Orthotopic liver transplantation (OLT) is the treatment. Detection and Treatment of Coronary Artery Disease in Liver Transplant Candidates

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1 REVIEW ARTICLE Detection and Treatment of Coronary Artery Disease in Liver Transplant Candidates Brian G. Keeffe, * Hannah Valantine, and Emmet B. Keeffe Patients with end-stage liver disease and coronary artery disease (CAD) being considered for orthotopic liver transplantation (OLT) present a difficult dilemma. The availability of multiple screening tests and newer treatment options for CAD prompted this review. Recent data suggest that the prevalence of CAD in patients with cirrhosis is much greater than previously believed and likely mirrors or exceeds the prevalence rate in the healthy population. The morbidity and mortality of patients with CAD who undergo OLT without treatment are unacceptably high, making identification of patients with CAD before OLT an important consideration. Patients with documented CAD or major clinical predictors of CAD should undergo cardiac catheterization before OLT. Those with advanced CAD not amenable to interventional therapy or with poor cardiac function are not candidates for OLT. Dobutamine stress echocardiogram appears to be an excellent means of screening patients with intermediate or minor clinical predictors of CAD before OLT. Patients found to have mild or moderate CAD should be aggressively treated medically and, if necessary and feasible based on hepatic reserve, by percutaneous or, less likely, surgical intervention pre-olt to correct obstructive coronary lesions. Prospective studies regarding optimal screening strategies for the presence of CAD and the indications, timing, and outcomes of interventional therapy in patients with advanced cirrhosis are lacking and much needed. (Liver Transpl 2001;7: ) Orthotopic liver transplantation (OLT) is the treatment of choice for patients with irreversible endstage liver disease (ESLD). 1 During the initial experience with OLT in the 1980s, most transplant programs set an upper age limit of 50 years for transplant candidates. However, in the late 1980s and early 1990s, there was continued refinement in transplant selection criteria and increased performance of OLT in patients aged older than 60 years, a population at increased risk for coronary artery disease (CAD). Analysis of data from the United Network for Organ Sharing showed slightly, although significantly, reduced survival in patients aged older than 50 years and, to a greater extent, older than 60 years of age (Table 1). 2 Reduced survival is more apparent at 4 and 7 years post-olt. In addition, a study of 735 patients analyzed according to age younger than 60 years or 60 years or older showed lower patient survival in older transplant recipients (81% v 90%; P.004), which was largely secondary to such nonhepatic causes as infectious, neurological, and cardiac diseases. 3 These data emphasize the need for careful follow-up and more aggressive medical interventions in elderly patients post-olt. The prevalence of CAD increases with age. 4 Thus, evaluation of older patients for OLT will predictably result in the identification of more patients with coexistent CAD and ESLD. The presence of these 2 conditions leads to clinical dilemmas, such as which patients have prohibitive operative risks secondary to severe CAD and should be excluded from OLT, and what is the timing and necessity of treating moderate CAD in patients who remain potential candidates for OLT. There are no data regarding the ideal management of patients with ESLD and moderate CAD, including treatment by medical means only, coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), or coronary stenting. Furthermore, there are no clear guidelines regarding whether CAD is best treated before versus after OLT. This review focuses on the prevalence of CAD in patients with ESLD, the outcome of OLT in patients with CAD, and indications and best tests to screen for CAD in patients undergoing evaluation for OLT. Finally, suggested management guidelines for patients with both CAD and ESLD are proposed. Prevalence of CAD in Patients With ESLD For many years, it was commonly believed that the prevalence of CAD was lower among patients with cirrhosis than in the healthy population. This theory stemmed from a number of autopsy studies showing less pathological evidence of atherosclerosis or myocardial infarction in patients with cirrhosis. 5-7 Potential From the *Department of Medicine and Divisions of Cardiovascular Medicine and Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA. Address reprint requests to Emmet B. Keeffe, MD, Stanford University Medical Center, 750 Welch Rd, Ste 210, Palo Alto, CA Telephone: ; FAX: ; ekeeffe@stanford.edu Copyright 2001 by the American Association for the Study of Liver Diseases /01/ $35.00/0 doi: /jlts Liver Transplantation, Vol 7, No 9 (September), 2001: pp

