Pretransplant coronary artery disease is a predictor for myocardial infarction and cardiac death after liver transplantation

Pretransplant coronary artery disease is a predictor for myocardial infarction and cardiac death after liver transplantation

European Journal of Internal Medicine xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect European Journal of Internal Medicine journal hom...

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European Journal of Internal Medicine xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim

Original Article

Pretransplant coronary artery disease is a predictor for myocardial infarction and cardiac death after liver transplantation ⁎

F. Darsteina, , M. Hoppe-Lotichiusb, J. Vollmara, V. Weyer-Elberichc, A. Zimmermannd, ⁎ J. Mittlerb, G. Ottob, H. Langb, P.R. Gallea, T. Zimmermanna, a

First Department of Internal Medicine, Gastroenterology and Hepatology, Universitätsmedizin Mainz, Mainz, Germany Department of Hepatobiliary and Transplantation Surgery, Universitätsmedizin Mainz, Mainz, Germany c Division of Biostatistics and Bioinformatics, Universitätsmedizin Mainz, Mainz, Germany d First Department of Internal Medicine, Endocrinology and Metabolic Diseases, Universitätsmedizin Mainz, Mainz, Germany b

A R T I C L E I N F O

A B S T R A C T

Keywords: Liver transplantation Coronary heart disease Cardiovascular events Myocardial infarction

Background: Cardiovascular disease is a serious problem of liver transplant (LT) recipients because of increased cardiovascular risk due to immunosuppressive therapy, higher age, intraoperative risk and comorbidities (such as diabetes and nicotine abuse). Reported frequency of cardiovascular events after LT shows a high variability between different LT cohorts. Our aim was to analyze a cohort of LT recipients from a single center in Germany to evaluate frequency of the cardiovascular endpoints (CVE) myocardial infarction and/or cardiac death after LT and to investigate correlations of CVE post LT with pretransplant patient characteristics. Patients: In total, data from 352 LT patients were analyzed. Patients were identified from an administrative transplant database, and all data were retrieved from patients' charts and reports. Results: During the median follow-up of 4.0 (0 −13) years, 10 cases of CVE were documented (six myocardial infarctions and four coronary deaths). The frequency of CVE did not differ according to classic cardiovascular risk factors such as body mass index (p = 0.071), total cholesterol (p = 0.533), hypertension (p = 0.747), smoking (p = 1.000) and pretransplant diabetes mellitus (p = 0.146). In patients with pretransplant coronary heart disease (n = 24; 6.8%) CVE were found more frequently (p = 0.024). Conclusion: In summary, we found a rate of 2.8% CVE after LT in a German transplant cohort. Pretransplant CHD was the only risk factor for CVE, but showed no significant impact on overall survival.

1. Introduction Liver transplantation (LT) is indicated for severe acute or advanced chronic liver disease when the limits of medical therapy have been reached [1]. Due to improvement in intensive care management, surgical technique and immunosuppression, the 5 year-survival rates increased to 71% [2]. As result of improved long-term survival, cardiovascular mortality became increasingly important because most cases of cardiovascular deaths (81.3%) occurred beyond 5 years after LT [3]. Coronary heart disease (CHD) is a major cause of mortality in the general population. Several factors, such as immunosuppression, weight gain or the development of diabetes mellitus (DM) contribute to an increased cardiovascular risk after LT [4]. In LT recipients who survived the first year post-transplant, cardiovascular mortality is the third leading cause of death [5]. To decrease cardiac mortality recent clinical practice guidelines recommend screening for CHD in all patients undergoing evaluation for ⁎

LT in case of cardiovascular risk factors (chronic smokers, patients over the age of 50, personal or family history of heart disease or diabetes) [6]. Initial assessment should be made using dobutamine stress echocardiography, and positive test results should be confirmed with cardiac catheterization [1]. Although, there is a strong recommendation for the use of dobutamine stress echocardiography certified by Martin et al., several authors report limitations of stress echocardiography as screening test due to poor sensitivity, specificity, as well as poor positive predictive value [7,8]. Beside treatment of risk factors, a percutaneous coronary intervention is a safe intervention in order to reduce CVE [9,10]. Dual antiplatelet therapy after treatment with cardiac stents is associated with complications such as high rates of gastrointestinal bleeding. So it remains unclear, whether the cardiovascular benefits of cardiac stents outweigh the bleeding risk [11]. However, cardiac complications after LT are mainly pulmonary oedema and pleural effusion, whereas myocardial infarction is rare [12].

