Coronary artery disease (CAD) is an important cause of morbidity and mortality in patients with chronic kidney disease (CKD) either before or after renal transplantation. For that reason, most transplant centers perform noninvasive or invasive, or sometimes both of these, coronary tests before including patients on the waiting list. However, it is still to be proved that coronary disease assessment would necessarily identify patients who are at high risk of cardiovascular (CV) events and death after transplantation. It is also unclear whether coronary intervention performed before the operation will improve the posttransplant prognosis.
In our center, we started a prospective, observational study to determine the best clinical and CV investigation for the detection of CAD and prediction of CV events in patients on the kidney transplant waiting list.1,2
MATERIALS AND METHODS
This work was performed according with the postulates of the Helsinki declaration, and all patients provided a signed informed consent. This was a single-center retrospective analysis of data prospectively collected on 535 patients who underwent renal transplantation between 2004 and 2014. All individuals belonged to a larger adult (>18 years old) group of patients (the KiHeart Cohort); had been treated by hemodialysis; were candidates to receive their first kidney graft from a deceased donor at the Renal Transplant Unit, Division of Urology, University of São Paulo Medical School; and were referred to the Heart Institute (InCor) for CV assessment, before being formally included on the waiting list. From the original population of 1720 individuals, 24 were excluded because of incomplete data, leaving 1696 patients for analysis. The mean waiting time on the list was 27.5 ± 22.5 months. The leading criterion to determine allocation for transplantation was HLA matching. Allocation of deceased donor kidneys was centrally directed based on a computerized algorithm. The same surgical team performed all operations at the university hospital where patients were also followed up.
Study Protocol
Figures 1 and 2 show the flow diagrams of coronary assessment for the entire CKD population and for patients who underwent renal transplantation, respectively. A prespecified comprehensive clinical and CV investigation was performed before patients were included on the list. All patients had a 12-lead resting EKG and a transthoracic echocardiogram as part of their evaluation. We initially performed a clinical stratification as proposed by the American Society of Transplantation3 2
FIGURE 1: Flow diagram of coronary artery disease assessment in CKD patients on the waiting list for renal transplantation (
2,3,7 ). *Patients with angina were assessed by coronary angiography independently of risk factors.
FIGURE 2: Flow diagram of pretransplant coronary assessment in renal transplant patients.
Patients having noninvasive testing suggestive of CAD or multiple (more than 1) risk factors, like 50 years or older; diabetes, types 1 or 2; or having CV disease, such as angina, previous myocardial infarction or stroke, left ventricular dysfunction, or extracardiac atherosclerosis were eligible for coronary angiography. Significant CAD was arbitrarily defined as luminal stenosis of 70% or greater in 1 or more epicardial arteries or a 50% narrowing of a main left coronary artery by visual estimation from 2 independent experts. Patients with significant CAD were evaluated according with the American Heart Association/American College of Cardiology criteria for vascular intervention4 5,6 2,7,8 9
On study inception, patients had been treated by maintenance hemodialysis for at least 3 months, performed in 4-hour sessions, 3 times/week using a bicarbonate bath. Patients were maintained on statins, aspirin, angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), and b-blockers, regardless of symptoms or results of evaluation, according to current guidelines for secondary prevention of CV events,10 2
Patients were followed up from the time of transplantation until death or occurrence of coronary events. Routine immunosuppression consisted of prednisone, mycophenolate, and tacrolimus (81% of the patients), or cyclosporine (19% of the patients). End points were the incidence of coronary events, defined as myocardial infarction, unstable angina, or sudden death, and death by any cause. We performed a separate analysis on the effect of coronary intervention on survival in patients on the waiting list transplanted or not transplanted, considering as the starting point the date of coronary assessment and death as the end point. The purpose of that analysis was to take into account the effect of intervention-related deaths on survival. For obvious reasons, that was not possible to achieve using the date of engraftment as the starting point.
Statistical Analysis
Values are expressed as means, standard deviation of the means, medians, and percentages. For analysis of the data, we used the SPSS statistical program (SPSS Statistics, version 20.0; IBM, Armonk, NY). Univariate analysis was performed with chi-square testing, Student t test, analysis of variance, Mann-Whitney test, or median test, as indicated. Survival curves were constructed using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards model was used to verify the variables independently associated with outcomes. The variables selected for multivariate Cox model were those showing a significant association in univariate testing plus CAD, sex, diabetes, CV disease, and age. A P value of less than 0.05 was considered significant.
