Trials and Tribulations of Cardiac Screening Asymptomatic Kidney and Liver Transplant Candidates

The American Heart Association (AHA) has released a scientific statement highlighting screening challenges, emerging evidence, and new approaches for the pre-transplant evaluation of kidney or liver transplant candidates deemed at high risk for major adverse cardiovascular events (MACE). This is an important issue as the significant burden of cardiovascular disease in the setting of end-stage organ disease makes peri- and post-operative MACE a major concern. The statement summarizes the paradox between the current ubiquitous practice of screening for coronary heart disease (CHD) in candidates deemed at high risk for MACE (defined heterogeneously by each transplant center) versus the scant evidence base to support it among some cohorts. While many suggestions in the AHA statement are compatible for both solid organ settings, there are some distinctions for liver versus kidney transplantation and other distinctions for symptomatic versus non symptomatic transplant candidates.

Cardiac screening for CHD in symptomatic kidney or liver transplant candidates is easily justified, with good evidence base to support further investigation and/or intervention, and the AHA statement includes rational investigation pathways. However, cardiac screening for CHD in asymptomatic individuals is also endorsed with stratified pathways despite weaker evidence base. Some asymptomatic kidney transplant candidates will escape additional cardiac testing if they fulfill all the following criteria: 1) normal electrocardiogram, 2) normal resting transthoracic echocardiogram, 3) no additional risk factors (age <60 years, no diabetes mellitus, no smoking, no peripheral arterial disease, no cerebrovascular disease) and, 4) duration of combined dialysis and prior kidney transplant <5 years). Similarly, a handful of asymptomatic liver transplant candidates will also escape the need for additional testing: 1) age <40 years, 2) ability to achieve ≥4 metabolic equivalent of tasks (METs), 3) no non-alcohol related steatohepatitis (NASH) and, 4) no CHD risk factors (including hyperlipidemia/dyslipidemia, diabetes, hypertension/history of hypertension, chronic kidney disease, left ventricular hypertrophy, family history of premature CHD, active or past tobacco use, coronary artery calcification score >0). However, this represents a minority of kidney or liver transplant candidates, and most will be subjected to additional cardiac testing to be deemed suitable for waitlisting.

While acknowledging dissenting voices that question the utility of such strategies in asymptomatic transplant candidates, the AHA statement justifies their rationale for stratified screening of asymptomatic abdominal transplant candidates based on four key factors. Firstly, echocardiography is recommended for CHD screening of every kidney or liver transplant candidate, and this is sensible. Echocardiography is widely available, inexpensive and clinically useful. Not only does echocardiography evaluate left ventricular ejection fraction, which has important peri- and post-operative management considerations, it can identify significant valvular heart disease that may require intervention prior to transplantation surgery. This is important as the epidemiology, natural history and risk associated with untreated valvular heart disease after transplantation is not well defined. Echocardiography comes with important caveats; in isolation they should be interpreted with caution. For example, left ventricular dysfunction is common for people with kidney failure¹ and liver failure² and there is good evidence that successful organ transplantation improves this. However, even advocates of a more laisse-faire philosophy to cardiac screening of asymptomatic kidney or liver transplant candidates have little objection with echocardiography.

Secondly, there are concerns at failing to identify a subset of kidney or liver transplant candidates with undetected left main stem disease (LMSD) who may benefit from revascularization. LMSD portends a significantly high prognostic risk due to the large myocardial territory at risk, ranging from 75% to 100%, depending on the dominance of the left coronary circulation.³ Significant LMSD, defined as greater than 50% stenosis, is recommended for revascularization across international guidelines. However, asymptomatic but significant LMSD is not very common. An historical cohort of 13,228 coronary angiograms between 1999 and 2002 identified only 476 (3.6%) with significant LMSD (defined as ≥60% stenosis).⁴ After excluding 200 patients with previous bypass surgery, only 276 (2.1%) had evidence of unprotected LMSD. Caveats for interpreting this data to waitlist candidates includes the historical cohort from two decades ago, only 42% of the LMSD cohort undergoing elective coronary angiography (therefore presumed asymptomatic) and only 4% had evidence of renal impairment (with no mention of liver disease). It is unclear what the prevalence of asymptomatic but significant LMSD is in kidney or liver failure cohorts who undergo transplant assessment but in the contemporary era may be very low. Subjecting over half of all kidney or liver transplant candidates to additional cardiac tests to identify this unknown cohort is akin to “using a sledgehammer to crack a nut”.

Thirdly, while ISCHEMIA-CKD showed no benefit from revascularization in advanced CKD or kidney failure patients with stable CHD, it did not specifically assess the optimal strategy to reduce perioperative events in the context of kidney transplantation.⁵ No randomized controlled trial (RCT) has explored the benefit of screening versus not screening high risk kidney or liver transplant candidates for CHD. The closest comparators are the CARP and DECREASE-V studies, both of which observed no benefit from prophylactic revascularization in asymptomatic vascular surgery candidates.^5,6 In the absence of a definitive RCT, propensity-score matched cohort studies suggest screening for asymptomatic coronary artery disease in low-to-moderate risk kidney transplant candidates does not predict post-transplant MACE.⁷ However, transplant professionals are hesitant to adopt such evidence to the specific setting of kidney and/or liver failure prior to transplantation surgery. This clinical equipoise has led to significant heterogeneity in clinical practice, which leads to inequity of care across transplant centers. From a kidney transplant perspective, a recent survey of kidney transplant units in the United Kingdom highlighted significant enthusiasm for a targeted RCT comparing screening versus non-screening.⁸ However, such RCTs were muted in the United States over a decade ago but proved challenging to establish.⁹ Definitive RCTs randomizing cardiac screening for asymptomatic kidney or liver transplant candidates before joining the waitlist list, however challenging, must be considered a top research priority.

