MELD-XI Score Predicts Early Mortality in Patients After Heart Transplantation

MELD-XI Score Predicts Early Mortality in Patients After Heart Transplantation Joshua C. Grimm, MD, Ashish S. Shah, MD, J. Trent Magruder, MD, Arman Kilic, MD, Vicente Valero, III, MD, Samuel P. Dungan, BA, Ryan J. Tedford, MD, Stuart D. Russell, MD, Glenn J. R. Whitman, MD, and Christopher M. Sciortino, MD, PhD Divisions of Cardiac Surgery and Cardiology, The Johns Hopkins Hospital, Baltimore, Maryland

Background. The aim of this study was to determine the utility of the Model for End-Stage Liver Disease Excluding INR (MELD-XI) in predicting early outcomes (30 days and 1 year) and late outcomes (5 years) in patients after orthotopic heart transplantation (OHT). Methods. The United Network for Organ Sharing database was queried for all adult patients (aged ‡18 years) undergoing OHT from 2000 to 2012. A MELD-XI was calculated and the population stratified into score quartiles. Early and late survivals were compared among the MELD-XI cohorts. Multivariable Cox proportional hazards models were constructed to determine the capacity of MELD-XI (when modeled both as a categoric and a continuous variable) to predict 30-day, 1-year, and 5-year mortality. Conditional models were also designed to determine the effect of early mortality on long-term survival. Results. A total of 22,597 patients were included for analysis. The MELD-XI cutoff scores were established as follows: low (£10.5), low-intermediate (10.6 to 12.6), intermediate-high (12.7 to 16.4), and high (>16.4). The

high MELD-XI cohort experienced statistically worse 30day, 1-year, and 5-year unconditional survivals when compared with patients with low scores (p < 0.001). Similarly, a high MELD-XI score was also predictive of early and late mortality (p < 0.001) after risk adjustment. There was, however, no difference in 5-year survival between the high score and low score cohorts after accounting for 1-year deaths. Subanalysis of patients bridged to transplant with a continuous-flow left ventricular assist device demonstrated similar findings. Conclusions. This is the first known study to examine the relationship between a high MELD-XI score and outcomes in patients after OHT. Patients with hepatic or renal dysfunction before OHT should be closely monitored and aggressively optimized as early mortality appears to drive long-term outcomes.

L

LVAD patients, are managed with systemic anticoagulation, resulting in elevations in the INR irrespective of hepatic synthetic function. Accordingly, a modification to the existing MELD, the Model for EndStage Liver Disease Excluding INR (MELD-XI) was established [6]. Although this alternative scoring system, which omits INR in its final calculation, has been utilized to identify patients at risk for mortality after LVAD implantation [7], its ability to predict outcomes in patients undergoing OHT is currently unknown.

iver dysfunction is a common sequela of heart failure [1]. The pathogenesis includes poor global perfusion as well as hepatic congestion secondary to right ventricular failure [1, 2]. These derangements have been shown to improve within six months to one year after orthotopic heart transplantation (OHT) [3]. The Model for End-Stage Liver Disease (MELD), a composite of the serum bilirubin, creatinine and international normalized ratio (INR), has been validated as an accurate metric of the degree of liver disease and has been utilized as a predictor of survival in medically treated patients with congestive heart failure [4] as well as those supported with a left ventricular assist device (LVAD) [3, 5]. There are limitations, however, in the application of this scoring system in this capacity. Considerable proportions of heart failure patients, and essentially all Accepted for publication July 9, 2015. Presented at the Thirty-fifth Annual Meeting of The International Society for Heart and Lung Transplantation, Nice, France, April 15–18, 2015. Address correspondence to Dr Sciortino, 1800 Orleans, Zayed 7107, Baltimore, MD 21287; e-mail: [email protected].

Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier

(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons

Patients and Methods Patient Selection and Exclusion Criteria Necessary approval for this study was obtained from The Johns Hopkins Hospital Institutional Review Board. The United Network for Organ Sharing database was queried for all adult patients (
18 years of age) undergoing OHT from January 1, 2000, to December 31, 2012. Patients who underwent simultaneous thoracic or abdominal solid organ transplantation were excluded from analysis. 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.07.026

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Table 1. Recipient, Donor, Operative, and Postoperative Characteristics Stratified by Model for End-Stage Liver Disease Excluding INR Score Cohorta Characteristics Recipient characteristics Age, years Male Race White Hispanic Black Other Body mass index, kg/m2 Serum bilirubin, mg/dL Serum creatinine, mg/dL GFR, mL $ min1 $ 1.73 m2 Diabetes mellitus Pulmonary hypertension Etiology Nonischemic dilated CM Ischemic dilated CM Congenital heart disease CAD or valvular disease Cardiac retransplantation Other Previous thoracic transplantation Inotropes Days on wait list ECMO LVAD Pulsatile Continuous Intensive care unit care Ventilated Donor characteristics Age, years Male Body mass index, kg/m2 Diabetes mellitus Hypertension Cigarette use Cytomegalovirus positive Operative characteristics Ischemic time, hours Anastomotic technique Orthotopic bicaval anastomosis Orthotopic traditional Orthotopic total (bicaval, PV) Sex match Postoperative outcomes Stroke New onset renal failure a

Low n ¼ 5,443

Low-Intermediate n ¼ 5,731

Intermediate-High n ¼ 5,900

High n ¼ 5,523

49.3  13.2 59.8 (3,257/5,443)

52.5  12.2 77.8 (4,457/5,731)

53.4  12.1 81.6 (4,816/5,900)

53.1  11.8 81.6 (4,504/5,523)

71.6 (3,897/5,443) 9.0 (490/5,443) 15.0 (817/5,443) 4.4 (239/5,443) 26.4  4.9 0.7  0.3 0.9  0.1 69.2  12.8 21.6 (1,173/5,428) 49.6 (2,579/5,199)

72.8 (4,170/5,731) 7.2 (410/5,731) 16.4 (938/5,731) 3.7 (213/5,731) 26.8  4.8 0.8  0.4 1.1  0.1 54.9  11.7 23.9 (1,360/5,693) 52.2 (2,881/5,517)

72.9 (4,299/5,900) 6.2 (366/5,900) 18.0 (1,059/5,900) 3.0 (176/5,900) 27.0  4.8 1.2  0.8 1.4  0.3 44.7  13.7 25.5 (1,501/5,876) 29.0 (3,334/5,654)

71.4 (3,942/5,523) 6.4 (354/5,523) 19.2 (1,058/5,523) 3.1 (169/5,526) 26.8  4.7 2.4  4.3 1.9  1.0 28.0  15.7 25.1 (1,361/5,421) 62.5 (3,242/5,184)

47.0 34.9 3.3 6.0 1.3 7.5 1.4 38.6 81 0.6

(2,556/5,443) (1,897/5,443) (181/5,443) (329/5,443) (72/5,443) (408/5,443) (74/5,443) (2,102/5,443) (25–218) (30/5,443)

42.4 40.0 2.5 6.9 2.0 6.2 2.0 42.3 88 0.4

(2,430/5,731) (2,290/5,731) (142/5,731) (398/5,731) (115/5,731) (356/5,731) (115/5,731) (2,425/5,731) (27–241) (23/5,731)

44.0 38.5 2.0 6.8 3.0 5.9 3.1 44.0 75.5 0.7

(2,594/5,900) (2,269/5,900) (115/5,900) (399/5,900) (175/5,900) (348/5,900) (183/5,900) (2,593/5,900) (23–211) (39/5,900)

42.5 36.8 2.3 7.3 4.9 6.1 5.0 47.5 85 1.3

(2,349/5,523) (2,032/5,523) (129/5,523) (404/5,523) (273/5,523) (336/5,523) (277/5,523) (2,622/5,523) (22–292) (71/5,523)

