Multivessel Coronary Artery Disease Predicts Mortality, Length of Stay, and Pressor Requirements After Liver Transplantation

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1 LIVER TRANSPLANTATION 16: , 2010 ORIGINAL ARTICLE Multivessel Coronary Artery Disease Predicts Mortality, Length of Stay, and Pressor Requirements After Liver Transplantation Celina M. Yong, 1 Madan Sharma, 1 Victor Ochoa, 1 Freddy Abnousi, 1 John Roberts, 2 Nathan M. Bass, 2 Claus U. Niemann, 3 Stephen Shiboski, 4 Megha Prasad, 1 Mehdi Tavakol, 2 Thomas A. Ports, 1 Gabriel Gregoratos, 1 Yerem Yeghiazarians, 1 and Andrew J. Boyle 1 1 Division of Cardiology, Department of Medicine; 2 Division of Transplantation, Department of Surgery; 3 Department of Anesthesia and Perioperative Care; and 4 Department of Epidemiology and Statistics, University of California San Francisco, San Francisco, CA The optimal preoperative cardiac evaluation strategy for patients with end-stage liver disease (ESLD) undergoing liver transplantation remains unknown. Patients are frequently referred for cardiac catheterization, but the effects of coronary artery disease (CAD) on posttransplant mortality are also unknown. We sought to determine the contribution of CAD and multivessel CAD in particular to posttransplant mortality. We performed a retrospective study of ESLD patients undergoing cardiac catheterization before liver transplant surgery between August 1, 2004 and August 1, 2007 to determine the effects of CAD on outcomes after transplantation. Among 83 patients who underwent left heart catheterization, 47 underwent liver transplantation during the follow-up period. Twenty-one of all ESLD patients who underwent liver transplantation (45%) had CAD. Fifteen of the transplant patients with CAD (71%) had multivessel disease. Among transplant patients, the presence of multivessel CAD (versus no CAD) was predictive of mortality (27% versus 4%, P ¼ 0.046), increased length of stay (22 versus 15 days, P ¼ 0.050), and postoperative pressor requirements (27% versus 4%, P ¼ 0.029). Interestingly, neither the presence of any CAD nor the severity of stenosis in any single coronary artery predicted mortality. Furthermore, none of the traditional clinical predictors (age, gender, diabetes, creatinine, ejection fraction, and Model for End-Stage Liver Disease score) were predictive of mortality among transplant recipients. In conclusion, multivessel CAD is associated with higher mortality after liver transplantation when it is documented angiographically before transplantation, even in the absence of severe coronary artery stenosis. This study provides preliminary evidence showing that there may be significant prognostic value in coronary angiography as a part of the pretransplant workup. Liver Transpl 16: , VC 2010 AASLD. Received February 1, 2010; accepted June 11, For patients with end-stage liver disease (ESLD), the only definitive treatment is orthotopic liver transplantation (OLT). However, OLT carries substantial morbidity and mortality risks because of the posttransplant hypercoagulable state, 1,2 stresses associated with major abdominal surgery, 3 vascular complications, 4 and hemodynamic shifts in the setting of high resting cardiac output and low systemic vascular resistance (SVR). 5 Because of these risks and limited organ availability, transplant centers aim to optimize the allocation of resources and posttransplant outcomes thorough pretransplant workups. In addition to a history, physical examination, electrocardiogram (ECG), chest X-ray (CXR), and echocardiogram, various strategies for the evaluation of coronary artery disease (CAD) may be pursued, with the Abbreviations: CAD, coronary artery disease; CXR, chest X-ray; ECG, electrocardiogram; EF, ejection fraction; ESLD, end-stage liver disease; LAD, left anterior descending; LHC, left heart catheterization; MELD, Model for End-Stage Liver Disease; OLT, orthotopic liver transplantation; RHC, right heart catheterization; SVR, systemic vascular resistance; TTE, transthoracic echocardiogram; UCSF, University of California San Francisco. Address reprint requests to Andrew J. Boyle, M.B.B.S., Ph.D., Division of Cardiology, Department of Medicine, University of California San Francisco, 505 Parnassus Avenue, Box 0124, San Francisco, CA Telephone: ; FAX: ; aboyle@medicine.ucsf.edu DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2010 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 16, No. 11, 2010 YONG ET AL chosen strategy depending on the transplant center. The cardiac evaluation may