Over the last decade the age of liver transplant (LT) recipients and the likelihood of coronary artery disease (CAD) in this population have increased. There are no multicenter studies that have examined the impact of CAD on LT outcomes. In this historical cohort study, we identified adult LT recipients who underwent angiography prior to transplantation at seven institutions over a 12-year period. For each patient we recorded demographic data, recipient and donor risk factors, duration of follow-up, the presence of angiographically proven obstructive CAD (≥50% stenosis) and post-LT survival. Obstructive CAD was present in 151 of 630 patients, the CAD(+) group. Nonobstructive CAD was found in 479 patients, the CAD(−) group. Patient survival was similar for the CAD(+) group (adjusted HR 1.13, CI = [0.79, 1.62], p = 0.493) compared to the CAD(−) group. The CAD(+) patients were further stratified into severe (CADsev, >70% stenosis, n = 96), and moderate CAD (CADmod, 50–70% stenosis, n = 55) groups. Survival for the CADsev (adjusted HR = 1.26, CI = [0.83, 1.91], p = 0.277) and CADmod (adjusted HR = 0.93, CI = [0.52, 1.66], p = 0.797) groups were similar to the CAD(−) group. We conclude that when current CAD treatment strategies are employed prior to transplant, post-LT survival is not significantly different between patients with and without obstructive CAD.
Recent studies have demonstrated a prevalence of coronary artery disease (CAD) in orthotopic liver transplant (LT) candidates as high, or higher, than in the general population (1995, 2001, 2006). Despite the increased prevalence of CAD in LT candidates, there are few studies that have characterized the effect of CAD severity and treatment on the outcome of LT patients (1996, 2008, 2008, 2010). Due to the aging of patients with end-stage liver disease (ESLD), an increasing number of older patients on LT waitlists, and limited organ resources, coronary angiography is increasingly advocated to evaluate LT candidates (2010-2012) Angiography is often employed in place of noninvasive testing in the evaluation of older and higher risk candidates, as noninvasive tests for myocardial ischemia have varying degrees of reliability in LT candidates (2008, 1996, 1998, 2006, 2002, 2009). To date, no multicenter study has investigated the post-LT survival of patients with angiographically proven obstructive CAD.
We report the results of our analysis of 630 patients who underwent angiography prior to LT at seven U.S. institutions over a 12-year period ending in December 2010. Our primary aim is to characterize post-LT survival in patients with angiographically proven obstructive CAD compared to patients without angiographic evidence of obstructive CAD. Our secondary aim is to identify the effects of treated CAD, stratified by severity, on post-LT survival. Based on preliminary single center data, we hypothesized that LT recipients with obstructive CAD have posttransplant survival similar to LT recipients without angiographic evidence of obstructive CAD.
Materials and Methods
Study population and data collection
After Investigational Review Board approval (I.R.B. approval number 10-001807), seven institutions (University of California Los Angeles, University of California San Francisco, University of Pittsburgh Medical Center, Vanderbilt University, Mayo Clinic, Columbia University and Cleveland Clinic) reviewed the medical records of adult patients who underwent a primary LT over a 12-year period ending in December 2010 to identify patients whose pretransplant evaluation included coronary angiography. Patients were identified by a search of the databases at each institution and followed through June 2011 to determine post-LT survival. During the database search, the records of LT recipients were cross-referenced with angiography data collected by the liver transplant and cardiology services at each respective institution. Patients that underwent coronary angiography prior to LT were included in the study. Patients that underwent angiography but did not undergo LT were not included in the study. Patients were selected for preoperative angiography based on established screening criteria at each institution. Angiography was performed on patients over 40 years of age with an abnormal or equivocal noninvasive cardiac stress test, in patients over the age of 50 years with multiple cardiac risk factors including diabetes, and in patients with a previous history of CAD. The preoperative cardiac evaluation paradigms at each center were not standardized and therefore were not identified as a study variable. Catheterization results were categorized as CAD positive (≥50% stenosis of one or more vessels), the CAD (+) group, or negative (<50% stenosis), the CAD(−) group. Coronary stenoses of any major epicardial coronary artery were recorded; some centers reported stenoses of branches of the major coronary arteries. Positive angiography results were further stratified based on the degree of stenosis as severe CAD (>70% stenosis), the CADsev group, or moderate CAD (50–70% stenosis), the CADmod group. In the case of multiple CAs, the angiography prior to the LT was used in the analysis, except in those patients that underwent coronary interventions in which case the angiography performed prior to the intervention was used. Patients with a history of previous remote coronary intervention were stratified to the CADsev group.