3.7 14.2 25.5 1.6

(200/5,404) (768/5,404) (1,385/5,443) (90/5,443)

3.1 13.0 25.6 1.7

(179/5,721) (746/5,721) (1,469/5,731) (96/5,731)

3.6 12.2 29.2 2.3

(208/5,821) (710/5,821) (1,721/5,900) (136/5,900)

3.4 8.0 37.3 5.0

(183/5,450) (434/5,450) (2,060/5,523) (2,76/5,523)

<0.001 <0.001 0.002 <0.001 <0.001 0.32 0.12 <0.001 0.69

31.0  12.1 64.5 (3,512/5,443) 26.2  5.5 2.9 (158/5,428) 21.7 (1,178/5,430) 20.7 (1,119/5,407) 61.7 (3,347/5,429)

31.6  12.1 72.1 (4,131/5,731) 26.7  5.9 2.7 (155/5,700) 21.4 (1,219/5,708) 23.1 (1,309/5,675) 61.3 (3,502/5,711)

31.6  12.3 74.4 (4,388/5,900) 26.7  5.4 2.5 (146/5,888) 21.2 (1,244/5,883) 22.2 (1,301/5,855) 61.9 (3,636/5,876)

32.0  12.3 74.1 (4,091/5,523) 26.8  5.5 2.4 (132/5,508) 19.9 (1,097/5,503) 24.6 (1,347/5,481) 60.8 (3,351/5,509)

3.2  1.0

3.2  1.0

3.2  1.0

3.2  1.1

61.3 35.4 3.3 68.1

(3,336/5,439) (1,926/5,439) (177/5,439) (3,706/5,443)

2.0 (108/5,344) 4.7 (253/5,368)

59.8 37.2 3.0 73.3

(3,428/5,729) (2,129/5,729) (172/5,729) (4,203/5,731)

2.0 (113/5,632) 6.3 (354/5,655)

61.3 35.5 3.2 74.2

(3,613/5,897) (2,094/5,897) (190/5,897) (4,378/5,900)

2.2 (129/5,796) 9.1 (529/5,818)

58.3 38.9 2.8 74.1

(3,216/5,515) (2145/5,515) (154/5,515) (4,092/5,523)

3.1 (165/5,401) 11.8 (605/5,110)

p Value <0.001 <0.001 <0.001

<0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

<0.001 <0.001 0.001 <0.001 <0.001

0.02 0.002

<0.001 0.001 <0.001

Score cohort: low, 10.5 or less; low-intermediate, 10.6 to 12.6; intermediate-high, 12.7 to 16.4; and high, greater than 16.4.

Values are mean  SD, percent (n/N), or median (interquartile range). CAD ¼ coronary artery disease; CM ¼ cardiomyopathy; ECMO ¼ extracorporeal membrane oxygenation; rate; INR ¼ international normalized ratio; LVAD ¼ left ventricular assist device; PV ¼ pulmonary vein.

GFR ¼ glomerular filtration

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Calculation of MELD-XI and Generation of Cohorts The MELD-XI score was defined as follows: MELD-XI ¼ 5.11  ln(serum bilirubin) þ 11.76  ln(serum creatinine) þ 9.44 [6]. Per convention, patients with endstage renal disease requiring dialysis were administered a maximum serum creatinine of 4 mg/dL. The lower limit of serum bilirubin and creatinine was set at 1 mg/dL to generate a minimum score of 9.44. The MELD-XI cohorts (low, low-intermediate, intermediate-high, and high) were established based on quartile stratification. Serum bilirubin and creatinine values utilized in the calculation represent those at the time of transplant.

