Bringing Harmony to the Cacophony of Cardiovascular Disease Assessment for Potential Kidney Liver Transplant Candidates. A Case for Assimilating the New AHA/ACCF Guidelines

The publication this month of the AHA/ACCF scientific statement “Cardiovascular Disease Evaluation and Management Among Kidney and Liver Transplant Candidates” by Eagle et al. might be initially interpreted by some as evidence of guideline “saturation” particularly in light of the extensive 2007 AHA/ACCF preoperative guidelines for non-cardiac surgery and the recently revised guidelines for indications for coronary artery bypass graft surgery.^1,2 However, as a cardiologist who oversees the preoperative assessment of potential renal and pancreas recipients at a very large program that continues to expand the limits for potential recipients and donors alike, the extensive review and synthesis of the available literature on multiple topics applicable to these transplant candidates is much appreciated. Adaptation of these guidelines will likely improve uniformity of care across centers and minimize testing of limited value. Cohesion of cardiac preoperative risk assessment and management across centers can’t be understated with many transplant candidates seeking listing at multiple centers to potentially improve their chance of transplantation. Currently, these patients are often faced with divergent opinions and conflicting requests for preoperative cardiac testing ranging from no testing to routine coronary angiography.

Perceptively, the authors of these guidelines first address the issue of the need for separate guidelines for renal and liver transplant patients in the first section of the document. With 85,000 patients awaiting a kidney or pancreas as of 2010, these patients are likely to be encountered in the practices of many general cardiologists. With dialysis being available to an increasingly older and sicker patient population it comes as no surprise that potential transplant receipts are older and increasing medically complex despite typically being “asymptomatic” from a cardiovascular standpoint. Based on Medicare claims data, the incidence of myocardial infarction during the three years after being listed for renal transplantation (a typical waiting time) ranges from 8.7% to 16.7%.^3,4 Complicating a harmonious approach to cardiovascular preoperative risk assessment in this inherently high-risk population is the divergence of preoperative risk assessment guidelines from two major professional societies. First, the familiar ACC/AHA “Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery” doesn’t recommend further cardiovascular testing in individuals who can perform 4 METS of work.¹ However, this guideline is not specific to organ transplant recipients and anticipates that surgery will soon follow the evaluation. In contrast, the 2005 National Kidney Foundation “Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients” recommends more aggressive screening of end-stage renal disease (ESRD) patients.⁵ This includes annual non-invasive cardiac testing in ESRD patients with diabetes or known coronary disease while awaiting transplant. The details of these prior intermittently conflicting guideline documents are provided in detail in Table 2 of the new AHA/ACCF guidelines. The heterogeneity of the approach to renal transplant evaluations has been shown with surveys and retrospective analysis of Medicare claims. At a center and patient level, compliance with the more aggressive screening guidelines can be troublesome, with seemingly suitable transplant candidates being passed over at last minute due to the absence of a negative or unchanged non-invasive stress test within the past 12 months. Recognition of this problem at our own institution necessitated a careful review of our outcome data, literature review, rewrite of our SOP’s and extensive educational efforts for all stake holders (cardiology, nephrology, surgery, anesthesia and administrative staff). The present guidelines present an extensive summary of available studies and summarize the efficacy of routine use of coronary angiography (Table 4), non-invasive testing (Table 5) and even measurement of cardiac troponins (Table 6). The authors highlight the diagnostic limitations of non-invasive testing for coronary disease and provide data suggesting the limited efficacy of adenosine as a myocardial microcirculation pharmacologic stress agent in diabetic patients with ESRD.⁶ The authors ultimately provide the following summary recommendations for initial evaluation and follow-up surveillance in potential kidney recipients without a recent acute coronary syndrome, decompensated heart failure or other high-risk cardiac condition.

1. Noninvasive stress testing may be considered in kidney transplant candidates with no active cardiac conditions based on the presence of multiple CAD risk factors regardless of functional status (Class IIb, Level of Evidence (LOE) C).
2. Currently there is no strong evidence for or against periodically screening asymptomatic kidney transplant candidates for myocardial ischemia while on the transplant waiting list to improve the risk of major adverse cardiac events (Class IIB, LOE C).

In recognition of the prognostic and management implications associated with an abnormal left ventricular ejection fraction (LVEF) the guidelines provide a higher level of recommendation for assessment of LVEF (Class IIa, level of evidence B).

1. It is reasonable to perform preoperative assessment of left ventricular function by echocardiography or Multi Gated Acquisition (MUGA) nuclear scan in potential kidney transplant candidates. There is currently no evidence for or against surveillance by repeated left ventricular function tests after listing for kidney transplantation.