RESULTS
Prediction of Coronary Events and Death by Any Cause
Table 1 shows the main baseline variables of renal transplant patients according to evidence of CAD based on clinical stratification and coronary angiography. The median observation time was 39.3 months for the whole population. Eighty-five percent of our patients were asymptomatic. A little over 50% of our patients was considered at low risk of CAD and did not undergo pretransplant coronary angiography. The remaining 44% was considered eligible for invasive testing. In that group, we found significant stenosis in 136 patients, or 25% of the total original population of 535 individuals. During follow-up, 20 patients returned to dialysis. They were not censored at this point and were followed up until death or a coronary event like the others patients.
TABLE 1: Baseline characteristics of renal transplant patients with ≥70% coronary narrowing (Group 1), nonsignificant coronary artery disease (Group 2), and low-risk patients not eligible for coronary angiography (Group 3)
Because of the criteria used to select patients for invasive testing, the groups differ in the majority of variables analyzed. Low-risk patients were younger and had a lower prevalence of diabetes, hypertension, angina, and CV disease. They were also less likely to be smokers or men and had lower BMI. In patients who underwent coronary angiography, those with significant CAD were older and had more diabetes and associated CV disease.
Figure 3 shows the coronary event-free survival in patients with CAD (group 1), patients with normal vessels or with less than 70% stenosis (group 2), and low-risk subjects not eligible for coronary angiography (group 3). Group 1 patients had reduced coronary event-free survival compared to the other groups. There was a trend for patients in group 2 to have a higher incidence of events compared with patients in group 3 (P = 0.06). The lowest incidence of events was observed in group 3. Table 2 shows the variables entered in the Cox-proportional model. Coronary artery disease (hazards ratio [HR], 3.81; 95% confidence interval [95% CI], 1.58-9.92; P = 0.003) and angina (HR, 2.17; 95% CI, 1.10-4.43; P = 0.02) were the independent predictors of coronary events.
FIGURE 3: Coronary event-free survival in renal transplant patients undergoing pretransplant coronary assessment.
TABLE 2: Multivariate analysis (Cox proportional hazards model) for variables associated with coronary events in renal transplant patients
Figure 4 depicts the incidence of death by any cause. Again, low-risk subjects not eligible for coronary angiography had the best survival rate that differed significantly from those observed in patients with significant CAD and in those with less relevant coronary narrowing. The survival rates of the 2 latter groups were similar. Therefore, coronary assessment identified patients at increased risk of posttransplant coronary events. However, it did not differentiate between the risk of death in patients with and those without significant CAD. The independent predictors of death (Table 3 ) were age (HR, 1.04; 95% CI, 1.01-1.06; P = 0.001) and diabetes (HR, 1.63; 95% CI, 1.11-2.39; P = 0.01).
FIGURE 4: Death by any cause in renal transplant patients undergoing pretransplant coronary assessment.
TABLE 3: Multivariate analysis (Cox proportional hazards model) for variables associated with death by any cause in renal transplant patients
Effect of Coronary Intervention on Prognosis
Forty-nine of 136 patients with CAD underwent myocardial revascularization before transplantation based on American Heart Association/American College of Cardiology guidelines for coronary intervention,4
Table 4 compares the characteristics of patients treated medically with those treated by intervention (CABG or PCI) plus medical treatment. The groups differed only in the prevalence of hypertension, which was higher in patients receiving medical treatment, and CV disease, which was more prevalent in patients who underwent intervention. In all other aspects, the groups were well balanced.
TABLE 4: Baseline characteristics of renal transplant patients with coronary artery disease treated by coronary intervention (CABG or PCI) or medical treatment
Figure 5 shows the effect of coronary intervention on the incidence of posttransplant coronary events. There was a difference that fell short of achieving statistical significance (P = 0.057), suggesting a reduced incidence of events in patients undergoing intervention. Intervention did not alter the incidence of death by any cause (Fig. 6 ).
FIGURE 5: Effect of pretransplant coronary intervention on coronary event-free survival in renal transplant patients.
FIGURE 6: Effect of pretransplant coronary intervention on death by any cause in renal transplant patients.