Statistical Analysis Baseline recipient, donor, and transplant specific characteristics as well as postoperative outcomes were compared among the MELD-XI cohorts. Short-term (30day) and long-term (1-year and 5-year) conditional and unconditional survivals were estimated with the KaplanMeier method with differences provided by the log rank test. Risk-adjusted Cox proportional hazards models were constructed to determine the ability of the MELD-XI (as both a categoric and continuous variable) to independently predict 30-day, 1-year, and 5-year mortality. Covariates with a p value less than 0.20 on exploratory univariate analysis were then manually included, based on the likelihood ratio test and Akaike information criterion, into a multivariable model. Subanalysis of patients bridged to OHT with a continuous flow LVAD was also performed. Continuous variables are expressed as mean  SD parametric or median (interquartile range [IQR]) nonparametric, and were compared among the MELD-XI cohorts with analysis of variance or the Kruskal-Wallis test, respectively. Categoric variables are represented as percentage (number) and were compared with Pearson’s c2 test. Significance was established at a p value less than 0.05. Statistical analysis was performed using STATA software, version 12 (StataCorp, College Station, TX).

Results Baseline Characteristics A total of 24,369 patients underwent OHT during the study period. The MELD-XI scores could not be calculated for 1,023 patients (4.2%) and 749 additional patients (3.1%) were excluded owing to simultaneous abdominal or thoracic transplantation. In total, 22,597 patients were included for analysis. The median MELD-XI score

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population was 12.7 (IQR: 10.6 to 16.3). This value decreased every year during the study interval: 2000, 14.6 (IQR: 11.4, 25.7) versus 2012, 12.3 (IQR: 9.4 to 15.1, p ¼ 0.001). After stratification into relatively equal sized quartiles, the following score cohorts were created: low (10.5), low-intermediate (10.6 to 12.6), intermediate-high (12.7 to 16.4), and high (>16.4). When comparing the MELD-XI cohorts, some important differences were observed in baseline recipient characteristics (Table 1). Notably, patients with high MELD-XI scores had a greater serum bilirubin and creatinine and lower glomerular filtration rate as well as a greater incidence of pretransplant inotrope administration, extracorporeal membrane oxygenation support, intensive care unit level management, and mechanical ventilation. There were also subtle differences with respect to donor-specific characteristics in the high MELD-XI cohort, which included a greater age and body mass index (Table 1). This cohort also underwent transplantation with allografts exposed to longer ischemic times (Table 1).

Impact of MELD-XI Score on Survival The high MELD-XI cohort experienced statistically worse 30-day survival (92.8% versus 97.0%, p < 0.001), 1-year survival (83.3% versus 91.7%, p < 0.001), and 5-year survival (70.0% versus 78.2%, p < 0.001) when compared with the low score cohort (Table 2, Fig 1). To ensure that differences in 1-year and 5-year survival were not influenced solely by early mortality, conditional survival was also examined. After excluding 6-month deaths, the gap between 1-year survivals diminished but was still worse in the high MELD-XI cohort (96.4% versus 97.3%, p ¼ 0.04). There was no difference in 5-year survival—conditional on 1-year survival, however—between patients with high and low MELD-XI scores (83.0% versus 81.0%, p ¼ 0.11; Table 3). In multivariable Cox proportional hazards modeling, a high MELD-XI score was an independent predictor of post-OHT mortality (Table 4). That was true when the MELD-XI score was modeled as both a categoric and continuous variable. The high MELD-XI cohort experienced a significantly increased hazard of 30-day, 1-year, and 5-year death. Conditional mortality paralleled the findings of the survival analyses. More specifically, although a high MELD-XI score continued to be significantly associated with conditional 1-year mortality, it was not predictive of 5-year mortality among patients who survived 1 year (Table 5).

Table 2. Unconditional Survival Stratified by Model for End-Stage Liver Disease Excluding INR Score Cohort Low % (95% CI)

Low-Intermediate % (95% CI)

Intermediate-High % (95% CI)

High % (95% CI)

p Value

97.0% (96.5%–97.4%) 91.7% (90.9%–92.4%) 78.2% (76.8%–79.5%)

96.6% (96.15–97.0%) 90.8% (90.0%–91.5%) 77.5% (76.2%–78.7%)

95.6% (95.1%–96.1%) 89.0% (88.2%–89.8%) 74.9% (73.6%–76.2%)

92.8% (92.2%–93.5%) 83.3% (82.3%–84.3%) 70.0% (68.7%–71.3%)

<0.001 <0.001 <0.001

Survival Thirty days One year Five years

CI ¼ confidence interval;

INR ¼ international normalized ratio.

