log-rank p = 0.8 when comparing mild/moderate/severe groups only); (B) PH defined by transpulmonary gradient (overall log-rank p b 0.0001; and log-rank p = 0.44 when comparing mild/moderate/severe groups only); and (C) PH defined by mean pulmonary artery pressure (overall log-rank p = 0.0001; and log-rank p = 0.52 when comparing mild/ moderate/severe groups only).
4. Discussion This study, which represents the real-world experience from the largest multi-center registry of heart transplant recipients in the US, highlights several important findings. First, our analyses show that pre-transplant PH was a modest, although significant, risk factor for early but not long-term post-transplant mortality. Second, the presence of severe PH as classified by PVR, TPG, or mean PA pressure was not
associated with an increased risk for mortality when compared to patients with mild/moderate PH. Finally, although the incidence and severity of pre-transplant PH was lesser in patients who were bridged to transplant with MCS, we found no difference in survival among patients with mild/moderate PH vs. severe PH in this sub-group either. These findings have important clinical implications in patient selection for heart transplantation. Since ~20% of deaths early after transplantation are attributed to allograft right ventricular failure, the current ISHLT guidelines consider the presence of severe pre-transplant PH as a relative contraindication for heart transplantation [6]. However, a recent study by Chang et al. that reported increased mortality in patients with elevated pre-transplant PVR [4] showed that greater than 50% of the deaths in the 1st year were attributable to cellular rejection, rather than allograft dysfunction. While multiple studies have shown an adverse association between severe pre-transplant PH and post-transplant mortality [16–20], others have yielded conflicting results [4,7–14,21]. Studies supporting the current practice guidelines have either been limited by short follow-up duration or lacked sufficient statistical power to examine the effect of pre-transplant PH on longterm post-transplant survival. In the current study, PVR ≥ 5 WU was associated with a 28%, 14%, and 9% increased risk of 30-day, 6-month, and 1-year mortality respectively, but not of 10-year mortality when compared to patients without PH (PVR b 2.5 WU). Furthermore, the impact of milder degrees of pre-transplant PH on post-transplant survival has not been well studied. While some studies have reported a ~2.5-fold increase in short-term mortality [8,22], others have failed to show such a differential effect on early compared to late mortality following transplantation [4,11]. Our results suggest that
K. Vakil et al. / International Journal of Cardiology 176 (2014) 595–599
mild/moderate PH is a significant predictor of 30-day, 6-month, 1-, and 5-year mortality, but not 10-year mortality. Most importantly, our analyses show that early- or long-term survival after heart transplantation did not differ significantly between patients with mild/moderate versus severe pre-transplant PH irrespective of the presence of pretransplant MCS. As such, although pre-transplant PH is a risk factor for mortality, its severity does not seem to be a discriminating factor for poor survival following heart transplantation. To validate our results further, we used other hemodynamic indices such as mean PA pressure and TPG to classify PH severity. While mean PA pressure has been traditionally used to define PH, unlike PVR and TPG, it fails to provide accurate information on the degree of intrinsic resistance in the pulmonary vasculature. As expected, we found excellent correlation between distributions of PVR and TPG in our cohort, whereas the correlation of PVR or TPG with mean PA pressure, was modest. Despite the sub-optimal correlation between mean PA pressure and other indices of PH, our results were consistent irrespective of the definition used to classify PH severity. Our study has a few limitations. First, given that UNOS gathers data only on the hemodynamics closest to the time of transplantation, information of ‘reversibility’ of PH was not available. Thus, it is likely that patients with severe PH with potentially reversible disease may indeed have milder degrees of PH at the time of transplant due to optimization of their pre-transplant hemodynamics. Alternatively, there could be a selection bias that patients with truly severe disease may have been denied heart transplantation. However, to minimize the impact of this on our findings, we validated our results using PVR and TPG for PH classification, which are less likely to be affected by alterations in left heart function than are mean PA pressures. Further, given that having pre-transplant MCS is likely to near-optimize reversible PH [23], we performed sub-group analyses in patients with LVAD or TAH that yielded similar results. Secondly, the retrospective nature of this study relies on individual transplant centers for the quality of data reporting. Third, since post-transplant management is likely to be influenced by center-dependent practices, we cannot account for institutional factors that may have impacted post-transplant survival. Lastly, prior studies have reported adverse association between recurrence of PH after transplantation and survival [24]. Since UNOS does not have data on posttransplant hemodynamic indices or allograft right ventricular function, we were unable to investigate this association. In conclusion, pre-transplant PH (PVR ≥ 2.5 WU) is associated with a modestly increased risk of early, but not long-term mortality when compared to patients without pre-transplant PH. Importantly, the severity of pre-transplant PH, as assessed by PVR, TPG, or mean PA pressure, does not appear to be a discriminating factor for poor survival in patients listed for heart transplantation. Studies to assess strategies for managing pre-transplant PH and their impact on post-transplant outcomes are warranted. Financial disclosures and conflicts of interest This work was supported in part by Health Resources and Services Administration contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. None of the authors have any financial disclosures or other conflicts of interests to disclose.
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