Abstract
Introduction: Lung transplantation (LT) is a lifesaving procedure in patients with end stage lung failure. The prevalence of coronary artery disease (CAD) in patients with lung disease is comparably high, and coronary angiography is widely used for coronary anatomy assessment prior to LT. Detection of significant CAD usually results in revascularization to minimize posttransplant cardiovascular events. We aim to examine the prognostic significance of CAD interventions on LT candidates pre- and post-LT. Methods: From a retrospective registry of 450 LT candidates undergoing cardiac catheterization during 2014–2019, patients were assessed for the presence of significant CAD and percutaneous coronary intervention. The primary outcome was defined as occurrence of major advance cardiac events (MACE) in LT candidates while on the waiting list. MACE comprising of cardiovascular mortality, nonfatal myocardial infarction, target-vessel revascularization, and coronary artery bypass graft surgery. Secondary outcomes were the occurrence of MACE posttransplant according to the coronary intervention status. Results: MACE was recorded in 22 LT candidates, with a higher incidence in the intervention group compared to the nonintervention group (8.3% vs. 4.4%, p = 0.007). 28.6% of MACE events in the intervention group occurred in the first month after intervention. Cardiovascular mortality accounted for 8.6% of all deaths, without significant difference between the intervention and nonintervention group (16.0% vs. 7.2%, p = 0.155). The rates of MACE post-LT were mildly and nonsignificantly increased in the intervention group compared to the nonintervention group (11.1% vs. 4.5%, p = 0.18). Conclusion: Pre-LT routine coronary intervention does not necessarily protect patients from experiencing MACE while on the waiting list or post-LT.
Introduction
The prevalence of coronary artery disease (CAD) in patients with lung disease is comparably high, especially among patients with chronic obstructive lung disease (COPD) and idiopathic pulmonary fibrosis [1‒3]. Coronary angiography (CA) is widely used for coronary anatomy assessment in lung transplant (LT) candidates [4], although this is not mandatory according to guidelines [5‒7]. The general burden of atherosclerotic disease was found to be associated with reduced overall survival and is thus used for risk assessment of end-organ disease after transplantation [8‒10]. Moreover, the detection of significant CAD usually results in revascularization via surgical bypass or percutaneous intervention (PCI) of the affected artery, aiming to minimize posttransplant cardiovascular events [11‒13].
Previous studies assessing groups of LT candidates have found significant CAD in 10–11% of the patients [10, 14‒18]. Nevertheless, the rates of cardiovascular events in LT candidates, while on the waiting list, are not reported, and the rates of cardiovascular events posttransplant vary significantly in different series. One publication examining 274 LT patients reported 1.7% cardiovascular mortality in patients with CAD versus 0.6% in those without CAD during 1-year follow-up [19]. Another cohort reported 1-year rate of cardiovascular events in 11.9% of the patients with CAD compared to 0.6% of the patients with nonsignificant CAD (p < 0.001) [20]. We aim to examine the prognostic significance of coronary artery intervention in a large contemporary cohort of LT candidates in two time periods – while on the waiting list, and after lung transplant.
Methods
This is an observational study based on a retrospective cohort of LT candidates evaluated by CA at two campuses of Rabin Medical Center (Beilinson and Hasharon hospitals) from January 2014 to December 2019. Data were entered into a registry following ICD-9 diagnoses to monitor patient-related variables and demographics, angiographic findings, and clinical events. Mortality outcome was retrieved through the hospital administration system, which is updated by the Israel’s Ministry of Health’s registry. The study included patients aged 18 years or older. For each patient, a comprehensive medical history was collected, including demographics (age and gender), medical history (diabetes, hypertension, smoking, COPD, peripheral vascular disease (PVD), cerebrovascular accidents (CVAs), and lipid profile), lung failure etiology, and lung transplant records (date and single lung or double lung transplant). Pretransplant cardiac workup details were recorded including basic echocardiographic data, right heart catheterization, CA, and intervention. Patients were categorized based on their coronary intervention status.
