Prognostic value of coronary risk factors, exercise capacity and single photon emission computed tomography in liver transplantation candidates: A 5-year follow-up study

Abstract

Background: Although consensus-based guidelines support noninvasive stress testing prior to orthotopic liver transplantation (OLT), the optimal screening strategy for assessment of coronary artery disease in patients with end-stage liver disease (ESLD) is unclear. This study sought to determine the relative predictive value of coronary risk factors, functional capacity, and single photon emission computed tomography (SPECT) on major adverse cardiovascular events and all-cause mortality in liver transplantation candidates.

Methods: Prior to listing for transplantation, 404 consecutive ESLD patients were referred to a University hospital for cardiovascular (CV) risk stratification. All subjects met at least one of the following criteria: inability to perform > 4 METs by history (62%), insulin-treated diabetes mellitus (53%), serum creatinine > 1.72 mg/dL (8%), history of MI, PCI or CABG (5%), stable angina (3%), cerebrovascular disease (1%), peripheral vascular disease (1%). Subjects underwent Technetium-99m SPECT with multislice coronary artery calcium scoring (CACS) using exercise treadmill or standard adenosine stress in those unable to achieve 85% maximal heart rate (Siemens Symbia T16). Abnormal perfusion was defined as a summed stress score (SSS) ≥ 4.

Results: Of the 404 patients, 158 (age 59 ± 9 years; male 68%) subsequently underwent transplantation and were included in the primary analysis. Of those, 50 (32%) died after a mean duration follow-up of 5.4 years (maximal 10.9 years). Most deaths (78%) were attributed to noncardiovascular causes (malignancy, sepsis, renal failure). Of the 32 subjects with abnormal perfusion (20%), nine (6%) had a high-risk perfusion abnormality defined as a total perfusion defect size (PDS) ≥ 15% and/or an ischemic PDS ≥ 10%. Kaplan-Meier survival curves demonstrated abnormal perfusion was associated with increased CV mortality (generalized Wilcoxon, P = 0.014) but not all-cause death. Subjects with both abnormal perfusion and an inability to exercise > 4 METs had the lowest survival from all-cause death (P = 0.038). Abnormal perfusion was a strong independent predictor of CV death (adjusted HR 4.2; 95% CI 1.4 to 12.3; P = 0.019) and MACE (adjusted HR 7.7; 95% CI 1.4 to 42.4; P = 0.018) in a multivariate Cox regression model that included age, sex, diabetes, smoking and the ability to exercise > 4 METs. There was no association between CACS and the extent of perfusion abnormality, nor with outcomes.

Conclusions: Most deaths following OLT are noncardiovascular. Nonetheless, abnormal perfusion is prevalent in this high-risk population and a stronger predictor of cardiovascular morbidity and mortality than functional status. A combined assessment of functional status and myocardial perfusion identifies those at highest risk of all-cause death. (Exercise Capacity and Single Photon Emission Computed Tomography in Liver Transplantation Candidates [ExSPECT]; ClinicalTrials.gov Identifier: NCT03864497).

Keywords: SPECT; diagnostic and prognostic application; exercise testing; outcomes research; vasodilators.

© 2020. The Author(s).

Figures

Figure 1

Study consort diagram. Abbreviations: OLT, orthotopic liver transplantation; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery

Figure 2

Relation between CACS severity and stress SPECT results (n = 84). The percentage of subjects with a normal SPECT result was highest in those with minimal CACS (P < 0.001). A 4 × 2 contingency analysis was performed using a two-tailed Fisher’s exact test to determine significance

Figure 3

Kaplan–Meier curve for unadjusted cumulative survival from (A) cardiovascular death and (B) all-cause death according to perfusion dichotomized by a summed stress score ≥ 4. Two-sided generalized Wilcoxon tests were used to determine significance

Figure 4

Kaplan–Meier curve for unadjusted cumulative survival from (A) cardiovascular death and (B) all-cause death according to functional capacity dichotomized by estimated METs ≤ 4. Two-sided generalized Wilcoxon tests were used to determine significance

Figure 5

Kaplan–Meier curve for unadjusted cumulative survival from (A) cardiovascular death and (B) all-cause death according to integrated results of SPECT and exercise capacity. Two-sided generalized Wilcoxon tests were used to determine significance

Figure 6

Annualized event rates for (A) cardiovascular death and (B) all-cause death according to integrated results of SPECT and exercise capacity. (A) For each subgroup (number of CV deaths/number of patients): METs ≥ 4, normal perfusion (1/59); METs <4, normal perfusion (4/67); METs ≥ 4, abnormal perfusion (2/15); METS <4, abnormal perfusion (4/17). (B) For each subgroup (number of all-cause deaths / number of patients): METs ≥ 4, normal perfusion (15/60); METs <4, normal perfusion (26/66); METs ≥ 4, abnormal perfusion (2/15); METS <4, abnormal perfusion (7/17)

Figure 7

Incremental predictive value of exercise capacity and stress SPECT results over clinical information to predict cardiovascular death. The clinical data entered into the global Chi-square analysis model included age, sex, diabetes, smoking history. Abnormality on SPECT (defined as SSS ≥ 4) and exercise capacity (METs