A Retrospective Study of 518 Kidney Transplant Recipients to Evaluate the Association of Antiplatelet Therapy With Long-Term Cardiovascular Events and All-Cause Mortality

Introduction

Kidney transplantation (KT) – the gold standard treatment for end-stage renal disease – is associated with improved patient survival, quality of life, and reduced long-term healthcare costs [1]. Nevertheless, patients who have received a renal transplant experience a persistently elevated risk of cardiovascular disease (CVD), and those with pre-existing CVD have an increased risk of major adverse cardiovascular events (MACE) including myocardial infarction and embolic stroke [2]. CVD causes the majority (approximately 25%) of deaths after KT [3,4]. In addition to conventional risk factors for MACE, KT recipients (KTRs) are exposed to less common risk factors such as mineral and bone disorders, elevated homocysteine levels, anemia, proteinuria, chronic immunosuppression, and chronic inflammation [5,6].

Antiplatelet (AP) drugs are a mainstay of therapy for MACE prevention in patients with known CVD [7]. Although the role of AP therapy in secondary prevention is well established, its role in primary prevention among at-risk populations remains poorly defined. Studies evaluating AP therapy for primary prevention in patients with diabetes have produced controversial findings: some have shown benefit and others have revealed no clear effect [8–14]. Currently, societal guidelines do not recommend AP therapy for primary prevention in KTRs. Overall, there is a paucity of data regarding the value of AP therapy for preventing long-term MACE in KTRs, and some studies have suggested that KTRs exhibit resistance to AP therapy [15,16]. Any potential benefit of AP therapy in patients with end-stage renal disease must also be weighed against the increased risk of bleeding due to uremia-associated platelet dysfunction [16,17].

The primary aim of this study, which included 518 KTRs from a single center, was to retrospectively evaluate the association between post-transplant AP therapy and long-term adverse outcomes in KTRs. Specifically, we sought to determine whether AP therapy was associated with a reduced risk of a composite outcome of MACE and all-cause mortality after KT. A prespecified secondary aim was to assess the safety of AP therapy by evaluating the incidence of major bleeding events. A separate subgroup analysis was performed among KTRs without known pre-existing CVD to examine the potential role of AP therapy in a primary prevention context.

Material and Methods

DATA SOURCE AND STUDY POPULATION:

Study approval was obtained from the Institutional Review Board of Saint Louis University (protocol #34091), along with a waiver of informed consent. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. We conducted a retrospective study of KTRs at our institution between January 2015 and January 2024. Patients younger than 18 years and those who did not attend follow-up at our institution were excluded. AP exposure was defined a priori based on discharge medications after KT and longitudinal medication reconciliation documented in the electronic medical record. Patients were classified into the AP group if they were discharged on and maintained single-agent AP therapy throughout follow-up. Patients not receiving AP therapy at discharge or during follow-up were classified as the no-antiplatelet (NoAP) group. Patients receiving dual AP therapy or systemic anticoagulation at any point during follow-up were excluded to minimize exposure heterogeneity and confounding by indication. For primary prevention analysis, patients with a diagnosis of atherosclerotic coronary artery disease, peripheral arterial disease, or cerebrovascular disease prior to transplantation were excluded (eg, patients with atherosclerotic disease identified on carotid Doppler, coronary angiography, or peripheral angiography).

DATA COLLECTION:

Patients were evaluated through comprehensive electronic medical record review. Demographic characteristics, comorbidities, laboratory data, echocardiographic parameters, medication use, and cardiovascular events were systematically abstracted from clinical charts. Cardiovascular outcomes included cardiovascular death, ischemic or hemorrhagic stroke, unstable angina, nonfatal myocardial infarction, sustained ventricular arrhythmia, and heart failure hospitalization. Heart failure hospitalizations were reviewed by the investigators to ensure that the corresponding admission was primarily for worsening heart failure and that each patient met criteria for inpatient treatment. Major bleeding events were defined according to the International Society on Thrombosis and Haemostasis guidelines: bleeding resulting in a decrease in hemoglobin of at least 2 g/dL, transfusion of at least 2 units of blood, or symptomatic bleeding at a critical site. To minimize bias, data collection regarding AP exposure was performed independently from outcome adjudication, and investigators collecting outcome data were blinded to AP therapy status.