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Fig 1. Unconditional survival stratified by Model for End-Stage Liver Disease Excluding INR (MELD-XI) cohort: low (solid line), lowintermediate (dashed line), intermediate-high (dotted line), and high (broken line). The high MELD-XI score cohort had significantly worse survival at 30 days, 1 year, and 5 years (log rank p < 0.001 for each period).

Subanalysis of Patients Bridged to OHT With Continuous-Flow LVAD A total of 2,658 patients (11.8%) was bridged to OHT with a continuous-flow LVAD. The predictive ability of the MELD-XI score within this cohort is crucial given the universal use of anticoagulation therapy for LVAD patients. Not only was there a significant difference in 30-day survival (92.0% versus 97.5%, p < 0.001), 1-year survival (81.3% versus 92.7%, p < 0.001), and 5-year survival (64.3% versus 77.8%, p < 0.001) between the high and low MELD-XI cohorts (Fig 2), respectively, there was also a very significantly increased hazard of mortality, ranging between 1.89 at 5 years and 3.08 at 30 days (p < 0.001 for 30 days, 1 year, and 5 years; Table 6).

Association Between Postoperative Renal Failure and MELD-XI Score Although not originally a primary outcome of interest, there was a strong association between the need for postoperative hemodialysis and an increasing MELD-XI score. The overall rate of new onset renal failure necessitating hemodialysis in the study was 7.9%. The high score cohort had the greatest incidence (11.8%) when compared with the other three groups (low 4.7%, lowintermediate 6.3%, intermediate-high 9.1%; p < 0.001). When modeled as a categoric variable, an intermediatehigh MELD-XI score (odds ratio 1.89, 95% CI: 1.60 to 2.24, p < 0.001) or high score (odds ratio 2.54, 95% CI: 2.16 to 3.01, p < 0.001) independently predicted postoperative renal failure after risk adjustment with a series of donorand transplant-specific variables (age, body mass index, diabetes mellitus, pulmonary hypertension, intensive

care unit status, preoperative mechanical ventilation, and allograft ischemic time). Similar results were evident when MELD-XI was modeled as a continuous variable (odds ratio 1.06, 95% CI: 1.05 to 1.07, p < 0.001). In each MELD-XI cohort, 30-day and 1-year survivals were significantly reduced in patients who had postoperative renal failure (p < 0.001). Among patients who had renal failure, however, there was no difference in survival based on MELD-XI score.

Impact of MELD-XI on Patients With Baseline Low Creatinine To demonstrate that the difference in survival witnessed in the high MELD-XI cohort was not merely a consequence of baseline renal dysfunction, Kaplan-Meier analysis was performed in patients with a serum creatinine less than 1 mg/dL (25th percentile). Within this cohort, patients with a high MELD-XI score had diminished 30-day survival (94.5% versus 97.3%, p ¼ 0.001), 1year survival (87.6% versus 92.3%, p < 0.001), and 5-year survival (74.2% versus 79.2%, p ¼ 0.001). Again, a high MELD-XI score was an independent predictor of 30-day mortality (hazard ratio 1.05, 95% CI: 1.12 to 2.57, p ¼ 0.01), 1-year mortality (hazard ratio 1.74, 95% CI: 1.34 to 2.26, p < 0.001), and 5-year mortality (hazard ratio 1.38, 95% CI: 1.15 to 1.66, p < 0.001) among patients with a normal baseline creatinine level.