Demographic characteristics and survival variables selected from the Scientific Registry of Transplant Recipients (SRTR) risk-adjustment models were compared between the CADsev, CADmod and CAD(−) groups (2012). Demographic characteristics included age, gender and model for end-stage liver disease (MELD) score at the time of LT. Recipient risk factors for survival included a history of renal failure (identified by a history of pre-LT dialysis), organ-perfusion support (pre-LT mechanical ventilation) and post-LT retransplantation (redo LT). Patients with a history of previous LT prior to angiography were excluded. Patients that underwent simultaneous liver kidney transplantation (SLKT) and living-related liver transplantation (LRLT) were included. Donor factors included in the analysis were donor age, race, height, cause of death (COD), partial/split donor organ, donation after cardiac death (DCD), donor location (regional or national) and cold ischemia time (CIT).
All patients underwent standard perioperative surgical and anesthetic management as per the respective institutions. Date of angiography, date of coronary intervention(s) when applicable, date of LT and date of death or last date of follow-up were recorded in all patients.
All cause post-LT mortality was recorded up to the last date of follow-up and was considered the primary outcome. The method of CAD treatment was categorized by type for each patient in the CAD(+) group. Invasive CAD treatment consisted of percutaneous transluminal coronary angioplasty (PTCA), bare metal coronary stenting (BMS), drug eluting coronary stenting (DES), coronary artery bypass graft surgery (CABG) and/or a combination of techniques.
Statistical analysis was performed with SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). We compared demographic characteristics and risk factors across the CAD(−), CADmod and CADsev groups. All results are expressed as mean (SD) for normally distributed continuous variables, median (IQR = interquartile range) for nonnormally distributed continuous variables or n (%) for categorical variables. p-Values for comparing the groups were computed using the Kruskal–Wallis test for continuous variables or the chi-square test for categorical variables. Survival curves by CAD groups were computed using the Kaplan–Meier method and compared across groups using the log-rank test. We used Cox regression to assess the impact of the CAD group on mortality before and after adjustment for the previously described recipient and donor covariates, using the no CAD group as the reference category. The following predictor variables had missing values ranging from 2.2% to 11.3%: donor COD (2.2%), donor race (3.0%), partial/split graft (9.7%), graft location (3.8%), donor age (2.4%), donor height (11.3%) and CIT (2.5%). All missing values were singly imputed using the Markov Chain Monte Carlo (MCMC) method. Predictor variables were selected in the final model if they satisfied p<0.15 using the backward stepwise procedure and/or if they were known to be clinically important with HR in the appropriate direction of ≥1.2 or ≤0.8. We reported the unadjusted and adjusted hazard ratios with corresponding confidence intervals and p-values using the Cox model. We computed the adjusted survival estimates in each group at 6, 12, 24 and 36 months post-LT under the Cox model and compared the estimates in each CAD group with the CAD(−) group. Noninferiority was defined as a ≤ 10% reduction in survival in any of the CAD groups compared to the CAD(−) reference group. Therefore, if the lower confidence bound for the difference between any of the CAD groups and the CAD(−) group is less than 10%, we deem this difference noninferior.
We performed additional analyses to examine the effect of pretransplant coronary intervention on mortality using Cox regression. We used the Cox model-derived mortality rate ratios to assess for the effect of transplant center on mortality.
Based on preliminary data from a single center of 115 LT patients that underwent angiography prior to LT, we performed a power analysis to determine the sample size required to detect a 10% 1-year mortality difference between CADsev and CAD(−) patients. This preliminary data demonstrated a 15% prevalence of CADsev (>70% stenosis) and a 1 year survival in the CAD(−) group of approximately 80%. For a desired power of 80% at a 0.05 significance level, with a median follow-up of 30 months, a total sample size of approximately 640 patients is required (540 subjects in the CAD(−) group and 90 in the CADsev group).
A p-value < 0.05 was considered statistically significant. All significance tests were two-sided.