OUTCOMES:

The primary outcome of this study was a composite of MACE and all-cause mortality. MACE was defined as cardiovascular death, ischemic stroke, hemorrhagic stroke, unstable angina, nonfatal myocardial infarction, sustained ventricular arrhythmia, and heart failure hospitalization. Secondary outcomes included major and minor bleeding events.

STATISTICAL ANALYSIS:

Baseline characteristics were summarized using means and standard deviations or medians with interquartile ranges for continuous variables, and counts with percentages for categorical variables. Between-group comparisons were performed using the Mann-Whitney U test for continuous variables and the chi-square test for categorical variables. Survival status and outcome events were obtained from longitudinal follow-up documentation in institutional electronic health records, including inpatient admissions, outpatient encounters, and recorded deaths. All-cause mortality was identified via clinical documentation and institutional records. Kaplan-Meier survival curves were constructed to estimate event-free survival, and the log-rank test was used to compare survival distributions between cohorts. Cox proportional hazards regression was performed to adjust for the time to event, generating hazard ratios for study endpoints according to treatment group. Time to event was calculated from the date of KT to the first event of interest or last known follow-up. Regression models were adjusted for covariates associated with the primary endpoints, as identified in univariate regression analyses. The proportional hazards assumption was assessed through Schoenfeld residuals, including both global and covariate-specific tests, and by visual inspection of scaled Schoenfeld residual plots. All statistical analyses were conducted using Stata software (StataCorp LLC; College Station, TX, USA), and a 2-tailed P value <0.05 was considered statistically significant.

Results

BASELINE DATA:

Of the 518 KTRs who met the study inclusion and exclusion criteria, 343 (66.2%) and 175 (33.8%) were classified in the NoAP and AP groups, respectively. Among patients in the AP group, 174 (99.4%) received acetylsalicylic acid throughout follow-up, and 1 (0.6%) received clopidogrel. Baseline and echocardiographic characteristics are presented in Tables 1 and 2, respectively. Patients in the AP group were significantly older and had higher prevalences of medical comorbidities, including diabetes, coronary artery disease, and cerebrovascular disease. They were also more likely to receive hemodialysis and beta-adrenergic antagonists. Echocardiographic parameters did not significantly differ between groups. In the primary prevention subgroup (n=368), 92 (25%) received AP therapy (AP primary prevention group) and 276 (75%) did not. Similar to the overall cohort, patients in the AP primary prevention group were older and had more comorbidities, including obstructive sleep apnea and diabetes.

STUDY OUTCOMES:

Median follow-up times (in months) were 52.5 (interquartile range [IQR]: 33.1–71.1), 52.9 (IQR: 30.0–79.3), 55.9 (IQR: 32.9–71.6), and 52.9 (IQR: 31.2–78.2) for the AP, NoAP, AP primary prevention and NoAP primary prevention groups, respectively. At 60 months of follow-up, there were no statistically significant differences in the rates of total MACE or individual outcomes between groups, except for unstable angina, which showed a significantly higher rate in the AP group (Table 3). Moreover, there were no significant differences in major bleeding events between the groups.

SURVIVAL ANALYSIS AND REGRESSION MODELS:

In the unadjusted regression analysis, AP therapy was not significantly associated with MACE or the composite outcome. Age, coronary artery disease, hemodialysis, and cerebrovascular disease were associated with total MACE. Age, diabetes, coronary artery disease, prior myocardial infarction, and hemodialysis were associated with the composite outcome (Table 4). In the primary prevention subgroup, no statistically significant differences were observed concerning any individual or composite outcomes (Table 5). Only age and hemodialysis were significantly associated with the composite outcome. Unadjusted Kaplan-Meier survival curves showed no significant difference in event-free survival between groups (Figures 1, 2). In the Cox proportional hazards model for the composite outcome, after adjustment for confounding variables identified during univariate regression analysis, AP therapy was associated with a lower risk of the composite outcome (MACE and all-cause mortality) in the overall cohort (hazard ratio 0.67, 95% confidence interval 0.45–0.99, P=0.046). Other variables independently associated with the composite outcome included age, coronary artery disease, diabetes, and hemodialysis (Table 6). AP therapy was not associated with total MACE (Table 7). In the primary prevention subgroup, AP therapy was not significantly associated with either MACE or the composite outcome (Tables 6, 7). There was no evidence of violation of the proportional hazards model assumptions.