Study Endpoints
In-hospital and clinical events were retrospectively collected in the institutional database. When indicated, records from other hospitals were acquired to verify the events in the follow-up period. The primary outcome was defined as occurrence of major advance cardiac events (MACEs) in LT candidates while on the waiting list. MACE comprising of cardiovascular mortality, nonfatal myocardial infarction (MI), target-vessel revascularization, and coronary artery bypass graft surgery. MI was defined according to the fourth universal definition of MI type 1 or type 2 [21]. Secondary outcome was all-cause mortality. A separate analysis assessing the occurrence of MACE and all-cause mortality posttransplant was performed in patients who underwent LT. In this analysis, events were recorded only if they occurred posttransplant.
Statistical Methods
To test the association between two categorical variables the χ2 test as well as the Fisher’s exact test was used. The comparison of a quantitative variable between two independent groups was performed by using the two-sample t test. The logistic regression multivariate model was applied for simultaneously assessing the effect of several variables on a dichotomous dependent variable. The model was applied using the “ENTER” method or the Stepwise, Forward, Likelihood ratio method. The Kaplan-Meier model was used for assessing the effect of categorical variables on survival, using the log-rank test for comparing survival curves. All statistical tests were two-tailed, and a p value of 0.05 or less was considered statistically significant.
Results
A total of 450 LT candidates undergoing cardiac catheterization during 2014–2019 were available for analysis. The most common etiology of lung failure was pulmonary fibrosis and ILD, followed by COPD (Table 1). On CA, 22.4% of the patients had obstructive CAD. 14.2% had single vessel disease, 6.4% had two affected vessels and 1.7% had multivessel disease. The left anterior descending coronary artery was affected in 51.5% of the patients with CAD, followed by the left circumflex coronary artery (43.6%), right coronary artery (42.6%), and left main disease (5.9%). A total of 84 patients (19.7%) underwent PCI. The prevalence of significant CAD was highest among patients with pulmonary fibrosis and COPD (Table 1). Concerning traditional risk factors, diabetes, hypertension, dyslipidemia, and male gender were highly more prevalent in the intervention group compared to the nonintervention group. Past diagnosis of ischemic heart disease was present in over 90% of the patients who required intervention compared to only 10.4% in the nonintervention group (Table 2). Duration of follow-up was 34.02 ± 24.50 months.
Etiologies of lung failure
Etiology of lung failure . | Prevalence, % . | Prevalence of CAD, % . |
---|---|---|
Fibrosis and ILD | 49.7 | 50.3 |
COPD | 34.4 | 18.5 |
Other (toxic or autoimmune) | 7.2 | 12.5 |
PPAH | 5.7 | 17.4 |
Bronchi-ectasia | 2.9 | 9.1 |
Etiology of lung failure . | Prevalence, % . | Prevalence of CAD, % . |
---|---|---|
Fibrosis and ILD | 49.7 | 50.3 |
COPD | 34.4 | 18.5 |
Other (toxic or autoimmune) | 7.2 | 12.5 |
PPAH | 5.7 | 17.4 |
Bronchi-ectasia | 2.9 | 9.1 |
ILD, interstitial lung disease; COPD, chronic obstructive pulmonary disease; PPAH, primary pulmonary arterial hypertension; CAD, coronary artery disease.