2 756 Keeffe, Valantine, and Keeffe Table 1. Survival After Adult OLT by Age Survival (%) Age (yr) No. of Patients 1Yr 4Yr 7Yr , , , * 7, , *Relative risk for death, 1.5; P.001. Relative risk for death, 2.1; P.001. Data from United Network for Organ Sharing database, ; n 24,900 patients. 2 explanations for the protective effect of cirrhosis on the coronary circulation made theoretical sense. Patients with ESLD often have lower serum cholesterol levels than patients with normal hepatic synthetic function. 8 In addition, patients with advanced cirrhosis develop peripheral vasodilatation, thus reducing arterial blood pressure and potentially neutralizing a second major cardiac risk factor. 9 Furthermore, greater estrogen levels found in patients with cirrhosis were believed to be potentially beneficial in the prevention of atherosclerosis. 7 Finally, because alcoholic cirrhosis is a common cause of ESLD and the protective effect of moderate alcohol consumption by elevating high-density lipoprotein levels and lowering cardiovascular mortality has been repeatedly documented, it was believed that alcohol use was another factor that might explain lower rates of CAD in patients with cirrhosis However, in recent years, a number of studies have shown an expected or greater prevalence of CAD in patients with ESLD, and the hypothesis of a protective effect of cirrhosis on coronary arteries is no longer believed to be valid. Carey et al 15 found a 27% prevalence of moderate to severe CAD, based on angiography, in 37 patients being evaluated for OLT. In this study, all patients aged older than 50 years or those aged older than 45 years with cholestatic liver disease being considered for OLT underwent angiography. The presence of CAD was defined as moderate to severe, based on the percentage of stenosis seen on coronary angiography. An unexpected finding was the presence of clinically undetected moderate CAD (30% to 70% occlusive lesions) in 13.3% of patients. The presence of diabetes mellitus was the only independent risk factor found to be a significant predictor for CAD in this relatively small study. The association of CAD with such traditional cardiac risk factors as hypertension, positive family history, and male sex did not reach statistical significance, and there was no significant association between cholestatic liver disease and CAD. Results of cardiac catheterization in an asymptomatic age-matched control population with normal hepatic function were not compared; therefore, it cannot be concluded that the study of Carey et al 15 proves a greater prevalence of CAD in patients with ESLD than in a matched healthy population. However, this study suggests that CAD may be more prevalent in patients with ESLD than previously suspected. Several other studies have evaluated the prevalence of significant CAD in patients being evaluated for OLT. Morris et al 16 found that 5.6% of 608 patients aged older than 40 years undergoing OLT had documented CAD, although the diagnostic criteria were not explicitly stated. Plotkin et al, 17 using data from both cardiac catheterization and dobutamine stress echocardiogram (DSE), documented significant CAD, defined as 70% or greater stenosis within a major coronary artery, in 2 of 40 patients (5%) who underwent OLT. In another report evaluating the role of DSE in screening patients with cirrhosis for CAD, Donovan et al 18 found that 2.5% of 165 patients had CAD, defined as greater than 50% coronary artery stenosis on cardiac catheterization. In this study, patients had angiograms performed based on clinical suspicion of CAD or positive DSE results. In summary, the exact prevalence of CAD in patients with ESLD being evaluated for OLT is unclear based on the variable definitions used for significant CAD in the published literature, ranging from greater than 30% to greater than 70% occlusive coronary artery lesions. However, based on data from the 4 studies cited, the prevalence rate ranged from 2.5% to 27% (Table 2) Given a 2.5% prevalence rate of CAD in asymptomatic men in the general population, 19 the former belief that CAD was uncommon in patients with cirrhosis no longer appears to be true. The prevalence rate of CAD in ESLD is at least the same and probably greater than in the general population. Outcome of OLT in Patients With ESLD and Coexistent CAD The relevance of documenting CAD in patients with ESLD stems from the reported high morbidity and mortality rates in these patients after OLT. Plotkin et al, 20 in a retrospective study of 32 patients with known CAD who underwent OLT, found an overall mortality rate of 50% and morbidity rate of 81%. Twenty patients had undergone CABG between 6 months and 12 years before OLT, 2 patients had undergone simul-

3 CAD in OLT Candidates 757 Table 2. Prevalence of CAD in Liver Transplant Patients Reference No. Definition of Significant CAD Prevalence of CAD Comments Carey et al %-70% Stenosis, moderate; 70% stenosis, severe 10 (27%) Diabetes mellitus was risk factor for CAD; cardiac catheterization in patients age 50 yr Morris et al Criteria not explicitly stated 34 (5.6%) Patients age 40 yr studied Plotkin et al % Stenosis 2 (5%) Patients studied by catheterization and DSE Donovan et al % Stenosis 4 (2.5%) Catheterization in patients with suspicion for CAD or positive DSE result taneous CABG and OLT, 9 patients were managed medically, and 1 patient had undergone PTCA 4 years before OLT. More than half of the 16 patients who underwent cardiac catheterization before OLT had lesions greater than 50% in 1 or more native or grafted vessels; interventions were not performed on these lesions. Morris et al 16 found similar morbidity and mortality rates in a small series of 3 patients; 2 patients underwent CABG before OLT, and 1 patient underwent combined OLT and CABG. Several case reports have documented success in single cases of either combining CABG with OLT or performing CABG shortly after OLT Reasons for the high rates of morbidity and mortality in patients with CAD who undergo OLT are likely multifactorial. Cardiac function of the transplant recipient must be adequate to handle major hemodynamic alterations, both intraoperatively and perioperatively. Marked hemodynamic instability can occur intraoperatively at the time of hepatectomy, as well as when perfusion is reestablished to the grafted liver. 