Corresponding authors. E-mail addresses: [email protected] (F. Darstein), [email protected] (T. Zimmermann).

https://doi.org/10.1016/j.ejim.2017.12.001 Received 12 March 2017; Received in revised form 20 November 2017; Accepted 5 December 2017 0953-6205/ © 2017 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.

Please cite this article as: Darstein, F., European Journal of Internal Medicine (2017), https://doi.org/10.1016/j.ejim.2017.12.001

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triglycerides > 150 mg/dl, for LDL-cholesterol > 160 mg/dl and for HDL-cholesterol < 40 mg/dl. Additionally we looked for statin treatment prior to LT. According to World Health Organization guidelines [16] the presence of diabetes mellitus was based on self-reported usage of antidiabetic medication and/or fasting plasma glucose levels ≥ 7.0 mmol/l and/or postload plasma glucose levels ≥11.1 mmol/l. As the diagnosis was made before LT the diagnosis was called pretransplant diabetes. We defined arterial hypertension as use of antihypertensive medication before LT [17] with the exception of non-selective beta-blockers, e.g. propranolol, given for prophylaxis in patients with esophageal varices [18]. During evaluation for LT, patients underwent a modified screening for cardiovascular diseases based on AASLD recommendations [1,6]: by electrocardiogram, echocardiography, pulmonary function testing, arterial blood gas, long-term blood pressure recordings, echocardiography and dobutamine stress echocardiography. In case of positive stress echocardiography, pathologic echocardiography, age > 60 years, diabetes mellitus for over 10 years or known coronary artery disease or nicotine abuse a left heart catheter with coronarangiography was performed. Patients transplanted before 2005 were screened with transthoracic echocardiography without additional stress echocardiography. Coronary heart disease was defined as manifestation of atherosclerosis in the coronary vessels with stenosis (of any degree) diagnosed by cardiac catheterization. Left ventricular ejection fraction was defined as normal (> 55%) or reduced (< 55%). A common immunosuppressive regimen was the combination of a calcineurin inhibitor (tacrolimus or cyclosporine) with mycophenolate mofetil (MMF). Target trough levels were 5–7 ng/ml for tacrolimus during the first year and 3–5 ng/ml after one year. For cyclosporine target trough levels were 70–90 ng/ml during the first year and 50–70 ng/ml thereafter. Target trough levels were chosen by experience from our center in combination with reported data from other centers [19]. All patients were followed up at least every three to six months at our outpatient clinic. Follow-up and the primary endpoint cardiovascular event (CVE, defined as myocardial infarction and/or cardiac death) were documented. The observation period ended on December, 31th, 2011. For descriptive analysis continuous variables were expressed as median (with inter quartile range (IQR)). Differences between groups were compared using the exact Fisher test for two categorical variables and the nonparametric Mann-Whitney-U test was calculated for differences in two groups for continuous outcome variables. Additionally a univariate logistic regression analysis was performed with the binary outcome variable CVE and the independent variable preexisting CHD. Odds ratio, as well as the corresponding 95% confidence limits and p values are presented. The survival time was estimated using the Kaplan-Meier method, and survival between groups was compared by the nonparametric logrank test. P-values < 0.05 were considered significant. Statistical analysis was performed using IBM SPSS statistics version 22 (SPSS Inc., Chicago, IL, USA). This research was approved by the local ethics committee of Rhineland-Palatinate and was conducted according to the ethical guidelines of the Declaration of Helsinki 1975 and Good Clinical Practice guidelines. Informed consent of patients was obtained during the evaluation process for liver transplantation, with general approval to use anonymous data in clinical studies.