We identified a total of 630 LT patients that underwent pretransplant angiography at the seven participating centers. Of the 630 patients that underwent preoperative angiography followed by LT, we identified 151 CAD(+) patients and 479 CAD(−) patients. The CAD(+) patients were further stratified by CAD severity into the CADsev (n = 96) and CADmod (n = 55) groups.
Demographic characteristics and recipient and donor organ covariates were compared between the CAD(−), CADmod and CADsev groups (Table 1). The three groups differed significantly by MELD (p < 0.0001) and gender (p = 0.003), and approached significance for recipient age (p = 0.056) and donor cause of death (p = 0.058). The mean MELD ranged from 21 to 26 and was highest in the CAD(−) group and lowest in the CADsev group. For all groups, the mean MELD (SD) was 22 (2010). There were more male patients in the CADmod (86%) and CADsev (78%) groups compared to the CAD(−) group (67%). Mean recipient age ranged from 58 to 61 and was slightly higher in the CADmod group. None of the other factors differed significantly between the groups. Overall, there were 55 SLKT and 29 LDLT. The prevalence of obstructive CAD in our patient population was 23.8%. The median follow-up (or time to death) in all patients was 24.5 months (8.9–45.0). By patient group, the median follow-up was 22.4 (7.8–41.5) in the CAD(−) group, 25.8 (11.8–51.3) in the CADmod group and 28.2 (14.1–55.2) in the CADsev group.
Table 1. Descriptive statistics by the CAD group
CAD (−) n = 479
CAD moderate n = 55
CAD severe n = 96
Data listed as mean ± SD or n (%). CAD = coronary artery disease; MELD = model end-stage liver disease; COD = cause of death; CVA, cerebrovascular accident.
There were 161 deaths (26%) in the entire cohort. There were 44 deaths (29%) in the CAD(+) group and 117 deaths (24%) in the CAD(−) group. We compared survival between the patient groups before and after adjustment for the previously described recipient and donor risk factors (Table 2). There was no difference in both unadjusted and adjusted survival between the CAD(+) and CAD(−) groups (unadjusted HR = 1.05; 95% CI = 0.74–1.49, p = 0.780, adjusted HR = 1.13; 95% CI: 0.79–1.62, p = 0.493) (Figures 1A and B). We also compared survival in the CADmod and CADsev groups to the CAD(−) group before and after adjustment (Figures 2A and B). There was no difference in unadjusted and adjusted survival for both the CADsev group (unadjusted HR = 1.17; 95% CI = 0.78–1.74, p = 0.444, adjusted HR = 1.26; 95% CI 0.83–1.91, p = 0.277) and the CADmod group (unadjusted HR = 0.85; 95% CI = 0.48–1.51, p = 0.576, adjusted HR = 0.93; 95% CI: 0.52–1.66, p = 0.797). Higher MELD, redo LT, and national graft location were associated with higher mortality, while increased donor height was associated with a lower mortality (Table 3). In addition we compared adjusted survival in all CAD groups to the CAD(−) group at the following times post-LT: 6 months, 12 months, 24 months and 36 months (Table 4). The survival of the CAD(+) group was not inferior to the CAD(−) group in the first 24 months post-LT. The survival of the CADmod group was not inferior to the CAD(−) group in the first 36 months post-LT, and the survival of the CADsev group was not inferior to the CAD(−) group in the first 6 months post-LT.
Table 2. Summary of unadjusted and adjusted survival by CAD group
Table 3. Cox regression results for the assessment of the CAD group versus mortality after LT adjusting for the covariates
HR (95% CI)
CAD = coronary artery disease; LT = liver transplant; HR = hazards ratio; CI = confidence interval; MELD = model end-stage liver disease; DCD = donation after cardiac death; CIT = cold ischemia time; COD = cause of death.
*Versus anoxia/CVA/living donor. **Not included in final model because p > 0.15 and 0.8 < HR < 1.2.