24 In addition, immediately postoperatively, systemic vascular resistance is elevated and cardiac output decreases as normal liver function is reestablished after engraftment. 25 Another possible, although probably less likely, explanation for increased cardiac morbidity and mortality after OLT is the hypercoagulable state that occurs early after OLT. 26 Levels of protein C, protein S, and antithrombin III are depressed for 5 to 10 days after OLT and contribute to the hypercoagulable state. Rubin et al 27 retrospectively evaluated the electrocardiograms (ECGs) of 45 patients before and after OLT and compared findings with a similar cohort of patients undergoing major intra-abdominal surgery. Evidence of clinical myocardial ischemia, ischemic ECG changes, or both occurred in 13% of the transplant patients, whereas no ischemia was noted in patients after other abdominal operations. Of note, 4 of 6 patients with marked ECG abnormalities and ischemic events showed no evidence of significant obstructive CAD on coronary angiography. Rubin et al 27 postulated that these events might have been caused by coronary thrombi resulting from a hypercoagulable state that had lysed by the time cardiac catheterization was performed later. The combination of normal stresses of surgery, hemodynamic instability unique to OLT, a hypercoagulable state, and other unknown factors may contribute to the morbidity and mortality associated with OLT in patients with CAD. The key to preventing poor outcomes secondary to cardiac disease in transplant patients is to prospectively identify CAD in patients before OLT. Screening for CAD in Patients With ESLD Medical evaluation of the liver transplant candidate generally includes a history, physical examination, laboratory assessment, and additional tests, including ECG. To identify patients with CAD, special attention should be given to the patient s age, prior history of CAD (myocardial infarction, angina, or revascularization), chest pain suspicious of angina, congestive heart failure, diabetes mellitus, hypercholesterolemia, hypertension, tobacco use, or family history of CAD. Patients with any of these findings on history should be referred to a cardiologist for further evaluation. The cardiac evaluation of liver transplant candidates routinely includes, in addition to the thorough history and physical examination, an ECG and, in most centers, an echocardiogram. Further studies for specific evaluation for CAD include cardiac catheterization or functional studies, including exercise treadmill, stress thallium nuclear imaging, or DSE. The high rates of morbidity and mortality in patients with known CAD undergoing OLT detailed by Plotkin et al 20 have led to a consideration that

4 758 Keeffe, Valantine, and Keeffe patients with known CAD being evaluated for OLT should undergo cardiac catheterization, regardless of symptoms, ECG, or results of functional studies. A more difficult decision involves patients with a history of diabetes mellitus, but without known CAD or symptoms to suggest ischemic disease. Carey et al 15 found diabetes mellitus to be the only independent risk factor that predicted the presence of significant CAD in patients with ESLD. In addition, patients with diabetes can develop cardiac ischemia in the absence of symptoms more commonly than patients without diabetes. 28 For these reasons, many patients with diabetes undergo cardiac catheterization before OLT. For those who do not, a functional study, such as DSE, is indicated. For those patients in whom a cardiac catheterization is not initially performed as part of the cardiac evaluation before OLT, there are several screening tests for CAD from which to choose. The exercise treadmill is rarely an appropriate test for patients with ESLD, who often have poor functional and exercise capacity, but the treadmill has not been formally studied in such patients. Furthermore, in patients without cirrhosis, the sensitivity of the exercise treadmill test in detecting CAD is only 60% to 70%. 29 Both stress thallium imaging and DSE have much greater sensitivities, with ranges usually quoted from 85% to 90% in patients with normal hepatic function. 