Incidence and Risk Factors for Stroke after Combined Heart-Kidney and Heart-Liver Transplantation

Abstract

Objective:

While stroke is a well-recognized complication of isolated heart transplantation, stroke in patients undergoing simultaneous heart-liver (HLT) and heart-kidney transplantation (HKT) has not been explored. This study assessed postoperative stroke incidence, risk factors, and outcomes in HLT and HKT compared with isolated heart transplant.

Methods:

The United Network for Organ Sharing database was queried for adult patients undergoing HLT, HKT, and isolated heart transplant between 1994 and 2022. Patients were stratified by presence of in-hospital stroke after transplant. Post-transplant survival at one year was assessed using Kaplan-Meier analysis and log-rank tests. Separate multivariable logistic regression models were constructed to identify risk factors for stroke after HKT and HLT.

Results:

Of 2,326 HKT recipients, 85 experienced stroke, and of 442 HLT recipients, 19 experienced stroke. Stroke was more common after HKT and HLT than after isolated heart transplant (3.7% vs. 4.3% vs. 2.9%, p=0.01). One-year post-transplant survival was lower in those with stroke among both HKT recipients (64.5% vs. 88.7%, p(log-rank)<0.001) and HLT recipients (43.8% vs. 87.4%, p(log-rank)<0.001. Pre-transplant pVAD, prior stroke, postoperative dialysis, diabetes, prior cardiac surgery, and heart cold ischemic time were independent risk factors for stroke after HKT, after adjusting for age, sex, and need for blood transfusion on the waitlist. For HLT, postoperative dialysis was a significant risk factor.

Conclusions:

Stroke is more common after HKT and HLT than after isolated heart transplant, and results in poor survival. Independent risk factors for stroke include pre-transplant percutaneous VAD (HKT) and postoperative dialysis (HKT and HLT).

Introduction

Simultaneous heart-kidney transplantation (HKT) and heart-liver transplantation (HLT) represent definitive surgical treatments for end-stage heart and kidney or liver failure, respectively. The relationship between heart failure and end-stage dysfunction of the kidney or liver is bidirectional: primary heart failure, end-stage renal disease, and end-stage liver disease may all necessitate multi-organ transplantation.^1,2 Contemporary outcomes after HKT and HLT remain excellent, with 1-year survival rates of 85% or greater.^3,4

Stroke is a well-recognized complication after isolated heart, isolated kidney, and isolated liver transplantation.^2,5,6 In addition to classical cardiovascular risk factors such as hypertension and tobacco smoking, specific risk factors for stroke after single-organ transplantation include previous stroke, atrial fibrillation, post-transplant erythrocytosis, and, importantly, use of preoperative mechanical circulatory support (MCS).^7–9 Under the 2018 heart allocation update from the Organ Procurement and Transplantation Network (OPTN) and United Network for Organ Sharing (UNOS), status 1, 2, and 3 exclusively include patients requiring MCS.¹⁰ Use of MCS in the pre-transplant and post-transplant settings has increased in the last decade.¹¹

While postoperative stroke has been well characterized in isolated heart, kidney, and liver transplantation, studies reporting stroke outcomes in HKT and HLT remain sparse. To better understand the potential influences of multi-organ transplantation and the increasing frequency of MCS use in heart failure patients, the present study aims to describe the incidence, risk factors, and outcomes of postoperative stroke following simultaneous heart-kidney and heart-liver transplantation using a large national database.

Methods

We included adult (18 years and older) isolated heart, combined heart-kidney, and combined heart-liver recipients between January 01, 1994, and December 31, 2022, in the UNOS database. Recording of postoperative stroke in UNOS began in 1994, marking the beginning of the study period. Recipients were categorized by the presence or absence of postoperative stroke. Postoperative stroke was defined as acute, in-hospital stroke after transplant and prior to discharge. Baseline characteristics and outcomes were assessed using Wilcoxon rank-sum and chi-square testing for continuous and categorical variables, respectively. One-year post-transplant survival was assessed using time-to-event analysis and log-rank tests and visualized using Kaplan-Meier curves. Temporary MCS use was defined as extracorporeal membrane oxygenation (ECMO), percutaneous ventricular assist device (pVAD), or intra-aortic balloon pump (IABP) at transplant. Risk factors for stroke after HKT and HLT were identified using multivariable logistic regression and covariates were determined a priori based on clinical judgement. Covariates included age, sex, diabetes, prior stroke, prior cardiac surgery, blood transfusion on waitlist, pre-transplant pVAD, heart cold ischemic time, post-transplant dialysis for HKT recipients, and prior cardiac surgery and post-transplant dialysis for HLT recipients.

This study, titled “Prognostic Study of Survival after Solid Organ Transplantation in the United States” was approved by the Johns Hopkins Medicine Institutional Review Board on December 19, 2022, with a waiver of informed consent (IRB00352819). Procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation (institutional) and with the Helsinki Declaration of 1975.