MELD (per unit)
1.04 (1.02, 1.06)
Recipient age >55 years
1.30 (0.92, 1.84)
0.69 (0.43, 1.08)
Pre-LT mechanical ventilation
1.29 (0.71, 2.35)
2.82 (1.67, 4.78)
HR (95% CI)
1.45 (0.77, 2.74)
Donor age (years)
1.01 (1.00, 1.02)
Donor height (cm)
0.98 (0.97, 1.00)
Partial/split graft (vs. whole)
CIT (> 10 h)
Location: regional (vs. local)
1.14 (0.80, 1.61)
Location: national (vs. local)
1.66 (1.02, 2.69)
Donor COD: trauma*
1.22 (0.84, 1.76)
Donor COD: other*
1.44 (0.71, 2.91)
Donor race: African American (vs. white)
Donor race: other (vs. white)
Table 4. Adjusted survival by group: CAD (−), CAD (+), CADmod and CADsev (noninferiority assessments)
Adjusted survival by group
Adjusted% difference in survival versus CAD (−) group
90.4 ± 1.2%
89.2 ± 1.9%
−1.2% (−5.65, 3.22%)
85.7 ± 1.6%
83.9 ± 2.5%
−1.8% (−7.63, 4.12%)
81.2 ± 1.9%
78.9 ± 3.1%
−2.2% (−9.37, 4.90%)
77.3 ± 2.2%
74.7 ± 3.6%
−2.6% (−10.88, 5.63%)
CAD = coronary artery disease; FU = follow-up; adjusted survival data presented as% survival ± standard error; adjusted% difference in survival data presented as% difference (95% CI).
90.4 ± 1.2%
91.1 ± 2.5%
88.1 ± 2.4%
0.7% (−4.9, 6.2%)
−2.3% (−7.6, 2.9%)
85.7 ± 1.6%
86.7 ± 3.6%
82.3 ± 3.2%
1.0% (−6.7, 8.8%)
−3.4% (−10.4, 3.7%)
81.2 ± 1.9%
82.5 ± 4.6%
77.0 ± 4.0%
1.3% (−8.4, 11.0%)
−4.3% (−12.9, 4.4%)
77.3 ± 2.2%
78.8 ± 5.4%
72.3 ± 4.6%
1.5% (−9.9, 12.9%)
−5.0% (−14.9, 5.0%)
There were 80 patients that underwent coronary interventions prior to LT (nine patients with moderate CAD and 71 patients with severe CAD): two patients underwent PTCA alone, 46 patients underwent stent placement (15 DES and 32 BMS), 32 patients underwent CABG (five underwent combined LT/CABG) and five patients underwent a combination of coronary interventions. There were 71 patients (47%) (25 in the CADsev group and 46 in the CADmod group) that received no pre-LT coronary intervention. Patients with a history of a remote coronary intervention prior to angiography were categorized as having severe CAD (n = 17). To further examine the effect of pre-LT intervention on mortality, we divided all of the CAD patients (n = 151) by the presence of intervention (n = 80, 53%) and no intervention (n = 71, 47%) and compared the unadjusted and adjusted survival of these two groups with the CAD(−) group (n = 479) (Table 2). The intervention group had higher mortality compared to the CAD(−) group, which approached statistical significance (unadjusted HR = 1.42; 95% CI: 0.95–2.12, p = 0.087, adjusted HR = 1.45; 95% CI: 0.95–2.21, p = 0.086).
Multivessel disease, defined as more than one vessel with 50% or greater stenoses, was identified in 77 patients, representing 51% of the CAD(+) group. We compared survival between patients with single versus multivessel CAD (Table 5). Multivessel disease was not associated with increased mortality before or after adjusting for covariates (HR 0.94, p = 0.849; HR 0.75 p = 0.401, respectively). Multivessel CAD was significantly more frequent in the intervention group (65%) than in the nonintervention group (35%), p = 0.0003.
Table 5. Survival: multivessel versus single vessel CAD
We also investigated the center effect. There were significant differences between centers in number of patients, distribution of CAD groups, and MELD (p = 0.0001). The effect of the CAD group on mortality was unchanged after adjustment for center effect. We were unable to measure interactions between patient groups and centers as the sample sizes of each center were insufficient.
The primary finding of this multicenter study is that, when current preoperative CAD treatment strategies are employed, survival after liver transplantation is similar in patients with and without obstructive CAD as documented by angiography. This is true before and after adjustment for donor and recipient risk factors. Furthermore, similar survival was observed between patients without angiographic evidence of CAD compared to patients with varying degrees of CAD severity.