LT recipients represent an inhomogeneous cohort (pretransplant obese patients with NASH, cachectic patients with alcohol-induced liver cirrhosis, patients with hepatocellular carcinoma, etc.) [13]. The cardiac risk of LT recipients can vary between centers and within one center over the years, due to different underlying diseases [8]. Because of increasing diagnoses of diabetes and fatty liver disease, an increase of cardiac risk and CVE is likely [14]. In literature, the reported incidence rate of CVE after LT was widely variable (0–31%) and predictable risk factors for cardiovascular events were inconsistent [15]. The aim of our analysis was to determine the frequency of CVE after LT and to determine possible risk factors for CVE. 2. Patients and methods A total of 616 liver transplantations, performed at the University Medical Center of Mainz until June 1st, 2011, were evaluated. Patients were identified from an administrative transplant database, and all data were retrieved from patients' charts and reports to the cut-off date June 1st, 2011. Patients transplanted between December 1st, 2010 and June 1st, 2011 were excluded from analysis in order to achieve a follow-up of at least six months. The selection process of the study cohort is presented in Fig. 1. In addition to commonly used patient demographics, we reviewed the etiology of liver failure, hepatocellular carcinoma (HCC) status, and prevalence of hypertension and CHD. Pretransplant data about patients' body mass index (BMI), arterial hypertension, total cholesterol, LDL, HDL and triglycerides were collected as a part of baseline information prior to LT. In case of persisting nicotine abuse after LT, patients were stated as smokers. Former nicotine abuse was not taken into account. Cut off levels for cholesterol were > 200 mg/dl, for

616 LT

Exclusion of 25 LT with transplantation after December 1st 2010

Exclusion of 46 retransplantations

Exclusion of 20 LT with missing echocardiographic diagnostic Exclusion of 173 LT with missing or incomplete data

352 LT recipients remaining for analysis

3. Results Three hundred and fifty-two patients who underwent LT for different reasons were included. Baseline patient characteristics are listed in Table 1.

Fig. 1. Inclusion of patients.

2

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Table 1 Myocardial infarction and cardiac death in LT-recipients (n = 352).

Follow-up (years), median (min–max) Age (years), median (min–max) Gender, % (n) Male Female Etiology of liver disease, % (n) Alcohol Hepatitis B Hepatitis C Autoimmune, PBC, PSC Amyloidosis Cryptogenic Acute liver injury Hepatocellular carcinoma, % (n) BMI (kg/m2), median (IQR) Total cholesterol (mg/dl), median (IQR) Total cholesterol > 200 mg/dl, % (n) HDL-cholesterol (mg/dl), median (IQR) HDL-cholesterol < 40 mg/dl, % (n) LDL-cholesterol (mg/dl), median (IQR) LDL-cholesterol > 160 mg/dl, % (n) Triglycerides (mg/dl), median (IQR) Triglycerides > 150 mg/dl, % (n) Statin treatment, % (n) Hypertension, % (n) Nicotine, % (n) Pretransplant diabetes mellitus, % (n) Immunosuppression Tacrolimus, % (n) Cyclosporine, % (n) MMF, % (n) BPAR, % (n) CHD pretransplant labMELD-Score, median (IQR) ESRD, % (n) (at time of LT) Left ventricular hypertrophy, % (n) Left ventricular ejection fraction < 55%, % (n)

All LT recipients (n = 352)

Recipients with CVE (n = 10; 2.8%)

Recipients without CVE (n = 342; 97.2%)

P-value

4.0 (0–13) 56 (19–74)

3.5 (0–8) 58 (47–74)

4.0 (0–13) 56 (19–71)

0.340 0.407

68.5 (241) 31.5 (111)

90.0 (9) 10.0 (1)

67.8 (232) 32.2 (110)

0.180 0.180

39.8 (140) 13.9 (49) 25.9 (91) 6.8 (24) 4 (14) 4.5 (16) 3.1 (11) 40.3 (142) 25 (6) 133 (67.5) 14.1 (43/306) 41 (30) 46.6 (130/279) 72 (57.5) 4.98 (14/281) 88.5 (45) 13.2 (39/296) 2.0 (7) 61.4 (216) 21 (74) 27.6 (97)