include dobutamine stress echocardiography, nuclear myocardial perfusion imaging, computed tomography angiography, or left heart catheterization (LHC). Besides previously known CAD, indications for coronary angiography generally include 1 or more major risk factors for CAD or abnormal noninvasive testing. However, there is little evidence regarding which methods of cardiac evaluation predict posttransplant outcomes. Current guidelines for preoperative cardiac evaluations before noncardiac surgery are based on studies of patient cohorts not undergoing liver transplantation, so the optimal preoperative cardiac evaluation for liver transplant patients remains unknown. It was originally believed that liver disease had a protective effect against CAD. This protective effect was initially supported by early autopsy studies showing evidence of less atherosclerosis and myocardial infarction in patients with cirrhosis versus patients without cirrhosis. 6 At the time, it was theorized that a protective effect in cirrhosis might be secondary to lower blood pressures from peripheral vasodilation and improved lipid profiles. 7,8 However, more recent literature 9 13 has indicated that the incidence of CAD ranges from 2.5% to 27% in ESLD patients, and this is at least comparable to, if not greater than, the rate in the general population. Furthermore, the effects of CAD on outcomes after OLT remain incompletely characterized. We therefore sought to define the prevalence of angiographically proven CAD in our patients with ESLD and to assess whether CAD has prognostic significance for outcomes after liver transplantation in a contemporary US setting. PATIENTS AND METHODS The study was approved a priori by the University of California San Francisco (UCSF) Committee on Human Research. A retrospective search of the cardiac catheterization database was performed for procedures performed with the clinical indication of liver failure. Patients being considered for OLT at our institution undergo a standard cardiac workup including a history, physical examination, ECG, CXR, and transthoracic echocardiogram (TTE; Fig. 1). In addition, selected moderate-risk patients also undergo myocardial perfusion imaging (exercise or pharmacological). If patients are determined to be at high risk because of a history of more than 1 major cardiac risk factor, abnormal noninvasive testing, or an ejection fraction (EF) < 60% in the setting of low SVR, they undergo further testing with coronary angiography. We identified 510 ESLD patients consecutively evaluated for liver transplantation at UCSF from August 1, 2004 to August 1, 2007; 129 underwent cardiac catheterization (Fig. 2). Eighty-three of those who underwent cardiac catheterization underwent LHC, and we have previously described the rate of complications of cardiac catheterization in this cohort. 14 Figure 1. UCSF protocol for the cardiac evaluation before liver transplantation. *Major risk factors include tobacco, hyperlipidemia, diabetes mellitus, and hypertension. **Minor risk factors include male gender, postmenopausal status, and a family history of premature CAD. Forty-seven of all ESLD patients who underwent LHC ultimately received a liver transplant. The etiologies of liver disease for the 83 patients who were evaluated for liver transplant were as follows: 36% had hepatitis C, 23% had alcoholic liver disease, 14% had hepatitis B, 6% had nonalcoholic steatohepatitis, and 21% had less common causes (including amyloidosis, alpha-1 antitrypsin deficiency, primary sclerosing cholangitis, primary biliary cirrhosis, cryptogenic cirrhosis, and acetaminophen overdose). Additionally, 24% of the patients also had hepatocellular carcinoma in addition to one of the aforementioned diagnoses. The single patient evaluated for liver transplantation because of acetaminophen overdose recovered and ultimately did not receive a transplant, so no patients underwent transplantation for acute hepatic failure. We focused our analysis on the population of 47 ESLD patients who underwent both LHC and liver transplantation. To minimize variability in the results, a single cardiologist retrospectively completed quantitative coronary angiography on all patients who underwent LHC. He was blinded to the outcomes of all patients. Coronary artery stenosis was assessed in the left anterior descending (LAD) artery, right coronary artery, left circumflex artery, left main artery, and ramus intermedius artery (if present). The severity of CAD [defined as mild (<50% stenosis), moderate (50%-70%