We chose a survival difference of 10 percentage points as significant, since other known but not exclusionary risk factors for post-LT survival fall into this range, such as pre-LT mechanical ventilation, dialysis and retransplantation (2004, 2004). We chose to define obstructive CAD as 50% or greater diameter stenosis based on well-established standards (2001, 1986, 1994, 1989). We recognize that many patients in the CAD(−) group may actually have mild, nonobstructive CAD. We categorized the groups with no CAD and mild CAD together based on a report of similar long term mortality (1986). We chose patients without angiographic evidence of CAD as the comparator group to avoid the inclusion of patients who were evaluated exclusively with noninvasive CAD testing due to concerns over the lack of reliability of noninvasive CAD screening methods in the LT candidate population (2008, 1996, 1998, 2006, 2002, 2009).
Previously, few patients over the age of 50 were referred for LT and advanced CAD was considered a contraindication to liver transplantation (1996). As the U.S. population ages, so does the cohort of patients with ESLD (2007). With improvements in post-LT outcomes, age limits for LT candidates have been relaxed, as illustrated by the increased number of patients over age 65 that have entered the UNOS waitlist (2007, 2004). Early studies suggested that the prevalence of CAD in patients with ESLD was lower than the general population (1981). However, recent studies have shown that the prevalence of CAD in LT candidates is equal to or greater than the general population, with a prevalence approaching 25% (1995, 2001, 2006).
Despite the prevalence of CAD in LT candidates, the impact of CAD on the survival of LT patients has not been extensively studied. In three studies that address the risk of CAD in LT candidates that underwent preoperative angiography, the number of patients with CAD is small, ranging from 21 to 47 (2008, 2008, 2010). Furthermore, the mortality rates described in these studies vary considerably. In one of the earliest series reported by Plotkin, 32 LT recipients with angiographically proven CAD had an overall mortality of 50% over a 1- to 3-year follow-up period. Nearly a third of the deaths occurred within 3 months of LT (1996). Our data conflict with these results, suggesting that patients with a history of severe CAD, the majority of whom had undergone preoperative coronary intervention, can safely undergo LT and are not at a higher risk for short-term mortality. Our study was not designed to evaluate the effects of CAD treatment on post-LT survival. However, post-LT survival in patients with CAD appears to have improved over the last two decades, based upon our results compared to those of Plotkin. A combination of factors may be responsible, including improvements in the management of coronary risk factors, new drug therapy and new interventional techniques. Of note, only one of the 32 patients in Plotkin's report was treated with a percutaneous technique (PTCA), and none received stents. It is unclear to what degree a single factor, such as the availability of coronary stenting, accounts for the improvement in post-LT survival in patients with obstructive CAD.
We performed several additional exploratory analyses. We examined adjusted survival in the CAD(+), CADsev and CADmod groups at fixed time points (Table 4). The difference in survival between the CAD(+) and CAD(−) groups appears similar (1.2–2.6% inferior in the CAD(+) group) over 36 months. However, the certainty of this difference decreases over time (as exhibited by the widening confidence intervals) due to fewer patients in study. We also performed a subanalysis of the 80 CAD(+) patients that underwent a preoperative coronary intervention to compare their survival with the CAD(−) group, although our study was not a priori powered for this comparison (Table 2). This evaluation revealed a trend toward decreased survival in patients that underwent preoperative coronary intervention. Long-term (>1 year) survival rates following interventions such as PCI and CABG are known to be inferior to patients without obstructive CAD (1986, 2007, 2005). OLT recipients with a significant burden of CAD, identified by the need for revascularization, may be expected to have a progression of their CAD following LT secondary to the effects of chronic immunosuppression (2002). Vigorous post-LT CAD surveillance and aggressive CAD risk factor modification in recipients with advanced CAD is warranted.