70 (7) 10.0 (1) 2.2 (2) 0 (0) 0 (0) 0 (0) 0 (0) 40.0 (4) 28.5 (5) 131 (81) 10 (1) 38 (25.5) 50.0 (5) 60 (65.5) 0 (0) 75.0 (90.5) 20.0 (2) 10.0 (1) 70.0 (7) 20.0 (2) 50 (5)

38.9 (133) 14.0 (48) 26.0 (89) 7.0 (24) 4.1 (14) 4.7 (16) 3.2 (11) 40.4 (138) 25 (6) 133 (67.5) 14.1 (42) 41 (31) 46.3 (125) 72 (58.75) 5.1 (14) 89.0 (45.0) 12.9 (37) 1.8 (6) 61.1 (209) 21.1 (72) 26.9 (92)

0.096 1.000 1.000 1.000 1.000 1.000 1.000 1.000 0.071 0.533 1.000 0.364 0.738 0.357 1.000 0.716 0.337 0.184 0.747 1.000 0.146

56.3 (198) 30.4 (107) 72.7 (256) 27 (95) 6.8 (24) 16.5 (14.25) 14.1 (44) 38.4 (135) 1.7 (6)

70 (7) 40.0 (4) 50 (5) 30 (3) 30 (3) 23 (12.5) 20 (2) 60.0 (6) 0 (0)

55.8 (191) 30.1 (103) 73.1 (250) 26.9 (92) 6.1 (21) 16 (14.75) 14.1 (44) 37.7 (129) 1.8 (6)

0.523 0.499 0.470 0.733 0.024 0.095 0.639 0.191 1.000

Abbreviations: PBC = primary biliary cholangitis, PSC = primary sclerosing cholangitis, BMI = body mass index, MMF = mycophenolate mofetil, ESRD = end stage renal disease, CHD = coronary heart disease, BPAR = biopsy proven acute rejection, CVE = myocardial infarction and/or cardiac death, labMELD = calculated Model of End Stage Liver Disease.

LVEF of 30% (one patient with transthyretin amyloidosis, one patients with hepatitis B- and one patient with hepatitis C-associated liver cirrhosis) and three patients showed a LVEF of 45% (two patients with alcoholic liver cirrhosis and one patient with HCC in hepatitis C-associated liver cirrhosis). During the median follow up of 4.0 (0–13) years, CVE was diagnosed in 10 LT recipients (6 patients with myocardial infarction and 4 patients with cardiac death). Differences between patients with and without CVE are shown in Table 1. Preexisting CHD was significantly more frequent (p = 0.024) in patients with CVE (30%) compared to LT recipients without CVE (6.1%). Preexisting CHD was associated with CVE (p = 0.010; odds ratio 6.551; 95% CI 1.579–27.176) using logistic regression. R-square (Nagelkerke) was 0.064, according to a small effect [20]. 93 patients died during the observation period. A cardiac reason for death was found in 4 patients (4.3%). The leading cause of death was sepsis (n = 32, 34.4%). Other causes of death were cerebral hemorrhage (n = 6, 6.5%), liver failure (n = 6, 6.5%), intraoperative death (n = 4, 4.3%), HCC recurrence (n = 13, 14%) and other malignancies (n = 8, 8.6%). Other reasons for death were found in 21.5% (20 patients). Fig. 2. Coronary heart disease and patient survival.