30,31 No data exist on the use of stress thallium in screening patients with ESLD for CAD. Although potentially an attractive modality for screening, patients with ESLD often also require an echocardiogram as part of the preoperative evaluation to assess myocardial and valvular function. The use of DSE thus allows screening for CAD and, at the same time, assessment of myocardial function, valvular function, and pulmonary artery pressure. As a result of these multiple uses, DSE has become the study of choice in evaluating patients with ESLD and cardiac disease before OLT. Several trials have assessed the use of DSE in screening patients being evaluated for OLT and the presence of CAD. Using DSE, Donovan et al 18 evaluated 165 patients with a history or suspicion of cardiac disease, hypertension, diabetes, age older than 45 years, or alcoholic liver disease and those in whom there was a clinical suspicion of CAD and found inducible ischemia in 11 patients (6.6%). Cardiac catheterization with coronary angiography was performed on 9 of the 11 patients with an ischemic response on DSE. However, CAD was confirmed in only 3 of the 9 patients, giving a positive predictive value of only 33%. Nine other patients in whom DSE results were negative underwent cardiac catheterization because of high clinical suspicion of CAD; 1 of those patients was found to have 3-vessel coronary disease and was not offered OLT. One hundred forty-five patients had a negative DSE result and did not undergo cardiac catheterization. These 145 patients underwent OLT, and there were no perioperative ischemic events, yielding a negative predictive value close to 100%. Plotkin et al 17 performed DSE on 80 patients being evaluated for OLT based on more narrow criteria than those used by Donovan et al. 18 All patients with known CAD or diabetes mellitus, patients aged between 50 and 60 years with 2 or more risk factors for CAD, patients older than 60 years of age, and patients with symptoms suggestive of CAD or ECG findings suggestive of ischemia underwent study. Follow-up data with results of cardiac catheterization or clinical outcome of OLT were available in half the patients studied. They found a sensitivity of 100%, specificity of 90%, positive predictive value of 100%, and negative predictive value of 100% for DSE. Finally, Williams et al, 32 after excluding all patients with known CAD or symptoms suggestive of CAD, studied low- to moderate-risk patients with 1 or more cardiac risk factor with DSE and found a negative predictive value of only 86%. These data support the use of DSE as a screening tool for CAD in patients being evaluated for OLT. A normal DSE result is an excellent predictor that a patient with ESLD will tolerate OLT, but a positive test result is not as useful in predicting a poor outcome (Table 3). Clearly, positive and negative results with screening DSE become more significant as patients with known cardiac disease or more cardiac risk factors are included. The study of Williams et al 32 showed that the inclusion of lower risk patients diminished the value of a negative DSE result. Therefore, the dilemma is who to screen. Because it appears that patients with ESLD have a prevalence of CAD similar to or slightly greater than patients with normal hepatic function, the suggestion of both Plevak 33 and Plotkin et al 34 to follow the guidelines of the American College of Cardiology (ACC) and American Heart Association (AHA) for perioperative cardiovascular evaluation for noncardiac Table 3. Efficacy of DSE in Screening for CAD in Patients With ESLD Reference Positive Predictive Value (%) Negative Predictive Value (%) Donovan et al Plotkin et al Williams et al

5 CAD in OLT Candidates 759 surgery seems prudent for OLT until more definitive guidelines exist. The guidelines of the ACC and AHA combine the use of clinical predictors of active heart disease, functional capacity, surgery-specific risk, and the presence or lack of recent coronary evaluation to identify patients likely to benefit from such noninvasive testing as DSE. 35 Treatment of CAD in Patients With ESLD After the diagnosis of CAD is made in a patient with ESLD, the difficult issue of treatment must be considered. As noted, the study of Plotkin et al 20 showed that patients with significant CAD do not fare well after OLT. Therefore, a potentially attractive alternative is to treat CAD before OLT. Options for treating CAD include medical management and risk factor reduction, CABG, and PTCA with or without coronary stent placement. However, in patients with cirrhosis, the application of each of these treatment modalities differs from patients with normal hepatic function and requires special attention. Medical Management All patients with cirrhosis with known CAD should be managed medically, and aggressive risk reduction should be undertaken. Because there are no guidelines specific for these patients, they should be managed similarly to patients with normal liver function, based on the AHA consensus panel statement on comprehensive risk reduction for patients with coronary and other vascular disease. 36 Patients who smoke tobacco should be strongly encouraged to stop, and appropriate counseling and nicotine replacement therapy can be used as needed. Blood pressure should be controlled, and -blocker use should be considered in patients with portal hypertension and varices. Aggressive lipid management is important, with a primary goal of keeping low-density lipoprotein levels less than 100 mg/dl. Close attention should be given to liver test results while these patients are on lipid-reducing medications because many have side effects that include hepatotoxicity. Physical activity and weight control should be encouraged, if possible. Aggressive management of diabetes should be undertaken with diet and appropriate hypoglycemic medications, with a goal of keeping the hemoglobin A 1c value near 7% (normal value, 3% to 6%). Aspirin usually cannot be administered secondary to marked thrombocytopenia. Cautious use of low-dose angiotensin-converting enzyme inhibitors in patients who have had a myocardial infarction and have left ventricular dysfunction should be considered, with close monitoring of renal function. 