Understanding risk factors and predictors for stroke subtypes in the ENDURANCE trials

doi:10.1016/j.healun.2020.01.1330

The Journal of Heart and Lung Transplantation

Volume 39, Issue 7, July 2020, Pages 639-647

https://doi.org/10.1016/j.healun.2020.01.1330 Get rights and content

BACKGROUND

Stroke is a devastating morbidity associated with left ventricular assist device (LVAD) support. We report a comprehensive analysis of stroke subtypes in the ENDURANCE destination therapy (DT) and ENDURANCE Supplemental (DT2) trials.

METHODS

Patients in the combined HeartWare LVAD (HVAD) cohorts of the DT and DT2 trials were included. Neurologic events included ischemic stroke (ischemic cerebrovascular accident [ICVA]), hemorrhagic stroke (hemorrhagic cerebrovascular accident [HCVA]), and transient ischemic attack (TIA). Peri-operative strokes were defined as occurring within 2 weeks of the implant.

RESULTS

A total of 604 patients received an HVAD in the DT (n = 296) and DT2 (n = 308) trials. Over 2 years, 178 (29.5%) had at least 1 cerebrovascular accident (CVA). Forty-four (7.3%) had HCVAs, 116 (19.2%) had ICVAs, and 44 (7.3%) had TIAs. Thirty (5.0%) had peri-operative stroke. In multivariable analysis, sub-therapeutic international normalized ratio (INR) values were independently associated with peri-operative stroke. Supra- and/or sub-therapeutic INR values, peripheral vascular disease, and presence of left ventricular thrombus were independently associated with ICVA. No aspirin and supra- and/or sub-therapeutic INR values were independently associated with TIA. No aspirin, supra- and/or sub-therapeutic INR values, and prior stroke and/or TIA were associated with HCVA. In further analysis, mean arterial pressure (MAP) was higher in the ICVA (86.8mm Hg, p = 0.002 4) and TIA (88.8mm Hg, p<0.0001) groups, but not in HCVA, than in the No-CVA group (81.4mm Hg). Time in therapeutic range for INR was 65.3% for the No-CVA group, 62.9% (p = 0.59) for HCVA, 65.1% (p = 0.97) for ICVA, and 63.2% (p = 0.62) for TIA.

CONCLUSIONS

Supra- and sub-therapeutic INR values at the time of CVA were associated with all stroke subtypes >14 days post-implant. MAP was higher among those with ICVA and TIA but not with HCVA compared to without CVA. Our study demonstrates the challenges of anti-thrombotic therapy and blood pressure management in LVAD population.

Section snippets

Methods

The Heartware HVAD ENDURANCE and ENDURANCE Supplemental clinical trial designs have been described previously.⁷^,¹² Briefly, the ENDURANCE trial was a prospective, randomized, controlled, unblinded, multicenter trial that compared the safety and effectiveness of the Heartware HVAD system to a Food and Drug administration-approved LVAD in patients with end-stage heart failure who did not qualify for heart transplantation. The trial enrolled 297 patients on HVAD and 148 control patients who had

Results

A total of 604 patients were included in the study. As shown in Figure 1, a total of 178 patients (29.5%) had at least 1 CVA. Forty-four patients (7.3%) had at least 1 HCVA, 116 (19.2%) had at least 1 ICVA, and 44 (7.3%) had at least 1 TIA. Forty-eight (7.9%) had >1 CVA, and if the events were mixed (e.g., HCVA and ICVA), the patient was counted in each stroke subtype group. Seven events (1.2%, n = 4 patients) with known clinical causality were excluded from the analysis, including 5 (0.8%)

Discussion

Our study provides evidence of major modifiable risk factors that correlate with each LVAD-associated subtype of stroke. Most current publications related to LVAD have not analyzed peri-operative strokes separately. Two studies that did investigate this topic concluded that peri-operative stroke was a major cause of LVAD-associated stroke.²^,⁹ In the ENDURANCE trials, peri-operative stroke rate was approximately 5%, and most of these were ischemic events.

HCVA occurred in approximately 7% of our

Conclusions

Supra- and sub-therapeutic INR values at the time of CVA were associated with all stroke subtypes >14 days post-implant. MAPs were higher among those with ICVA and TIA but not with HCVA compared to without CVA. Our study demonstrates the challenges of anti-thrombotic therapy and blood pressure management in LVAD population.

Disclosure statement

Dr. Cho receives a grant from the Extracorporeal Life Support Organization. Dr. Teuteberg serves as speaking and/or advisory board for Medtronic; advisory board for Abiomed; advisory board for EcoR1; speaking and/or advisory board for CareDx; as a member of HeartMate 3 clinical events committee. Nicholas Hiivala, BME, is an employee of Medtronic Inc.The remaining authors have no conflicts of interest to disclose.