Our patient groups are not representative of the overall pool of LT candidates. Patients that undergo angiography are older and have a higher likelihood of chronic illness. According to the OPTN/SRTR 2010 Annual Report, adjusted 1-year survival for all deceased donor LTs performed in the United States from 2000 to 2008 (roughly the time period of our study) was 86.6–90.2% (S.E. 0.4–0.5%). Our results demonstrate a 1-year survival of 85.7% in the CAD(−) group and 83.9% in the CAD (+) group. Three-year survival in the 2010 annual report was 79.4–81.2% (S.E. 0.5–0.6%), and in our patients, 3-year survival is 77.3% in the CAD(−) group and 74.7% in the CAD(+) group. The differences in our survival data, compared to national data, are likely due to increased age, which are known to adversely impact long-term survival. The OPTN/SRTR 2010 Annual Report adjusts survival by recipient age. For recipients 50–64 years of age, 1-year survival was 86.1% (95% C.I. 85.3, 86.8) and 3-year survival was 76.9% (95% C.I. 76.0, 77.8). These results are very similar to our study group results, and reinforce the importance of patient age on LT survival. (2011).
This study has a number of limitations. Our study was a retrospective analysis of previously recorded medical data from seven centers. Potential biases due to the retrospective nature of this study may have occurred; overall survival was chosen as our primary outcome to minimize bias. Nevertheless, bias may remain if we failed to adjust for covariates that affected survival. We were unable to acquire a complete list of every LT candidate that presented for evaluation during the study period. Therefore, our methods did not allow us to comprehensively identify candidates that underwent angiography and then, for various reasons, did not undergo LT. Candidates may have died or may have been removed from the wait-list for non-CAD criteria. Some patients may have been excluded because of advanced CAD. Complications from angiography and/or coronary interventions that were not identified in our cohort may have contributed to morbidity or mortality that resulted in a candidate's exclusion from transplantation. Likewise, our retrospective methods did not allow us to comprehensively identify post-LT nonfatal cardiac complications or to determine cause of death. Preoperative information such as cardiac symptomatology, noninvasive stress testing results, ventricular function and exercise tolerance were not evaluated in this study. Our methods of classifying patients to CAD(−) and CAD(+) groups were based solely on the angiography report in their medical records. There was no review of coronary angiograms by an independent reviewer; however, this reflects the current standard. There may have been center differences in the interpretation of coronary angiograms that went undetected in our analysis. Our definition of CAD as ≥50% stenosis is based on previously published studies of angiographic standards used to define clinically significant obstructive CAD (2001, 1986, 1994, 1989). The degree of coronary stenosis that is clinically significant in the LT candidate is unknown, and does not take into account the presence of ruptured plaque or other pathology that is thrombogenic independent of obstructive CAD. The prevalence of CAD differed widely by center, reflecting differences in CAD detection and treatment paradigms that were not consistent. Although we attempted to evaluate adjusted mortality by transplant center, the sample sizes at each center were too small to determine interactions between center and mortality. We did not include CAD risk factors as covariates in our analysis, since intermediary factors are highly correlated and not independent of angiographic results. Nevertheless, differences between the CAD(+) and CAD(−) groups in factors that affect survival through mechanisms other than CAD may have had an impact on survival that we could not detect.
This is the first multicenter study of survival in LT recipients with angiographically proven CAD. When current CAD treatment strategies are employed there is no significant difference in post-LT survival between patients with and without obstructive CAD. Our results demonstrate that patients with obstructive CAD that have been selected as appropriate transplant candidates can undergo LT and have acceptable survival when compared to a historical age-matched cohort. As with other nonexclusionary risk factors such as renal failure, pre-LT mechanical ventilation and retransplantation, our results suggest that obstructive CAD should not preclude transplantation. The implications of these findings are significant. Given the aging of the LT candidate population, the known risks of cardiac disease and the shortage of donor organs, our results provide evidence that the use of donor organs in patients with obstructive CAD is warranted.
Dr. Wray had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Literature search, study design, data collection, data analysis, data interpretation, writing of the manuscript and creation of the figures: C.W. Literature search, study design, data analysis, data interpretation, writing of the manuscript and creation of the figures: R.H.S. Data collection, data analysis, data interpretation and creation of the figures: J.C.S. Data analysis, data interpretation, statistical analysis, writing of the manuscript and creation of the figures: D.M. Data collection, data analysis, data interpretation, writing of the manuscript and review of drafts: J.F. Collection, analysis, interpretation of the data and review of drafts: C.U.N., R.P., A.W., G.W., J.B.C. Analysis and interpretation of the data, writing of the manuscript, and review of the drafts: J.T. Interpretation of data and review of drafts: R.B. Collection, analysis and interpretation of the data: C.H., A.H., A.O., R.S.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.