Comment Hepatic dysfunction resulting from heart failure is a wellestablished phenomenon [1, 8] and confers a considerable

Table 3. Conditional Survivals Stratified by Model for End-Stage Liver Disease Excluding INR Score Cohort Low % (95% CI)

Low-Intermediate % (95% CI)

Intermediate-High % (95% CI)

High % (95% CI)

p Value

97.3% (96.8%–97.7%) 83.0% (81.7%–84.2%)

97.3% (96.8%–97.7%) 83.0% (81.8%–84.2%)

96.9% (96.4%–97.4%) 81.6% (80.3%–82.7%)

96.4% (95.8%–96.9%) 81.0% (79.7%–82.2%)

0.04 0.11

Survival One yeara Five yearsb a

Conditional on 6-month survival.

CI ¼ confidence interval;

b

Conditional on 1-year survival.

INR ¼ international normalized ratio.

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Table 4. Unconditional Predictive Models for Survival Stratified by Model for End-Stage Liver Disease Excluding INR Score 30 Daysa MELD-XI Score Increasing MELD-XI, continuous MELD-XI, categoric Low, 10.5 Low-intermediate, 10.6–12.6 Intermediate-high, 12.7–16.4 High, >16.4

1 Yearb

5 Yearsc

HR (95% CI)

p Value

HR (95% CI)

p Value

HR (95% CI)

p Value

1.06 (1.04–1.07)

<0.001

1.05 (1.04–1.06)

<0.001

1.03 (1.03–1.04)

<0.001

Reference 1.07 (0.86–1.33) 1.42 (1.15–1.75) 1.85 (1.51–2.28)

0.55 0.001 <0.001

Reference 1.09 (0.96–1.25) 1.27 (1.12–1.45) 1.76 (1.54–2.00)

0.17 <0.001 <0.001

Reference 1.04 (0.95–1.14) 1.19 (1.08–1.32) 1.42 (1.29–1.55)

0.42 <0.001 <0.001

a Risk adjusted for recipient (sex, body mass index, renal failure, etiology of heart disease, steroid use, extracorporeal membrane oxygenation, intensive b care unit status, mechanical ventilation), donor (age, hypertension, tobacco use), and operative (ischemic time, anastomotic technique) variables. Risk adjusted for recipient (age, sex, body mass index, diabetes mellitus, renal failure, etiology of heart disease, inotrope requirement, extracorporeal membrane oxygenation, intensive care unit status, bridge with left ventricular assist device, mechanical ventilation), donor (age, sex, hypertension, tobacco use, c cytomegalovirus positive), and operative (sex match, ischemic time, anastomotic technique) variables. Risk adjusted for recipient (sex, race, body mass index, diabetes, renal failure, etiology of heart disease, steroid use, inotrope requirement, intensive care unit status, extracorporeal membrane oxygenation, bridge with left ventricular assist device, mechanical ventilation), donor (age, sex, diabetes, hypertension, tobacco use, cytomegalovirus positive), and operative (sex match, ischemic time, anastomotic technique) variables.

CI ¼ confidence interval;

HR ¼ hazard ratio;

MELD-XI ¼ Model for End-Stage Liver Disease Excluding INR.

short-term and long-term survival disadvantage on both surgical patients [3, 5, 9, 10] and medical patients [4]. Kim and colleagues [4] examined the ability of the standard MELD score as well as two modified systems, the MELDNa (including serum sodium) and the MELD-XI, to predict survival outcomes of ambulatory patients with heart failure. They demonstrated a significant reduction in 1year survival (69.3% versus 90.4%, p < 0.001) in patients with high scores (>12). In their analysis, systemic anticoagulation therapy was also associated with poor survival (73.7% versus 86.4%, p ¼ 0.01) at 1 year [4], presumably due to the deleterious impact of atrial fibrillation on outcomes in this demographic [11]. Given the utilization of systemic anticoagulation therapy in LVAD patients, however, there is an inherent limitation in applying the MELD scoring system to this unique cohort and attributing an elevation in the INR to worsening hepatic synthetic function. Therefore, we analyzed more than 22,579 patients and found that an elevated pretransplant MELD-XI score was associated with diminished 30-day, 1-year, and 5-year unconditional survival. Although this cohort’s high risk