3 1244 YONG ET AL. LIVER TRANSPLANTATION, November 2010 TABLE 1. Baseline Clinical Data for All Liver Patients and Transplant Patients Figure 2. ESLD patient population. Numbers in parentheses indicate the number of patients who progressed to each stage of liver transplant evaluation and the breakdown of CAD among them as determined by LHC. All Liver Patients (n ¼ 83) Transplant Patients (n ¼ 47) Age (years) Gender, male/female (%) 58/42 58/42 Weight (kg) Body mass index (kg/m 2 ) EF (%) MELD score on date of LHC MELD score on date of transplant Heart rate (bpm) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Hemoglobin (g/dl) Hematocrit (%) Platelet count (10 9 /L) Creatinine (mg/dl) Diabetes (%) Etiology of liver disease Hepatitis C (%) Hepatitis B (%) Alcoholic liver disease (%) Nonalcoholic 6 9 steatohepatitis (%) Other (%) Concomitant hepatocellular carcinoma (%) Treatment Beta-blocker (%) Statin (%) Aspirin (%) Angiotensin-converting enzyme inhibitor (%) 10 7 stenosis), or severe (>70% stenosis in at least 1 major coronary artery)] and single-vessel involvement versus multivessel involvement (multivessel involvement was defined as stenosis of any severity affecting more than 1 vessel) were noted. Relevant demographic information and clinical parameters, including age, gender, diabetes, serum creatinine as a continuous variable (measured within 48 hours before LHC, the time at which patient risk is assessed), EF, and Model for End-Stage Liver Disease (MELD) score, were collected by chart review. 15 The clinical outcomes of all-cause mortality within 12 months of transplantation, the pressor requirements (a vasoconstrictor and/or an inotrope) within 5 days after transplantation, and the length of stay (days) for transplant hospitalization were also obtained by chart review. Data for mortality at 12 months were available for 100% of the transplant patients. Demographic data are presented as means and standard deviations unless otherwise stated. The association between predictor variables and binary outcomes (mortality and pressor requirements) was first examined with Fisher s exact test for categorical predictors or with the Wilcoxon rank-sum test for continuous predictors. Relationships between predictor variables with more than 2 categories and length of stay were examined with the Kruskal-Wallis test. Linear regression was used for continuous outcomes, and logistic regression was used for binary outcomes. Regression models included age, gender, diabetes, and serum creatinine as adjustment variables. All statistical tests were 2-sided and were based on 5% significance levels. Statistical analysis was performed with STATA version 10 (StataCorp, College Station, TX). RESULTS During the study period, 403 patients underwent liver transplantation at our center with an overall 12- month mortality rate of 9%. Eighty-three ESLD patients were referred for pretransplant LHC during the 3-year study period; 47 ultimately received a liver transplant during the same 3-year period. All-cause mortality was assessed 12 months after transplantation. Patient demographics are listed in Table 1. The prevalence of CAD in all 83 ESLD patients who underwent LHC was 43% (36/83); 13% (11/83) had single-vessel disease, and 30% (25/83) had

4 LIVER TRANSPLANTATION, Vol. 16, No. 11, 2010 YONG ET AL Figure 3. Multivessel CAD predicted posttransplant outcomes: (A) the mortality rate 1 year after transplantation (P ¼ 0.046, n ¼ 47), (B) the hospitalization length of stay (P ¼ 0.050, n ¼ 47), and (C) postoperative pressor requirements (P ¼ 0.029, n ¼ 47). multivessel disease. In terms of the severity of stenosis in patients with any CAD, 8% (3/36) had severe stenosis, 47% (17/36) had moderate stenosis, and 44% (16/36) had mild stenosis. Among the subset of 47 patients who received a liver transplant, 45% (21/47) had some degree of CAD. With respect to the extent of CAD, 13% (6/47) had single-vessel disease, and 32% (15/47) had multivessel disease. Thus, among transplant patients with any degree of CAD, the majority had multivessel disease (71%; 15/21). As for the severity of stenosis among transplant patients with CAD, 10% (2/21) had severe stenosis, 52% (11/21) had moderate stenosis, and 38% (8/21) had mild stenosis. In terms of the location of stenosis, no patients had left main disease greater than 50%. Among those with LAD disease, only 1 patient had proximal LAD disease; the remaining patients had mid-lad disease. The single patient with proximal LAD disease survived. Thus, the location of the disease in the left main or proximal LAD