37 CABG For those patients with significant stenoses in one or more coronary arteries, consideration must be given to surgical or percutaneous revascularization. There are no guidelines for the use of CABG in patients with ESLD. However, there are ACC and AHA guidelines for the use of CABG in patients with CAD and normal hepatic function. Class I indications for CABG are those in which there is clear evidence or agreement that the procedure is useful and effective. Depending on the clinical scenario, class I indications can include: (1) left main coronary artery stenosis; (2) significant stenosis of the proximal left anterior descending (LAD) artery and proximal left circumflex; (3) 3-vessel disease; (4) 2-vessel disease including the LAD artery and demonstrable ischemia on noninvasive testing; (5) 1- or 2-vessel disease not including the LAD artery, but with a large area of viable myocardium and high-risk criteria on noninvasive testing; and (6) disabling angina or ongoing ischemia despite maximal medical therapy when surgery can be performed with acceptable risk. 38 Outcomes of patients with cirrhosis undergoing CABG have not been specifically addressed in published form. However, two studies have assessed outcomes of patients with cirrhosis undergoing cardiac surgery. Bizouarn et al 39 prospectively studied 12 patients with Child s class A or B cirrhosis who underwent elective cardiac surgery. Both postoperative morbidity and significant complications after hospital discharge occurred in 58% of patients. In addition, both intensive care unit and total hospital stays were prolonged in these patients. Klemperer et al 40 retrospectively evaluated 13 patients with cirrhosis who underwent cardiac surgery. The overall perioperative mortality rate was 31%, and major complications occurred in 25% of patients with Child s class A cirrhosis and 100% of patients with Child s class B cirrhosis. This is in marked contrast to mortality and morbidity rates of 1.8% and 8.4% in patients without cirrhosis undergoing cardiac surgery, respectively. 41 In addition, postoperative chest tube output and transfusion requirements were nearly 3 times greater than average. Increased morbidity and mortality with cardiac surgery are expected in these patients. Initiation of cardiopulmonary bypass causes hemodilution of platelets and coagulation factors, as well as quantitative and qualitative platelet abnormalities that compromise an already poor hemostatic system in a patient with cirrhosis. 42 Anticoagulation with heparin may put the patient at

6 760 Keeffe, Valantine, and Keeffe further risk for bleeding. All these factors place a patient with cirrhosis at risk for gastrointestinal bleeding or bleeding related to surgical trauma. In addition, patients with ESLD often have compromised renal function that can be compromised further by undergoing bypass. 43 The potential for further hepatic deterioration after prolonged surgery with cardiopulmonary bypass is concerning, as well. A study of 3,041 adults undergoing cardiac surgery showed a 3% rate of hepatic dysfunction perioperatively. Patients with preexisting liver dysfunction had greater levels of mortality (11.4%) compared with those with normal liver function. 44 These data show what is generally well known by cardiothoracic surgeons, i.e., patients with ESLD are at very high risk for complications when undergoing CABG. PTCA PTCA is a less invasive method of revascularizing coronary lesions, either alone or in combination with stent placement. As with CABG, the outcomes of patients with cirrhosis undergoing PTCA or stent placement have not been formally studied. These interventions provide their own set of risks to patients with cirrhosis. The compromised renal function that often accompanies ESLD may make the patient with cirrhosis more likely to develop renal deterioration after contrast exposure. Carey et al 15 noted a 5.5% rate of transient renal impairment after coronary catheterization in a small series of patients. In addition, patients undergoing PTCA often are administered anticoagulant and antiplatelet medications, which increase the risk for bleeding in a patient with liver dysfunction. In particular, the new glycoprotein IIb/IIIa medications, as well as clopidogrel, which are often used after stent placement, have not been well studied in patients with ESLD. The glycoprotein IIb/IIIa medications are contraindicated in patients with a platelet count less than 100,000/ L, which occurs commonly in patients with ESLD, accompanied by portal hypertension and splenomegaly. There are no guidelines available for the optimal use of antiplatelet and anticoagulant medications when this difficult set of patients undergoes cardiac catheterization with or without intervention. However, the overall risk conferred by PTCA or stent placement is probably less than that with CABG. Treatment Synopsis How then is the patient with cirrhosis with CAD being considered for OLT best managed? Given the poor outcomes of patients with active CAD who undergo OLT, noted by Plotkin et al, 20 all patients with significant obstructive CAD found on preoperative screening should be treated before undergoing OLT. Treatment should include aggressive medical management of CAD, as detailed. 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