Baseline characteristics of LT candidates, according to the percutaneous coronary intervention status
. | No intervention (N = 345) . | Intervention (N = 84) . | p value . |
---|---|---|---|
Sex, male, % | 60.0 | 77.4 | p = 0.003 |
Age (mean ± SD), years | 61±7.6 | 64.2±9.3 | p = 0.001 |
COPD, % | 45.2 | 40.5 | p = 0.433 |
DM, % | 32.5 | 47.6 | p = 0.009 |
HTN, % | 30.7 | 57.1 | p < 0.001 |
Hyperlipidemia, % | 35.1 | 53.6 | p = 0.002 |
CKD, % | 7.6 | 10.7 | p = 0.356 |
Smoking, % | 37.4 | 44.0 | p = 0.217 |
Steroids, % | 44.2 | 36.9 | p = 0.144 |
Past CAD, % | 10.4 | 91.7 | p < 0.001 |
Good LV function (EF >=55%), % | 94.8 | 90.0 | p = 0.138 |
Mild LV dysfunction (45–55%), % | 4.6 | 7.5 | |
RV dysfunction, % | 11.0 | 10.0 | p = 0.788 |
Significant tricuspid regurgitation, % | 1.4 | 0.0 | p = 0.539 |
Mitral annulus calcification, % | 3.1 | 11.3 | p = 0.007 |
Moderate mitral stenosis, % | 0.6 | 0.0 | |
Significant mitral regurgitation, % | 0.9 | 2.5 | p = 0.653 |
Significant aortic valve stenosis, % | 0.6 | 0.0 | p = 1.000 |
. | No intervention (N = 345) . | Intervention (N = 84) . | p value . |
---|---|---|---|
Sex, male, % | 60.0 | 77.4 | p = 0.003 |
Age (mean ± SD), years | 61±7.6 | 64.2±9.3 | p = 0.001 |
COPD, % | 45.2 | 40.5 | p = 0.433 |
DM, % | 32.5 | 47.6 | p = 0.009 |
HTN, % | 30.7 | 57.1 | p < 0.001 |
Hyperlipidemia, % | 35.1 | 53.6 | p = 0.002 |
CKD, % | 7.6 | 10.7 | p = 0.356 |
Smoking, % | 37.4 | 44.0 | p = 0.217 |
Steroids, % | 44.2 | 36.9 | p = 0.144 |
Past CAD, % | 10.4 | 91.7 | p < 0.001 |
Good LV function (EF >=55%), % | 94.8 | 90.0 | p = 0.138 |
Mild LV dysfunction (45–55%), % | 4.6 | 7.5 | |
RV dysfunction, % | 11.0 | 10.0 | p = 0.788 |
Significant tricuspid regurgitation, % | 1.4 | 0.0 | p = 0.539 |
Mitral annulus calcification, % | 3.1 | 11.3 | p = 0.007 |
Moderate mitral stenosis, % | 0.6 | 0.0 | |
Significant mitral regurgitation, % | 0.9 | 2.5 | p = 0.653 |
Significant aortic valve stenosis, % | 0.6 | 0.0 | p = 1.000 |
COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; HTN, hypertension; CKD, chronic kidney disease; CAD, coronary artery disease; LV, left ventricle; RV, right ventricle; MAC, mitral annulus calcification.
During a mean follow-up of 28.13 ± 22.11 months, MACE was recorded in 22 out of 450 LT candidates who were listed for transplant. The incidence of MACE was higher in the intervention group with 8.3% event rate, compared to 4.4% event rate in the non-intervention group, p = 0.007. Differences were mainly driven by cardiovascular death and MI, with 28.6% events of cardiovascular death and 71.4% events of MI in the intervention group compared to 46.7% and 53.3% events in the nonintervention group. MACE was more likely to occur in the first-month post intervention; 28.6% of the events occurred in the first-month post intervention, compared to zero events at 1 month in the nonintervention group (Fig. 1).
MACE curve for patients on the waiting list, comparing patients who had intervention and patients who did not (p = 0.007).
MACE curve for patients on the waiting list, comparing patients who had intervention and patients who did not (p = 0.007).
Overall mortality was high, with 58.0% mortality in LT candidates during follow-up. No significant differences between the groups were observed: 64.6% in the intervention group and 57.3% in the nonintervention group (p = 0.36). The most common cause of death was respiratory failure (47.9%) and cardiovascular mortality accounted for 8.6% of the deaths, mostly heart failure (7.4%). The rate of cardiovascular mortality in the intervention group was 16.0% compared to 7.2% in the non-intervention group (p = 0.155). CVAs, not included in MACE, were recorded in 2.5% of the patients on the waiting list. None of them occurred in the intervention group.