Results

Of 2,326 HKT recipients, 85 (3.7%) experienced postoperative stroke, and of 442 HLT recipients, 19 (4.3%) experienced a postoperative stroke. Of 57,253 isolated heart transplant recipients, 1,625 (2.8%) experienced postoperative stroke. Stroke was more common after HKT and HLT than isolated heart transplants (p=0.01). HKT and HLT recipients differed from isolated heart recipients across demographic and clinical variables listed in Table S1.

Compared to HKT patients without post-transplant stroke, HKT recipients with post-transplant stroke were more likely to have diabetes (60% vs. 44%, p=0.004), prior stroke (17.3% vs. 7.0%, p<0.001), and required more pre-transplant pVAD (11.8% vs. 5.0%, p=0.006) and mechanical ventilation (5.9% vs. 1.6%, p=0.003, Table S2). There were no differences between groups in pre-transplant utilization of ECMO or IABP. Recipients with stroke also had longer heart cold ischemic time (3.5 vs. 3.2 hours, p=0.04) and greater post-transplant dialysis requirement (49.4% vs. 31.2%, p<0.001). The prevalence of postoperative stroke by mechanical circulatory support use at transplant is described in Table S4.

Compared to HLT patients without post-transplant stroke, HLT recipients with post-transplant stroke were more likely to have prior cardiac surgery (72.2% vs. 47.0%, p=0.04) and less likely to receive pre-transplant MCS (0% vs. 20.3%, p=0.03, Table S3). HLT recipients with stroke had longer heart cold ischemic time (3.7 vs. 3.2 hours, p=0.046) and greater post-transplant dialysis requirement (57.9% vs. 22.0%, p<0.001).

Over the study period, the yearly HKT volume increased from 12 in 1994 to 302 in 2022 (Figure S1). During this time, annual stroke incidence ranged from 0% to 16.6% and was most recently 6.0% in 2022. Yearly HLT volume increased from one transplant in 1995 to 62 in 2022. Annual stroke incidence ranged from 0% to 11.1% and was most recently 4.8% in 2022.

One-year post-transplant survival was lower in those with stroke among both HKT recipients (64.5% vs. 88.7%, p(log-rank) <0.001) and HLT recipients (43.8% vs. 87.4%, p(log-rank) <0.001, Figure 1) Pre-transplant pVAD, prior stroke, postoperative dialysis, diabetes, prior cardiac surgery, and heart cold ischemic time were independent risk factors for stroke after HKT, after adjusting for age, sex, and need for blood transfusion on the waitlist (Table 1). For HLT, postoperative dialysis was a significant risk factor for stroke (Table S5).

Figure 1.

Kaplan Meier curves showing one-year post-transplant survival for combined (A) heart-kidney and (B) heart-liver recipients with and without stroke.

Table 1.

Risk Factors for Stroke After Heart-Kidney Transplant

Multivariable Logistic Regression
Variable	Adjusted Odds Ratio (95% CI)
Percutaneous Ventricular Assist Device at Transplant	2.52 (1.22 – 5.21)
Prior Stroke	2.35 (1.22 – 4.54)
Post-operative Dialysis	1.68 (1.04 – 2.72)
Diabetes	1.66 (1.02 – 2.72)
Prior Cardiac Surgery	1.65 (1.01 – 2.70)
Heart Cold Ischemic Time (per hour)	1.24 (1.02 – 1.51)
Need for Blood Transfusion on Waitlist	1.07 (0.63 – 1.81)
Sex	1.32 (0.73 – 2.40)
Age (per year)	1.00 (0.97 – 1.02)

Significant values are bolded.

Discussion

In this national retrospective analysis of stroke after isolated heart, heart-kidney, and heart-liver transplantation, stroke occurred significantly more frequently in HKT (3.7%) and HLT (4.3%) compared to isolated heart transplantation (2.9%) from 1994–2022. Several independent risk factors were identified for stroke after HKT, while postoperative dialysis conferred increased stroke risk in both HKT and HLT. Furthermore, patients with stroke after HKT or HLT demonstrated reduced one-year survival compared to patients without stroke. Given the increased volumes of both HKT and HLT over the study period, the absolute number of patients with stroke after multi-organ transplantation continues to increase, and we found stroke incidence to be particularly high in the most recent year of study (in 2022, 6.0% for HKT and 4.8% for HLT).