4. Discussion

Survival of LT recipients with pretransplant CHD compared with recipients without CHD showed no significant difference (p = 0.861), as presented in Fig. 2. A reduced left ventricular ejection fraction (LVEF) pretransplant was found in 6 patients who underwent LT. Three patients showed a

Due to variability in underlying diseases and comorbidities of LT recipients from different countries and centers, evaluation of cardiac risk can differ from one transplant center to another [21,22]. In the literature, cardiac events were reported in up to 21% of cases, 3

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CHD before transplant (p = 0.010; odds ratio 6.551). This condition existed in 24 (6.8%) patients prior to LT, comparable with published data for another LT cohort (7.4%) [14]. Three out of 24 patients (12.5%) with CHD suffered from CVE during our observation period. Due to the correlation of CHD before transplant with CVE and the inclusion of cardiac death in CVE, increased mortality in patients with pretransplant CHD could be expected. However, overall survival did not differ between patients with pretransplant CHD and LT recipients without pretransplant CHD (p = 0.861). There are several possible explanations for this result: a higher rate of CVE would be necessary to show a significant difference in survival or many LT recipients who do not suffer from cardiac death suffer from other reasons for death. In literature, there are different data for the impact of CHD on survival after LT: reduced survival in case of multivessel CHD is reported, but also no influence of CHD on survival has been found [44–46]. Among all causes of death, in our cohort of LT recipients 4.3% (4/ 93) were caused by CVE. Further influences of cardiac diseases on death due to sepsis or on intraoperative death cannot be excluded. In the literature, a higher frequency of cardiovascular death is reported (up to 23% of all causes of death), maybe due to different pretransplant diseases or therapeutic differences between the two cohorts [47]. There are several limitations of our study: first of all, the analysis is retrospective and does only content data from one single center. Only few cardiac events occurred, so comparisons of risk factors and correlations are limited. Our analysis did not include post LT risk factors (other than immunosuppression), although the cardiovascular risk does not only depend on pretransplant comorbidities but also on post LT risk factors (like the development of dyslipidemia or obesity) [48]. From 616 LT performed at the University of Mainz, in our analysis 193 LT recipients were not analyzed because of missing clinical data or incomplete follow-up. Therefore, patients that missed the routine controls are underrepresented in our analysis resulting in a potential bias. Our analysis provides important data about an overall low cardiac mortality in our cohort of LT recipients, suggesting that current diagnostic and therapeutic guidelines are sufficient to avoid an inadequate high cardiac mortality (with consecutive organ loss) after LT. To further improve cardiovascular outcomes prospectively, multicenter studies with respect to the underlying disease, cardiac risk factors, the development of post LT risk factors and the benefit of different therapies (like statins, diabetes therapy or percutaneous coronary intervention) are necessary.

while in our cohort of LT recipients cardiac events were found in only 2.8% of patients [23]. One possible explanation for this difference is the variation in pretransplant underlying diseases [14]. According to this hypothesis we found lower median BMI values (25 vs. 28.5), lower rates of smokers (21% vs. 39%) and less frequent pretransplant DM (27.6 vs. 37.6%) in our cohort while comparing classic cardiac risk factors to the study mentioned above. One possible reason for a different distribution of the underlying diseases could be a higher incidence of these diseases in the general population of the country compared to the incidence in Germany [24,25]. For a better understanding of cardiac risk in our LT recipients we analyzed factors responsible for half of cardiac deaths in the general population (total cholesterol, obesity, arterial hypertension, smoking and diabetes) [26]. Several forms of dyslipidemia are reported depending on the etiology of liver cirrhosis [27]. In our cohort median total cholesterol (133 mg/dl) was lower than in the general population (about 180 mg/ dl) [28]. In concordance, we found normal values of median LDL-cholesterol (72 mg/dl), median HDL-cholesterol (41 mg/dl) and median triglycerides (88.5 mg/dl). Similar rates of abnormal HDL-cholesterol (46.59% in our collective vs. 39.8%) and abnormal triglycerides (13.2% in our collective vs. 7.2%) are described from other transplant centers for LT recipients [29]. The median BMI was slightly elevated with 25 kg, which corresponds to overweight [30]. However, the interpretation of weight and BMI in patients with liver cirrhosis is difficult because of confounding factors like ascites. Arterial hypertension was present in 61.4% (216/352) of LT recipients. In the general population, a similar or slightly lower prevalence of arterial hypertension could be expected in the corresponding age group [31,32]. Smoking was reported in 21% of LT recipients, which is comparable to smoking prevalence in the general population [33,34]. Pretransplant DM was diagnosed in 27.6% of patients. In the general population we would expect a lower prevalence of DM of about 9–12% [35,36]. The higher prevalence of diabetes in LT recipients could be explained by a higher rate of undetected diabetes in the general population [37]. Furthermore, high rates of diabetes in liver cirrhosis may be due to a so called hepatogenous DM [38,39]. Frequency of those five cardiovascular risk factors in our LT recipients was comparable to the frequency in general population, instead of a higher frequency of diabetes mellitus in LT recipients. However, in our cohort risk factors (mean cholesterol, median LDL-cholesterol, mean HDL-cholesterol, median triglycerides) were equally distributed in patients with and without CVE. Furthermore, other cardiovascular risk factors as BMI (p = 0.071), arterial hypertension (p = 0.747), smoking (p = 1.000) or pretransplant DM (p = 0.146) were not more frequent in patients with CVE. However, it is unlikely that those known risk factors have no effect on cardiac events in LT recipients [40]. Probably, a significant difference between patients with and without CVE could not be shown in our analysis due to a relatively short observation period (follow up of 4.0 years) and only few observed cardiac events. For the risk factors pretransplant DM, BMI, arterial hypertension, median LDL cholesterol and median triglycerides there was a trend towards more frequent risk factors in patients that develop CVE (without reaching statistical significance). Maybe statistical significance could be reached in a larger cohort with more CVE (due to more patients or longer observation period) [3]. Thus, we don't challenge the relevance of these risk factors in the transplant setting and we recommend therapeutic improvement if needed in all LT recipients. Depending on the single patient, therapeutic improvement may reach from medical therapy with control of risk factors up to percutaneous coronary intervention or coronary artery bypass grafting [41–43]. The only pretransplant risk factor associated with CVE was a known