profile extends beyond renal and hepatic dysfunction, the MELD-XI, even after adjustment for other recipient and donor specific factors, is a good predictor of early death after OHT. When 1-year survival was satisfied, however, there was no difference in long-term outcomes. This finding is consistent with previous work by Dichtl and colleagues [3] in which they demonstrated a significant improvement in the serum parameters of chronic hepatopathy and concluded that it was a potentially reversible process. In a similar study, Chokshi and colleagues [9] applied the MELD to heart failure patients undergoing OHT. They demonstrated an improvement in most pretransplant hepatobiliary markers by 2 months after transplant. Despite these physiologic corrections, their findings associated an elevated pretransplant MELD (>20) with worse morbidity and mortality after transplant [3]. Follow-up in this study was robust at 10 years after OHT, but the analysis did not examine the effect of early death on longterm survival. It is clear, however, that some markers of hepatic dysfunction are reversible and improve within a year after transplant and, therefore, one would expect its

Table 5. Conditional Predictive Model for Postoperative Mortality 1 Yeara MELD-XI Score Increasing MELD-XI, continuous MELD-XI, categoric Low, 10.5 Low-intermediate, 10.6–12.6 Intermediate-high, 12.7–16.4 High, >16.4

5 Yearsb

HR (95% CI)

p Value

HR (95% CI)

p Value

1.01 (1.01–1.04)

0.005

1.03 (1.01–1.04)

0.001

Reference 0.97 (0.85–1.11) 1.07 (0.94–1.21) 1.13 (0.99–1.29)

0.69 0.33 0.07

Reference 1.00 (0.78–1.28) 1.10 (0.86–1.42) 1.28 (1.00–1.65)

0.98 0.43 0.05

a Risk adjusted for recipient (age, sex, body mass index, diabetes mellitus, renal failure, etiology of heart disease, inotrope requirement, extracorporeal membrane oxygenation, intensive care unit status, bridge with left ventricular assist device, mechanical ventilation), donor (age, sex, hypertension, tobacco b Risk adjusted for recipient (sex, race, body use, cytomegalovirus positive), and operative (sex match, ischemic time, anastomotic technique) variables. mass index, diabetes, renal failure, etiology of heart disease, steroid use, inotrope requirement, intensive care unit status, extracorporeal membrane oxygenation, bridge with left ventricular assist device, mechanical ventilation), donor (age, sex, diabetes, hypertension, tobacco use, cytomegalovirus positive), and operative (sex match, ischemic time, anastomotic technique) variables.

CI ¼ confidence interval;

HR ¼ hazard ratio;

MELD-XI ¼ Model for End-Stage Liver Disease Excluding INR.

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Fig 2. Unconditional survival in patients bridged to orthotopic heart transplantation with a continuous-flow left ventricular assist device stratified by Model for End-Stage Liver Disease Excluding INR (MELD-XI) cohort: low (solid line), low-intermediate (dashed line), intermediate-high (dotted line), and high (broken line). The high MELD-XI score cohort had significantly worse survival at 30 days, 1 year, and 5 years (log rank p < 0.001 for each period).

impact on 5-year or 10-year outcomes to be heavily dependent on early survival. Utilizing the MELD-XI to identify and optimize this cohort of patients at risk for short-term morbidity or mortality could mitigate the influence of these complications on long-term results. It is important to note that survival was dramatically worse among patients who had renal failure after OHT for all MELD-XI scores. Expectedly, the highest MELD-XI cohort had the lowest pretransplant glomerular filtration rate and was highly susceptible to postoperative injury. There was no difference, however, between the 30-day, 1year, or 5-year survivals of patients with renal failure across all MELD-XI cohorts. Other studies have demonstrated the ill effects of cardiorenal syndrome on outcomes of patients with heart failure [12], and it appears to be a dominant factor in this analysis as well. The strongest association between MELD-XI and survival was evident among patients bridged to OHT with a continuous-flow LVAD. It was decided to focus mainly on continuous-flow devices as they represent the newest generation of ventricular assistance and are currently the most commonly implanted hardware. As systemic anticoagulation therapy is essential within this cohort, the MELD-XI has immediate applicability in patients with an

iatrogenically elevated INR, which might falsely drive a MELD score in the context of normal renal and hepatic function.