In the second part of the analysis, we examined the impact of pretransplant coronary intervention on the incidence of cardiovascular events posttransplant. During follow-up, 169 patients underwent lung transplant, 39.1% had received one lung, and 60.1% had a bilateral lung transplant. Characteristics of transplanted patients are detailed in supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000543400). Out of these 169 patients, 36 (21.3%) have had pretransplant coronary intervention. Mean follow-up posttransplant was 30.07 ± 23.81 months. The rates of posttransplant MACE were mildly and nonsignificantly increased in the intervention group compared to the nonintervention group, 11.1% vs. 4.5%; p = 0.18 (Fig. 2).
Posttransplant MACE curve comparing patients who had intervention and patients who did not (p = 0.18).
Posttransplant MACE curve comparing patients who had intervention and patients who did not (p = 0.18).
Overall mortality rate was 37.9% with no significant differences between the groups: 43.2% in the intervention group and 36.7% in the nonintervention group (p = 0.37). The most common cause of death was infection (42.2%), followed by respiratory failure (31.3%). Cardiovascular mortality accounted for 4.7% of the deaths, 6.3% in the intervention group, and 4.4% in the nonintervention (p = 0.58). CVAs were recorded in 4.7% of the patients posttransplant, 90% of them in the nonintervention group.
Discussion
The current study aimed to examine the prognostic impact of pretransplant coronary intervention in two different analyses: first, in LT candidates on the waiting list, and second, after transplant. We found that among patients on the waiting list, those who have required coronary intervention were more likely to experience MACE compared to the nonintervention group. This might be attributed by the risk factors found more commonly among the intervention group, although data may suggest contribution of the intervention itself with about a quarter of the events occurring in close proximity to it. Whether avoiding intervention in those with significant CAD and lung disease would have resulted in different rates of MACE is difficult to determine. Intervention could have potentially decreased the rates of events. Nevertheless, the close proximity of about a quarter of the cardiovascular events to the intervention suggests that the procedure itself may predispose patients to cardiovascular complications and recurrent PCI. Moreover, it is important to mention that mortality rates were overall high, with no significant differences between groups, and mild contribution of cardiovascular causes to mortality.
Posttransplant analysis revealed that the incidence of MACE and cardiovascular mortality was relatively low, without significant differences between groups. A possible explanation is that infection and respiratory failure are frequent etiologies of mortality in this population that occur early after transplant [22‒24], so that cardiovascular causes have only a minor contribution. One can assume that longer follow-up could have altered the results. Nevertheless, the low incidence of MACE and cardiovascular mortality in both groups challenges the policy of mandatory PCI to all LT patients with obstructive CAD. We suggest examining each patient’s complaints, cardiovascular history, and coronary anatomy in a multidisciplinary team in order to assess the balance between potential contribution and harm of PCI.
The study has a few limitations: first, it is based on a retrospective cohort. Second, due to the low number of events, multivariable analysis was not applied. Nevertheless, this is a large, contemporary study which reflects the real-world data of LT candidates and their presurgical coronary intervention.
Conclusion
Routine pre-lung transplant coronary intervention does not guarantee protection against MACE either while on the waiting list or after the transplant. The decision to intervene should be carefully tailored to each individual patient.
Statement of Ethics
The study protocol and data collection were approved by Rabin Medical Center Human Research Committee, according to the ethical guidelines of the 1975 declaration of Helsinki, Approval No. 0706-19-RMC. As the study utilized retrospective data, the need for informed consent was waived by the Research Committee (mentioned above).
Conflict of Interest Statement
All authors have no conflicts of interest to disclose.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
E.Y.: writing – original draft, formal analysis, and data curation; T.A.: validation and data curation; D.H.: conceptualization and investigation; Y.A.: investigation and visualization; R.K.: investigation and supervision; and K.S.: methodology, formal analysis, data curation, and writing – review and editing.
Data Availability Statement
The data supporting the findings of this study are not publicly accessible to protect the privacy of the research participants. However, they can be obtained from the corresponding author (K.S.) upon reasonable request.