coronary arteries was not associated with outcomes in our patient population. When we compared patients with multivessel CAD who received OLT versus patients without CAD who received OLT, we found no statistically significant differences in the donor risk parameters of age, gender, height, weight, cause of death, donation after cardiac death, and cold time. No patients who were evaluated for liver transplantation with cardiac catheterization were excluded from the transplant list because of a cardiac cause, and this indicated that the information from LHC was used only to determine whether further cardiac therapeutic intervention might be warranted before transplantation. For the patients who were evaluated but ultimately did not receive a liver transplant, the reasons for delisting included mental and social problems, follow-up failure, resolution of liver disease (eg, acetaminophen overdose), and death from noncardiac causes. One of the 2 transplant patients who had severe stenosis received percutaneous coronary intervention before successful liver transplantation, and the other, who had multivessel disease, died after combined liver transplantation and coronary artery bypass graft surgery. The decision to intervene in the severe stenosis of these 2 patients was made after LHC when the severe stenosis was identified and before transplantation with the hope of optimizing posttransplant outcomes. All other patients who received OLT did not undergo prior revascularization. Because only 1 patient was stented before transplantation, it is also unlikely that the impact of medication compliance with clopidogrel and aspirin affected mortality outcomes. Intraoperative transfusion requirements were higher among patients with multivessel CAD versus those without CAD (platelets, 1180 versus 492 ml, P ¼ 0.02; cell saver, 2020 versus 725 ml, P ¼ 0.02; packed red blood cells, 2350 versus 1250 ml, P ¼ 0.09; fresh frozen plasma, 2860 versus 2910 ml, P ¼ 0.9; estimated blood loss, 12,400 versus 3290 ml, P ¼ 0.2), but these increased transfusion requirements per se did not correspond to a statistically significant increase in posttransplant mortality (by the Wilcoxon rank-sum test). We found that the relationship of CAD with outcomes was dependent on the extent of CAD rather than the severity of stenosis. Patients with multivessel CAD had higher mortality within 12 months of transplant than patients with normal coronary arteries (27% versus 4%, P ¼ by univariate analysis with Fisher s exact test; Fig. 3A). As a reference, the 12-month mortality rate for all liver transplant recipients at UCSF during this period was 9%. The unadjusted odds ratio for 12-month mortality among multivessel CAD patients versus those without any CAD was 9.1 (95% confidence interval ¼ ). After multivariable regression analysis adjusted for age, gender, diabetes, and serum creatinine, the odds ratio for 12- month mortality among multivessel CAD patients versus those without any CAD was 12.6 (95% confidence

5 1246 YONG ET AL. LIVER TRANSPLANTATION, November 2010 interval ¼ ). In comparison with ESLD patients with normal coronary arteries, the presence of multivessel CAD also predicted a longer hospital length of stay ( versus days, P ¼ 0.050; Fig. 3B) and increased pressor use within 5 days after transplantation (27% versus 4%, P ¼ 0.029; Fig. 3C). As a reference, the transplant hospitalization length of stay is 10.4 days on average for all liver transplant recipients at UCSF. Although the severity of CAD (mild, moderate, or severe) based on the degree of luminal stenosis did not predict mortality, it was associated with higher rates of pressor use (100% in patients with severe stenosis versus 4% in patients with normal coronary arteries, P ¼ 0.002). That is, both the severity of CAD and the presence of multivessel CAD correlated with increased pressor usage. In this cohort, the presence of any degree of CAD was not associated with increased mortality, pressor requirements, or length of stay. None of the following clinical parameters predicted mortality after liver transplantation: age, gender, diabetes, elevated serum creatinine, EF, and MELD score. Elevated serum creatinine was associated with increased pressor use (odds ratio ¼ 7.1, 95% confidence interval ¼ , P ¼ 0.04) only. The MELD score at the time of transplant showed a trend toward being higher in patients who died within 12 months of transplant, but this was not statistically significant ( versus , P ¼ 0.08). Within 1 week after liver transplantation, the incidence of development