Discussion

In this single-center retrospective analysis of KTRs, the main finding was an independent association between AP therapy and the composite outcome of MACE and all-cause mortality in the overall cohort, but not in the primary prevention subgroup. AP therapy was not independently associated with any individual outcome or the composite outcome.

Our results are generally consistent with prior evidence. The associations of age, diabetes, hemodialysis, and coronary artery disease with adverse outcomes after KT have been reported [4,5,17]. In the present study, unstable angina, although uncommon, was significantly more frequent in the AP group (2% vs 0.3%). This finding likely reflects indication bias, given that these patients had higher prevalences of coronary artery disease and other high-risk features. It may also reflect surveillance bias because higher-risk patients have lower thresholds for chest-pain-related referral and admission. Apart from this finding, the AP group had a 33% relative risk reduction in the composite outcome (hazard ratio 0.67; 95% confidence interval: 0.45–0.99), driven by lower MACE incidence across multiple components rather than by a single dominant event type.

Although evidence regarding the effects of AP therapy in KTRs remains limited, clinical practice guidelines and consensus statements recommend its use for secondary prevention in the absence of contraindications [12,13]. This recommendation is partly extrapolated from well-established evidence supporting AP therapy for secondary prevention in the general population [7]. Due to the lack of conclusive evidence supporting AP therapy as a primary prevention strategy – particularly in more recent studies – the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines do not recommend its use in KTRs without CVD [13]. The use of AP therapy for primary prevention in the general population has also been controversial, even among individuals exhibiting elevated cardiovascular risk (eg, patients with diabetes) [8–14]. Some studies have revealed a potential reduction in MACE, whereas others have reported no significant benefit. Among patients with chronic kidney disease who are not KTRs, the benefits of AP therapy may outweigh the associated risks. In a meta-analysis by Su et al [18], which included 50 studies (27773 patients), 12 months of AP therapy was estimated to prevent 23 MACE events per 1000 individuals with chronic kidney disease, while causing 9 major bleeding events. In contrast, the present study did not show an association between AP therapy and major bleeding events. More recently, the ASCEND trial, which included 15480 participants, demonstrated that acetylsalicylic acid significantly reduced MACE incidence among patients with diabetes and no prior history of CVD, although it also significantly increased the risk of major bleeding. In a post hoc analysis of the FAVORIT trial that included 1962 KTRs, acetylsalicylic acid use was not significantly associated with lower rates of MACE, all-cause mortality, or renal failure [19]. Our study adds to the body of evidence evaluating the relationship of AP therapy with MACE, using a detailed database and a sizable patient cohort.

Several limitations should be considered when interpreting our findings. This retrospective analysis cannot establish causality and is subject to inherent biases related to the study design. Additionally, given the retrospective nature of the dataset, we were unable to determine the specific indications for AP therapy, which may have introduced indication bias. The dataset also included many time-varying covariates (eg, comorbidities, laboratory values, and medications) that may have substantially changed during follow-up. Furthermore, the dataset did not include detailed information concerning immunosuppressive regimens, longitudinal graft function, or rejection episodes; these factors could have influenced outcomes and contributed to residual confounding. The event counts for individual MACE components were relatively low, which may have constrained statistical power and the reliability of regression estimates. Finally, we were unable to determine the specific doses used or degree of adherence to AP therapy.

Conclusions

In this retrospective single-center study, maintenance AP therapy after KT was associated with a lower risk of the composite outcome of MACE and all-cause mortality in the overall cohort. No significant association was observed among the subset of patients without known CVD. Further studies – ideally prospective and adequately powered – are needed to determine how AP therapy should be optimally used for secondary prevention and which patient subsets, if any, can benefit from AP therapy for primary prevention.