5. Conclusion In summary, we found a low rate of 2.8% CVE after LT in a German transplant cohort. Compared to other transplant centers the rate of CVE is rather low. CHD pretransplant was the only risk factor associated with CVE, but showed no significant impact on survival. Diseases like sepsis, HCC recurrence or other malignancy were more often reasons for death compared to cardiac diseases. References [1] Martin P, DiMartini A, Feng S, Brown R, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology 2014;59:1144–65. (Baltimore, Md.). [2] Adam R, Karam V, Delvart V, O'Grady J, Mirza D, Klempnauer J, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol 2012;57:675–88. [3] Schoening WN, Buescher N, Rademacher S, Andreou A, Kuehn S, Neuhaus R, et al. Twenty-year longitudinal follow-up after orthotopic liver transplantation: a singlecenter experience of 313 consecutive cases. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 2013;13:2384–94. [4] Neal DA, Tom BD, Luan J, Wareham NJ, Gimson AE, Delriviere LD, et al. Is there disparity between risk and incidence of cardiovascular disease after liver transplant? Transplantation 2004;77:93–9. [5] Nicolau-Raducu R, Gitman M, Ganier D, Loss GE, Cohen AJ, Patel H, et al. Adverse cardiac events after orthotopic liver transplantation: a cross-sectional study in 389