Prior studies have reported rates of stroke after HKT and HLT using national data. Sherard et al. compared HKT outcomes between patients aged <65 years and patients 65 years and older and reported a total cohort stroke rate of 3.2% with no difference between the groups.³ Ohira et al. reported a matched comparison of HKT patients before versus after the 2018 heart allocation update, demonstrating a total cohort stroke rate of 4.5% with no difference between groups.¹² Rucker et al. compared simultaneous and sequential heart-liver transplantation and found no statistical difference in stroke between the groups.¹³ Our study included data from 1994–2022, which is more than any previous study examining stroke after HKT and HLT, and represents the most comprehensive national report on this topic to date. Our group recently reported stroke outcomes after combined heart-lung transplantation: stroke was more common in combined heart-lung compared to isolated heart transplantation, and independent risk factors for stroke were pre-transplant ECMO and pre-transplant implantable cardioverter/defibrillator.¹⁴ In our study, we did not find pre-transplant ECMO use to be more common among those who experienced stroke after HKT or HLT.

The increased number of strokes over time in HKT and HLT patients appears to be multifactorial. Disease states requiring tandem heart-kidney or heart-liver failure may intrinsically increase the risk of stroke, and the complexity of multiorgan transplantation additionally increases operative and cardiopulmonary bypass times, which compound this risk. In the HKT population, end-stage renal disease increases stroke incidence by over three-fold;¹⁵ similarly, patients requiring HLT may have Fontan circulation or cardiac amyloidosis known to increase the thrombotic burden.^16,17 Patients with end-stage liver disease requiring transplantation have an impairment in coagulation factor production and are at increased risk of bleeding, which may manifest as intracranial hemorrhage.

In our study, independent risk factors for stroke after HKT were – in order of magnitude – pre-transplant pVAD, previous stroke, postoperative dialysis, diabetes, previous cardiac surgery, and heart cold ischemic time. Previous stroke, redo sternotomy, and heart cold ischemic time have previously been reported as independent risk factors for postoperative stroke after isolated heart transplantation.¹⁸ Diabetes has also been demonstrated as an independent risk factor for stroke following both isolated heart and isolated kidney transplantation.^15,19 In keeping with isolated heart transplantation literature, MCS device conferred the greatest risk for stroke after HKT in our population.^5,18 Increased stroke risks with IABP²⁰, percutaneous VAD²¹, durable VAD²², and veno-arterial ECMO²³ have been well-documented. Different forms of MCS exert variable effects on cerebral embolism, perfusion, and autoregulation function; nonetheless, the increased thrombotic risk conferred by MCS necessitates anticoagulation, which may itself increase the risk of hemorrhage.^24,25

Concerning HLT, the only independent risk factor for postoperative stroke was postoperative dialysis, which was also observed in the HKT population. The need for dialysis may represent unresolved cardiac, renal, or hepatic dysfunction, but also independently confers additional risk of stroke.²⁶ Notably, HLT patients with stroke were less likely to receive pre-transplant MCS. While this may reflect a small absolute event size (n=19 stroke patients in HLT), prolonged and refractory cerebral hypoperfusion in the absence of MCS may increase stroke risk. Nonetheless, this relationship should be closely observed in future long-term studies with higher HLT volumes.

In both HKT and HLT, postoperative stroke was associated with decreased one-year survival, with a greater difference in HLT than HKT. The first 4 months after transplant conferred the greatest differential risk of mortality, after which survival curves of stroke and non-stroke patients progress with similar trajectories (Figure 1). This pattern is also demonstrated in isolated heart¹⁸ and heart-lung transplantation.¹⁴ Hong et al. further reported that preserved functional independence improved post-stroke prognosis, likely representing a surrogate for stroke severity.⁵

Limitations of this study are predominantly due to limited granularity of the UNOS national database. Preoperative details known to increase stroke risk – including presence of atrial arrhythmia, left ventricular thrombus, and ascending aortic or aortic arch atherosclerosis – were not reported. Intraoperative details such as cardiopulmonary bypass time and aortic cross-clamp time were also not captured. All of the above may plausibly influence the risk of stroke in the postoperative setting. Details of postoperative stroke, including severity, location, timing (specific postoperative day), and type (ischemic versus hemorrhagic) were not reported, which may influence functional prognosis and survival following stroke. The relationship between stroke and primary graft dysfunction in multi-organ recipients, and preoperative aspirin use additionally deserve study, but were not reported and were unavailable for analysis. Despite these limitations, our analyses included data from 1994–2022, which is more than any previous study examining stroke after HKT and HLT, and examined risk factors for stroke in these patients and included a breakdown of annual stroke incidence. Thus, we believe that our analysis is the most comprehensive national report to date on acute, in-hospital stroke after HKT and HLT.

Conclusions

Postoperative stroke is more common in heart-kidney and heart-liver transplantation compared to isolated heart transplantation, and stroke reduces one-year survival in both HKT and HLT. Independent risk factors for stroke include pre-transplant percutaneous VAD (HKT) and postoperative dialysis (HKT and HLT). Further study is required to delineate the relationship between different forms of pre-transplant mechanical circulatory support and postoperative stroke.