Another controversial issue the authors tackle is the use of prophylactic coronary revascularization to reduce perioperative cardiovascular risk as early data from a small randomized study suggested this could be an advantageous approach to reduce cardiovascular events in ESRD patients.⁷ The authors draw inferences from the neutral CARP and DECREASE V revascularization versus medical management trials of vascular surgery patients with coronary disease to ultimately recommend indications for revascularization in pre-transplant ESRD patients be identical to what is proposed in the 2011 ACCF/AHA Guidelines for Coronary Artery Bypass Graft Surgery (reproduced in Table 7 of the guidelines).² Review of these data re-emphasizes the poor intermediate term prognosis for ESRD patients even after successful revascularization with a 42% post-CABG 3-year survival in those with ESRD compared to an 85%-90% post-CABG 5-year survival in the general population.^8,9 The choice of the type of revascularization maybe also particularly important to discuss with the patient and interventional cardiologist. Due to risk for in-stent thrombosis, current guidelines consider transplantation within the following time periods (see below) based on the use of balloon angioplasty, bare metal stents and drug eluting stents to be contraindicated (Class III, LOE B). For patients with ESRD, not yet on dialysis, who have a living donor candidate and wish to avoid initiation of dialysis, choice of stent type is important.

1. Transplant surgery is not recommended within 4 weeks of coronary revascularization with balloon angioplasty; within 3 months of bare metal coronary stent placement and within 12 months of drug eluting stent placement, particularly if the anticipated time of post?stent dual antiplatelet therapy will be shortened.

The guidelines discuss in detail the evolving evidence for and against aggressive medical management of hypertension and hyperlipidemia as well as the perioperative use of beta-blockers. Particular time is spent with the recommendations for “statins” given the neutral results of the high profile 4D and AURORA studies in ESRD dialysis patients.^10,11 However, incorporating the recent results of the SHARP study, showing a similar benefit in ESRD dialysis patients as earlier stage renal patients, when evaluating fatal and non-fatal atherosclerotic events¹² along with analysis of vascular surgery specific trials of statins, the guideline authors recommend for patients undergoing renal transplantation, and where preoperative evaluation established unequivocal evidence of atherosclerosis, it is reasonable to initiate low to moderate dose statin therapy preoperatively and continue treatment postoperatively. (IIa, level of evidence B). For those already taking a statin it is recommended the statin be continued peri- and postoperatively (Class I, LOE B). It is also noted that statins have no role in preventing rejection postoperatively.

To a lesser extent the guidelines discuss the risk stratification and cardiovascular management of patients considered for liver transplantation. Compared to patients evaluated for renal transplantation, liver transplant candidates are typically younger, have less cardiac comorbidities, overall have much lower cardiovascular risk, but are more acutely ill as a result of their liver failure and have considerably shorter waiting times until transplantation. However, there are cardiopulmonary problems that are both unique and highly prevalent in patients with liver failure. These include pulmonary hypertension (pulmonary artery systolic pressure > 30 mm Hg in 20%)¹³ and the hepatopulmonary syndrome (prevalence of 47%)¹⁴ , defined as hypoxia from intrapulmonary shunts in patients with cirrhosis and portal hypertension. Severe pulmonary artery systolic blood pressure > 60 mmHg is associated with a poor prognosis in liver transplant patients and hypoxia due to the hepatopulmonary syndrome often resolves with transplantation. Due to the importance of identifying these conditions the guidelines recommend routine echocardiography (typically this would include an intravenous saline contrast injection) (Class IIa, LOE B). Identification of pulmonary hypertension with follow-up right heart catheterization (mean PA pressure ≥ 25 mm Hg with a normal pulmonary capillary wedge pressure and increased pulmonary vascular resistance) should necessitate referral to a physician with expertise in the management of pulmonary hypertension. In contrast, the evaluation for coronary disease with non-invasive testing should only be under taken under specific circumstances with <10% of liver transplant candidates having a positive stress response in an all-comers liver transplant candidate population. Because these patients are already vasodilated imaging tests based on pharmacologic vasodilators may perform poorly. Dobutamine stress echocardiography may be a better choice. For coronary angiography with the presence of a coagulopathy, vascular complications and major bleeding requiring transfusion are much more common than in controls. The guidelines report there is no information in the literature about percutaneous coronary interventions in liver failure patients with cirrhosis, but recommend bare metal stents to minimize the time requiring duel anti-platelet therapy. There is outcome data associated with CABG and it is directly associated with Child-Pugh class.¹⁵ One-year survival including in-hospital mortality was 80% in Childs A, 45% in Childs B, and 16% in Childs C patients respectively.

In summary, these guidelines represent a much need authoritative document reviewing the state of the evidence for preoperative risk assessment, pre- and perioperative care to mitigate cardiovascular risk in solid organ transplant candidates. If widely adopted, particularly by physicians and centers involved with renal transplantation, less heterogeneity would result, potentially expediting evaluations and further improving outcomes. However, as the authors suggest, there is still much to be learned as to what is the optimal evaluation and cardiovascular prevention strategies in these high-risk patients. These guidelines represent a great platform from which future clinical trials can be considered (Suggestions for such trials appear in the guidelines Box 2).