Finally, given the limited availability of deceased donor organs for transplantation, CHD screening may identify patients deemed to be at excessive risk of CHD-related adverse outcomes (regardless of intervention) for whom transplantation may not yield sufficient benefit to justify use of a scarce organ. This arguably is the main justification for current clinical practice but, if organ supply was not a concern, would we retain such rigorous CHD testing? The answer to this is likely yes as, mindful of regulatory oversight and/or medico-legal pressures to optimize the assessment process to mitigate perceived risk, transplant clinicians feel under pressure to conform to what is widely accepted as standard of care despite the lack of any robust evidence to support that notion. Even in the setting of RCTs, which provide the highest level of clinical evidence, cognitive biases can overrule well defined trial protocols. For example, high rates of revascularization were observed in both study arms from ISCHEMIA-CKD for waitlisted kidney transplant candidates at 33% versus 16% for invasive versus conservative guideline-directed medical therapy arms respectively.¹⁰ This crossover risk was 7-fold higher in waitlisted versus non-waitlisted study participants, likely skewing bias towards the null hypothesis and reducing study power to show any true difference. Revascularization decisions should be individualized, balancing known risks (e.g., upfront risk of triggering MACE and delay to listing) versus unknown benefit (e.g., prevention of cardiac events). For transplant clinicians, such decisions regarding waitlisted transplant candidates are driven by consideration of professional and/or institutional risk rather than any risk-versus-benefit calculation faced by the patient.

The AHA statement may be more pertinent to the United States than elsewhere. While CHD screening for asymptomatic kidney or liver transplant candidates is ubiquitous international practice, MACE rates are not globally equivalent. For example, MACE rates after kidney transplantation during the index admission in the United States are reported at 6.5% (n=9,592/147,431 for a 2004-2013 cohort) with 685 fatal MACE episodes (0.5%).¹¹ These rates contrast sharply with England, where MACE rates within the first 30-days post kidney transplantation are reported at only 0.9% (n=278/30,325 for a 2002-2018 cohort) with just 11 fatal MACE episodes [<0.1%]).¹² MACE rates after liver transplantation in the United States are reported higher at 8% within 30-days, although myocardial infarcts only comprised 7% of case and 43% of events were due to atrial fibrillation.¹³ No large epidemiological study reporting MACE rates after liver transplantation in Europe is reported. Disparity in care¹⁴ and post-transplant outcomes^15,16 between the United States and elsewhere is important to acknowledge, which will influence translatability of the AHA scientific statement to other countries. Why post-transplant MACE rates are higher in the United States than elsewhere is an intriguing question and warrants further investigation.

In the absence of direct clinical evidence, most clinicians and many centers will find it difficult to scrap CHD screening for any high-risk kidney or liver transplant candidates. The AHA statement is aligned with this reality, acknowledging clinical equipoise but understandably siding with caution rather than venturesome. However, current practice to screen most asymptomatic kidney or liver transplant candidates to rule out significant CHD is overzealous. The statement is not a clinical practice guideline, offering suggestions not recommendations, but could form the basis of future clinical practice guidelines. Such guidelines would be valuable as post-transplant MACE is a major cause of post-operative mortality and non-fatal MACE associated with inferior long-term survival.¹² Modification of pre-transplant cardio-metabolic risk factors should be encouraged using multi-disciplinary interventions. Strategies to mitigate the peri- and immediately post-operative MACE risk are required, being the high-risk period after kidney or liver transplantation for cardiac events. Focus on guideline-directed medical therapy to manage CHD is important, with optimization of strategies to implement transplant-specific practice. All these strategies are rationale, with no widely accepted standard of care, and should be actively explored. However, cardiac screening asymptomatic abdominal transplant candidates is considered standard of care despite evidence to the contrary. Among the large number of kidney or liver failure transplant candidates that are assessed, a small number of asymptomatic individuals may have critical CHD such as LMSD which may be amenable to intervention to reduce the risk of peri- or post-operative MACE. The best mechanism to identify this tiny minority, without disadvantaging the vast majority, is not clear. Lack of consensus due to sub-optimal clinical evidence is leading to heterogenous practice and inequity of access between different transplant units.

While the AHA statement is pragmatic, it should challenge the dogmatic practice of screening asymptomatic transplant candidates for CHD which is well intentioned but ineffectual. Providing wriggle room for centers to challenge the status quo, with innovation and disruptive practice, can ameliorate regulatory pressure for calculated risk taking.¹⁷ The current practice of cardiac screening asymptomatic transplant candidates seems illogical; we are searching for something to fix (CHD) despite lacking any evidence we can fix it (revascularization) and delaying or denying people receiving the thing that will actually reduce the risk (transplantation). The AHA statement is mindful of real-world practice but heedful of clinical equipoise. While expertly handling this juxtaposition with practical suggestions of who to scan, it deftly sidesteps the crucial philosophical question of why we scan. The latter is the more critical conundrum for the medical community to address.