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consecutive patients. Liver Transpl 2015;21:13–21. [6] Murray KF, Carithers RL. AASLD practice guidelines: evaluation of the patient for liver transplantation. Hepatology 2005;41:1407–32. [7] Snipelisky D, Levy M, Shapiro B. Utility of dobutamine stress echocardiography as part of the pre-liver transplant evaluation: an evaluation of its efficacy. Clin Cardiol 2014;37:468–72. [8] Patel S, Kiefer TL, Ahmed A, Ali ZA, Tremmel JA, Lee DP, et al. Comparison of the frequency of coronary artery disease in alcohol-related versus non-alcohol-related endstage liver disease. Am J Cardiol 2011;108:1552–5. [9] Azarbal B, Poommipanit P, Arbit B, Hage A, Patel J, Kittleson M, et al. Feasibility and safety of percutaneous coronary intervention in patients with end-stage liver disease referred for liver transplantation. Liver Transpl 2011;17:809–13. [10] Jacobs E, Singh V, Damluji A, Shah NR, Warsch JL, Ghanta R, et al. Safety of transradial cardiac catheterization in patients with end-stage liver disease. Catheter Cardiovasc Interv 2014;83:360–6. [11] Krill T, Brown G, Weideman RA, Cipher DJ, Spechler SJ, Brilakis E, et al. Patients with cirrhosis who have coronary artery disease treated with cardiac stents have high rates of gastrointestinal bleeding, but no increased mortality. Aliment Pharmacol Ther 2017;46:183–92. [12] Fouad TR, Abdel-Razek WM, Burak KW, Bain VG, Lee SS. Prediction of cardiac complications after liver transplantation. Transplantation 2009;87:763–70. [13] Gologorsky E, Pretto EA, Fukazawa K. Coronary artery disease and its risk factors in patients presenting for liver transplantation. J Clin Anesth 2013;25:618–23. [14] Vanwagner LB, Bhave M, Te HS, Feinglass J, Alvarez L, Rinella ME. Patients transplanted for nonalcoholic steatohepatitis are at increased risk for postoperative cardiovascular events. Hepatology 2012;56:1741–50. (Baltimore, Md.). [15] Konerman MA, Fritze D, Weinberg RL, Sonnenday CJ, Sharma P. Incidence of and risk assessment for adverse cardiovascular outcomes following liver transplantation: a systematic review. Transplantation 2017;101(7):1645–57. [16] Roglic G, Resnikoff S, Strong K, Unwin N. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. http://who.int/diabetes/publications/Definition%20and%20diagnosis%20of %20diabetes_new.pdf. [17] Basile J, Bloch MJ. Overview of hypertension in adults. https://www.uptodate. com/contents/overview-of-hypertension-in-adults?source=search_result&search= arterial%20hypertension&selectedTitle=1~150. [18] Longacre AV, Imaeda A, Garcia-Tsao G, Fraenkel L. A pilot project examining the predicted preferences of patients and physicians in the primary prophylaxis of variceal hemorrhage. Hepatology 2008;47:169–76. (Baltimore, Md.). [19] Boudjema K, Camus C, Saliba F, Calmus Y, Salamé E, Pageaux G, et al. Reduceddose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation. Am J Transplant 2011;23:498–509. [20] Cohen J. A power primer. Psychol Bull 1992;112:155–9. [21] Nemes B, Polak W, Ther G, Hendriks H, Kóbori L, Porte RJ, et al. Analysis of differences in outcome of two European liver transplant centers. Transpl Int 2006;19:372–80. [22] Volk ML, Reichert HA, ASF Lok, Hayward RA. Variation in organ quality between liver transplant centers. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 2011;11:958–64. [23] Malik MU, Russell SD, Pustavoitau A, Chacko M, Cosar AM, Thompson CB, et al. The predictors of post-transplant coronary events among liver transplant recipients. Hepatol Int 2016;10:974–82. [24] Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988–2012. JAMA 2015;314:1021–9. [25] Tamayo T, Brinks R, Hoyer A, Kuß OS, Rathmann W. The prevalence and incidence of diabetes in Germany. Dtsch Arztebl Int 2016;113:177–82. [26] Patel SA, Winkel M, Ali MK, Venkat Narayan KM, Mehta NK. Cardiovascular mortality associated with 5 leading risk factors: national and state preventable fractions estimated from survey data. Ann Intern Med 2015;163:245–53. [27] Kathleen EC, Cohen DE. Lipid and lipoprotein metabolism in liver disease. http:// www.ncbi.nlm.nih.gov/books/NBK326742/. [28] Farzadfar F, Finucane MM, Danaei G, Pelizzari PM, Cowan MJ, Paciorek CJ, et al. National, regional, and global trends in serum total cholesterol since 1980:

[29]

[30]

[31]

[32] [33]

[34] [35]

[36] [37]

[38]

[39]

[40] [41]

[42] [43]

[44]

[45]

[46]

[47] [48]