of congestive heart failure or ST-elevation myocardial infarction was zero. A review of the causes of death for the 5 patients who died after liver transplantation in our population showed that the etiologies included respiratory and renal failure, but none died from congestive heart failure or ST-elevation myocardial infarction. When the data were reanalyzed without the single patient who underwent combined coronary artery bypass graft surgery and liver transplantation, there was no change in the significance of our outcomes. DISCUSSION In our cohort of patients referred for preoperative cardiac catheterization, we report for the first time that multivessel CAD is the most powerful predictor of outcomes following liver transplantation, regardless of the severity of coronary stenoses. We found a high prevalence of CAD and, more importantly, multivessel CAD in these patients. Until now, there has been no evidence indicating that determining the extent of CAD before transplantation could predict any outcomes among posttransplant patients. The prevalence of CAD in our liver transplant population is in keeping with previous studies. Tiukenhoy- Laing et al. 13 reported a 26% prevalence, and Donovan et al. 11 reported a 25% prevalence by LHC. When McAvoy et al. 16 evaluated coronary artery calcification with thoracic computed tomography scans, they found that 37.6% had at least moderate coronary calcification. Our study indicates a 45% prevalence of CAD among OLT patients. This higher percentage could reflect our method of quantitative coronary analysis, in which we reported all degrees of stenosis rather than only stenoses above a certain threshold. If we separate out the patients with severe stenosis (>70%), our percentage of 4% correlates well with the cited prevalence of 5% by Morris et al., 10 5% by Plotkin et al., 9 and 6.5% by Safadi et al. 17 In 1996, Plotkin et al. 18 raised the suspicion that CAD may be detrimental to outcomes following OLT. They retrospectively examined patients with a historical diagnosis of CAD, some of whom had been revascularized, and they reported their postoperative mortality. In their study, only 9 patients underwent transplantation without prior revascularization; this was too small a number for any firm conclusions to be made, and they had no contemporaneous control group for comparing outcomes. In 2008, Diedrich et al. 19 examined the relationship between CAD and post liver transplant mortality, and they found a 1-year mortality rate of 12% in 42 patients with CAD versus 2% in those without CAD undergoing OLT, but this was not statistically significant. Most recently, in a retrospective study of 403 patients who underwent OLT, Safadi et al. 17 found conflicting results with respect to whether a history of CAD was predictive of death within 30 days of OLT. In their univariate analysis, it was predictive; however, in their multivariate analysis, the association was absent. These previous studies are consistent with our finding that the presence of CAD alone was not significantly associated with mortality at 1 year. However, no previous studies have stratified patients by the extent of CAD, which in our cohort showed a statistically significant association. After demonstrating a significant association between multivessel CAD and mortality, we performed a regression analysis to control for clinical factors. Although this small group had a large 95% confidence interval, by controlling for clinical factors, we showed that multivessel CAD maintained a powerful association with mortality after transplantation, and this suggested that in this group, the extent of CAD was the dominant factor driving 12-month mortality. Therefore, identifying patients with a greater bulk of atherosclerotic CAD, as evidenced by multivessel disease, may provide more powerful prognostic information in this patient group than simply the presence of CAD examined in previous studies. Most existing preoperative evaluations focus on the functional significance of coronary artery stenoses; therefore, stress testing is the mainstay of preoperative evaluation. Our data suggest that this may not be sufficient. For example, a patient with 50% lesions in all 3 major coronary arteries may have a negative functional study because the lesions may not be detected by nuclear perfusion imaging or stress echocardiography. Although the functional study would clear that patient for surgery, on the basis of our data, this patient would likely be at higher risk for 12-month mortality after liver transplant surgery.