Study Limitations There are several limitations worth noting in our analysis. First, the timing of the laboratory values to the time of transplant is unknown. We utilized serum bilirubin and creatinine that were recorded at the time of match, so it can be assumed that they represent the hepatic and renal function closes to the time of OHT. Similarly, the date of LVAD implant is not documented, and therefore, the effect of mechanical support on right ventricular function and recovery is unknown. Therefore, we are uncertain whether the reported MELD-XI represents an improvement or decline in hepatic or renal function in patients bridged with an LVAD. Postoperative renal failure requiring dialysis is a binary variable, and therefore, the acuity or chronicity of this dysfunction is indecipherable. Furthermore, as follow-up creatinine and bilirubin are not collected in the Standard Transplant Analysis and Research Files, calculation of a MELD-XI after transplant is precluded. Lastly, analysis is limited to the variables provided in the dataset. It does not include information

Table 6. Predictive Model for Mortality Among Patients Bridged to Orthotopic Heart Transplant With Continuous Flow Left Ventricular Assist Device Thirty-Day Mortalitya MELD-XI Score Increasing MELD-XI, continuous MELD-XI, categoric Low, 10.5 Low-intermediate, 10.6–12.6 Intermediate-high, 12.7–16.4 High, >16.4

One-Year Mortalityb

Five-Year Mortalityc

HR (95% CI)

p Value

HR (95% CI)

p Value

HR (95% CI)

p Value

1.10 (1.07–1.14)

<0.001

1.09 (1.07–1.12)

<0.001

1.07 (1.05–1.09)

<0.001

Ref 0.94 (0.19–1.82) 1.92 (1.08–3.43) 3.08 (1.72–5.53)

0.86 0.03 <0.001

Ref 1.02 (0.68–1.51) 1.54 (1.06–2.23) 2.60 (1.80–3.79)

0.94 0.02 <0.001

Ref 1.01 (0.744–1.38) 1.20 (0.89–1.62) 1.89 (1.38–2.57)

0.94 0.22 <0.001

a b Risk adjusted for recipient (age, sex, mechanical ventilation), donor (age), and operative (sex match, ischemic time) variables. Risk adjusted for recipient (age, body mass index, diabetes mellitus, waitlist duration, extracorporeal membrane oxygenation, mechanical ventilation), donor (cytomegac Risk adjusted for recipient (sex, race, body mass index, diabetes, etiology of heart lovirus positive) and operative (sex match, ischemic time) variables. disease, extracorporeal membrane oxygenation, intensive care unit status, mechanical ventilation), donor (age, body mass index), and operative (sex match, ischemic time) variables.

CI ¼ confidence interval;

HR ¼ hazard ratio;

MELD-XI ¼ Model for End-Stage Liver Disease Excluding INR.

Ann Thorac Surg 2015;-:-–-

regarding anticoagulation status, so the relationship between the MELD and MELD-XI in this unique population is unknown. It is also expected that there are confounders (eg, institutional volume) not accounted for in our riskadjusted models.

Conclusion This is the first known study to evaluate the ability of MELD-XI, which omits INR in its calculation, to predict short-term and long-term outcomes in patients after OHT. Our analysis demonstrated that patients with high MELD-XI scores experienced significantly worse 30-day and 1-year survival and were at risk for requiring postOHT dialysis. Although these findings should not preclude transplantation, it is critical to identify patients at high risk for early morbidity and mortality, as they greatly impact long-term outcomes.

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