The abovementioned results did not take into account the effect of the mortality associated with coronary intervention. To obtain an indirect appraisal of that effect, we performed an analysis of patients on the waiting list, transplanted, or not transplanted, with CAD using the date of assessment, instead of the date of engraftment as the starting point. We then followed up patients treated medically or by intervention until death. There was no difference in mortality between patients treated medically or by intervention plus medical therapy in patients with CAD (log-rank = 0.38). The crude 10-year survival was 65.7% and 65.9% for patients treated by intervention or medically, respectively. The crude mortality rate associated with surgery was 15%. We repeated the analysis in the totality of the cohort, which included patients with or without CAD, and again, we found no difference between patients who underwent coronary intervention or who received medical therapy only (P = 0.78).
DISCUSSION
Our investigation indicates that a pretransplant coronary work-up is useful in identifying renal transplant patients at increased risk of coronary events and death. Significant CAD predicted coronary events, whereas patients screened for coronary angiography had higher mortality, independent of the results of the invasive testing. On the other hand, we did not observe a difference in survival with coronary intervention.
This study emphasizes the importance of careful clinical selection before performing coronary angiography in renal transplant candidates who were mostly asymptomatic. Selecting patients for coronary angiography identified a large group of low-risk patients with great accuracy that could be safely transplanted without invasive coronary investigation.
Prediction of Coronary Events and Death by Any Cause
The incidence of acute coronary events was 3 times higher in patients with CAD compared with the low-risk group and 2 times higher than that in subjects with less significant coronary narrowing. There was a trend toward an increased incidence of events in individuals with less relevant CAD compared to low-risk subjects, which did not achieve statistical significance (P = 0.06). One could expect a higher incidence of events in patients with less relevant CAD, because it is well known that a common mechanism leading to acute coronary events is plaque rupture of a noncritical coronary stenosis.11
Less than 50% of our patients assessed by coronary angiography had relevant CAD, a figure close to that reported in the literature in CKD patients evaluated by angiography.12-14 15
Coronary angiography did not differentiate between patients with CAD and those with less significant coronary narrowing in terms of probability of death, possibly because patients selected for angiography had multiple risk factors that superseded the likely impact of CAD on survival. Another reason is that coronary deaths comprised only 13% of all deaths, reducing the statistical power of the sample. Even so, in individuals with CAD, the proportion of patients with coronary death was 2 times higher than that in subjects with less important lesions.
Effect of Coronary Intervention on Prognosis
The incidence of coronary events tended to be reduced in subjects who underwent intervention (P = 0.057). This negative result may be caused by the small number of patients and may not be conclusive. When the analysis was repeated excluding the first 3 posttransplant months, we detected a significant difference between groups (P = 0.032) favoring intervention. On the other hand, the lack of effect of intervention on the incidence of death was unambiguous, even considering that the impact of deaths caused by intervention could not be determined. Indirect evidence provided by the analysis of data in patients, transplanted or not transplanted, suggests that the impact of intervention-related deaths may not be important. However, it may become relevant when the number of patients undergoing surgery is large, considering that the mortality rate associated with surgery is high, as observed in this work and by other authors.
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There are no prospective trials conceived to define the best strategy to manage patients with advanced CKD and obstructive CAD using modern cardioprotective drugs. There are data concerning the effect of coronary intervention in patients on the transplant waiting list, most from single-center retrospective studies,13,16-18 19 7,16 20 12 21 14 4
CONCLUSIONS
Pretransplant work-up, conceived to identify patients with CAD, is useful to define a low-risk population that may be safely transplanted without in-depth CV evaluation and also indicates a group of individuals at increased posttransplant risk of coronary events and death. Medical and interventional treatments for CAD yielded similar results, but the severity of CAD differed in patients undergoing intervention or medical treatment.
Limitations
This was a retrospective analysis of a single-center cohort. The proportion of patients undergoing intervention was small and results of PCI and CABG were analyzed together. The impact of intervention-related deaths was not directly determined. Only metal bare stents were used. There were no prespecified criteria to refer patients. The number of patients removed from the list after CV evaluation was not assessed and the number of subjects reevaluated before receiving transplant was not determined. These shortcomings are balanced in part by the fact this was a real-world scenario, that data were prospectively collected according to a prespecified protocol, that treatment strategies were uniformly implemented in accordance with current guidelines and supervised by the same group of investigators.
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