6 LIVER TRANSPLANTATION, Vol. 16, No. 11, 2010 YONG ET AL This would be missed without an imaging modality that visualizes the coronary anatomy, such as invasive coronary angiography or computed tomography coronary angiography. Thus, the results of our study should make us cautious about the interpretations of negative noninvasive stress tests, which we usually interpret to have a strong negative predictive value; however, they may not accurately reflect the subset of patients with multivessel disease who are at a higher mortality risk versus those with no coronary disease. The need for an appropriate preoperative evaluation of cardiac risk is highlighted by the fact that as surgical transplant methods improve over time, the inclusion criteria for OLT candidates are expanding to allow older patients the opportunity to undergo OLT. In the 1980s, the age limit for most transplant programs was 50 years. However, since the 1990s, the age limit has been pushed beyond 60 years. According to the United Network for Organ Sharing database, the average age of OLT patients increased from 43 to 49 years from 1988 to Because CAD increases with age, 21 this raises concerns about ischemia as a major cause of postoperative morbidity and mortality. Audet et al. 22 specifically studied the outcomes of OLT recipients over the age of 65 years (34 of 502 transplant patients). In comparison with the younger transplant recipients, they found 2 significant differences: a higher prevalence of CAD in the older patients (50% versus 12% among the younger patients) and a higher rate of mortality secondary to cardiac causes in the older patients (8.8% versus 1.4% among the younger patients). In reviewing 735 patients, Zetterman et al. 23 found that in liver transplant recipients 60 years old or older, there were lower patient survival rates, mostly because of nonhepatic causes such as cardiac disease. These preliminary data have heightened concerns about increased cardiac risk associated with the aging transplant recipient population. In our study, CAD was a more powerful predictor of outcomes than age. Interestingly, our findings showed that none of the traditional clinical predictors of CAD were significantly correlated with mortality outcomes. Carey et al. 7 found diabetes mellitus to be an independent risk factor for CAD in ESLD patients. The MELD score, 15 elevated serum creatinine levels, 24 and age 25 have also been previously reported to independently predict post-olt mortality. Although we did not find these factors to be significantly prognostic, we did see that these clinical factors trended toward a prediction of mortality in our cohort. The most likely reason that we did not find statistically significant results for known traditional predictors of CAD and posttransplant mortality is our small numbers. However, the fact that we still showed that multivessel CAD was a predictor of mortality adds further weight to the robustness of our findings with respect to multivessel disease. This study has several limitations. It is a retrospective data analysis rather than a prospective cohort study and thus has limitations inherent to this type of analysis. The number of patients is small, and the follow-up period is only 12 months; however, the study evaluates a very select patient population. In addition, this is a single-center study; as such, the outcomes of liver transplantation in terms of mortality, length of stay, and pressor use may be unique to our medical center. Furthermore, because we did not pursue cardiac catheterization of all liver transplant recipients, we do not know whether this applies to the wider liver transplant population. We studied only high-risk patients as determined by the UCSF screening protocol because it would have been unethical to expose all ESLD patients to the risks of LHC if they did not have any risk factors. Therefore, our results are limited to only those referred for coronary angiography and cannot be extrapolated to those who are not predetermined to be at high risk. Some patients who underwent liver transplantation at our center received their preoperative coronary angiography at another center and were therefore not included in this analysis. However, our study is strengthened by the inclusion of contemporaneous controls from the same patient cohort, and this is a relatively large cohort in comparison with previously published series. We believe that these preliminary data can inform future clinical studies examining the use of preoperative screening in predicting outcomes following liver transplantation. Multivessel CAD is associated with higher mortality after liver transplantation when it is documented angiographically before transplantation, even in the absence of severe coronary artery stenosis. Traditional clinical predictors alone, such as age, gender, elevated serum creatinine, diabetes, and EF, may be insufficient for predicting mortality risk after transplantation. This study provides preliminary evidence showing that there may be significant prognostic value in defining the coronary artery anatomy as a part of the pretransplant workup. REFERENCES 1. Stahl R, Duncan A, Hooks MA, Henderson JM, Millikan WJ, Warren WD. A hypercoagulable state follows orthotopic liver transplantation. Hepatology 1990;12: Porte RJ. Coagulation and fibrinolysis in orthotopic liver transplantation: current views and insights. Semin Thromb Hemost 1993;19: Carbo J, Garcia-Samaniego J, Castellano G, Iñiguez A, Solís-Herruzo JA. Liver cirrhosis and mortality by abdominal surgery. 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