5

systematic analysis of health examination surveys and epidemiological studies with 321 country-years and 3.0 million participants. Lancet 2011;377:578–86. (London, England). Laish I, Braun M, Mor E, Sulkes J, Harif Y, Ben Ari Z. Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events. Liver Transpl 2011;17:15–22. Yoon JW, Jung C, Kim M, Park HE, Park KS, Jang HC, et al. Influence of the definition of “metabolically healthy obesity” on the progression of coronary artery calcification. PloS One 2017;12:e0178741. Janhsen K, Strube S, Starker A. Hypertonie. Gesundheitsberichterstattund des Bundes. 2008;12http://edoc.rki.de/documents/rki_fv/ren4T3cctjHcA/PDF/ 23zMV5WzsY6g_26.pdf. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988–2008. JAMA 2010;303:2043–50. Malarcher A, Dube S, Shaw L, Babb S, Kaufmann R. Quitting smoking among adults—United States, 2001–2010. MMWR Morb Mortal Wkly Rep 2011;60:1513–9. Lampert T, von der Lippe E, Müters S. Verbreitung des Rauchens in der Erwachsenenbevölkerung in Deutschland. Bundesgesundheitsbl 2013;56:802–8. Center of Disease Control. Rates of diagnosed diabetes per 100 civilian, non-institutionalized population, by age, United States, 1980–2014. http://www.cdc.gov/ diabetes/statistics/prev/national/figbyage.htm. Heidemann C, Du Y, Scheidt-Nave C. Diabetes mellitus in Deutschland. www.rki. de/gbe-kompakt; 2011. Brinks R, Bardenheier BH, Hoyer A, Lin J, Landwehr S, Gregg EW. Development and demonstration of a state model for the estimation of incidence of partly undetected chronic diseases. BMC Med Res Methodol 2015;15:98. García-Compeán D, González-González JA, Lavalle-González FJ, González-Moreno EI, Villarreal-Pérez JZ, Maldonado-Garza HJ. Current concepts in diabetes mellitus and chronic liver disease: clinical outcomes, hepatitis C virus association, and therapy. Dig Dis Sci 2016;61:371–80. García-Compeán D, Jáquez-Quintana JO, Lavalle-González FJ, Reyes-Cabello E, González-González JA, Muñoz-Espinosa LE, et al. The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study. Ann Hepatol 2012;11:240–8. Berry JD, Dyer A, Cai X, Garside DB, Ning H, Thomas A, et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012;366:321–9. Lentine KL, Costa SP, Weir MR, Robb JF, Fleisher LA, Kasiske BL, et al. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2012;60:434–80. Dalal A. Organ transplantation and drug eluting stents: perioperative challenges. World J Transplant 2016;6:620–31. Satapathy SK, Vanatta JM, Helmick RA, Flowers A, Kedia SK, Jiang Y, et al. Outcome of liver transplant recipients with revascularized coronary artery disease: a comparative analysis with and without cardiovascular risk factors. Transplantation 2017;101:793–803. Wray C, Scovotti JC, Tobis J, Niemann CU, Planinsic R, Walia A, et al. Liver transplantation outcome in patients with angiographically proven coronary artery disease: a multi-institutional study. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 2013;13:184–91. Yong CM, Sharma M, Ochoa V, Abnousi F, Roberts J, Bass NM, et al. Multivessel coronary artery disease predicts mortality, length of stay, and pressor requirements after liver transplantation. Liver Transpl 2010;16:1242–8. Skaro AI, Gallon LG, Lyuksemburg V, Jay CL, Zhao L, Ladner DP, et al. The impact of coronary artery disease on outcomes after liver transplantation. J Cardiovasc Med (Hagerstown) 2016;17:875–85. Daniel KE, Eickhoff J, Lucey MR. Why do patients die after a liver transplantation? Clin Transplant 2017;31:e12906. D'Avola D, Cuervas-Mons V, Martí J, Ortiz de Urbina J, Lladó L, Jimenez C, et al. Cardiovascular morbidity and mortality after liver transplantation: the protective role of mycophenolate mofetil. Liver Transpl 2017;23:498–509.