The authors acknowledge Brian Van Dorn and Kristie Wallace, Medtronic Inc, for

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Cited by (13)

Outcomes of heart transplant recipients with prior left ventricular assist device associated stroke
2023, Journal of Stroke and Cerebrovascular Diseases
Left ventricular assist devices (LVADs) improve survival in patients with end-stage heart failure but are associated with ischemic stroke and intracranial hemorrhage (ICH). The impact of LVAD-associated stroke on transplant candidacy and outcomes has not been characterized.
Adult patients undergoing LVAD implantation at Cleveland Clinic between 2004 to 2021 were reviewed and patients who developed ischemic stroke or ICH were identified. Post-transplant survival analysis was performed between patients with LVAD-associated stroke vs. without.
917 patients had an LVAD implantation of whom 244 (median age 57, 79% male) underwent subsequent transplant including 25 with prior LVAD-associated stroke. The 1- and 2-year survival after transplant in patients with LVAD-associated stroke were 100% and 95% respectively, compared with 92% and 90% in patients without stroke (p=0.156; p=0.323) Similarly, there was no difference in stroke incidence at 1- and 2 years after transplant between patients with LVAD-associated stroke (4% and 5%) and those without prior stroke (5% and 6%, p = 0.884; p=0.744).
In this single-center retrospective study, patients with LVAD-associated stroke were significantly less likely to undergo heart transplant, but those who underwent heart transplant had similar post-transplant outcomes as patients without history of LVAD-associated stroke. Given the similar outcomes seen in this population, history of LVAD-associated stroke should not be viewed as an absolute contraindication to subsequent heart transplant.
Neurologic Complications in Patients With Left Ventricular Assist Devices
2023, Canadian Journal of Cardiology
Citation Excerpt :
A specific INR target has been a source of debate over the past decade given the need to balance the risk of both IS and HS. In a post hoc analysis of the ENDURANCE trial, both supratherapeutic (> 3.0) and subtherapeutic (< 2.0) INR values were associated with increased risk of both HS and IS, which may reflect the difficulty of maintaining INR in the therapeutic target range with day-to-day fluctuations.41 Given these findings and the paucity of high-quality evidence, it appears reasonable to target an INR of 2.0-3.0 to prevent IS while reducing the risk of HS while keeping in mind the role that individual patients’ risk factors may play in balancing ischemic and hemorrhagic complications.39
Left ventricular assist device (LVAD) use has revolutionised the care of patients with advanced heart failure, allowing more patients to survive until heart transplantation and providing improved quality for patients unable to undergo transplantation. Despite these benefits, improvements in device technology, and better clinical care and experience, LVADs are associated with neurologic complications. This review provides information on the incidence, risk factors, and management of neurologic complications among LVAD patients. Although scant guidelines exist for the evaluation and management of neurologic complications in LVAD patients, a high index of suspicion can prompt early detection of neurologic complications which may improve overall neurologic outcomes. A better understanding of the implications of continuous circulatory flow on systemic and cerebral vasculature is necessary to reduce the common occurrence of neurologic complications in this population.
Les dispositifs d’assistance ventriculaire gauche (DAVG) ont révolutionné le traitement de l’insuffisance cardiaque avancée, car ils permettent à un plus grand nombre de patients de survivre en attendant de subir une transplantation cardiaque et procurent une meilleure qualité de vie aux patients qui ne peuvent subir une transplantation. Malgré ces bienfaits, les perfectionnements technologiques et l’amélioration des soins et des parcours cliniques, les DAVG sont associés à des complications neurologiques. Nous présentons dans cet article de synthèse des renseignements sur l’incidence, les facteurs de risque et la prise en charge des complications neurologiques chez les patients porteurs de DAVG. Peu de lignes directrices s’appliquent à l’évaluation et à la prise en charge des complications neurologiques chez ces patients. Néanmoins, un haut degré de suspicion peut mener à la détection précoce de telles complications et se traduire conséquemment par une amélioration globale des paramètres neurologiques. Il est nécessaire de mieux comprendre les répercussions d’un débit circulatoire continu sur les systèmes vasculaires systémique et cérébral afin de limiter la fréquence des complications neurologiques dans cette population.
Impact of frailty on mortality and morbidity in bridge to transplant recipients of contemporary durable mechanical circulatory support
2022, Journal of Heart and Lung Transplantation
Citation Excerpt :
This bears important implications for patient selection and communication of risks before LVAD implantation. Device-related adverse events remain a challenge in the care of LVAD supported patients.21,22 Pre-existing patient and pump-related factors interact in a complex manner to result in hemocompatibility related adverse events.
Frailty is associated with adverse outcomes in advanced heart failure. We studied the impact of frailty on postoperative outcomes in bridge to transplant (BTT) durable mechanical circulatory support (MCS) recipients.
Patients undergoing left ventricular assist device (LVAD, n = 96) or biventricular support (BiV, n = 11) as BTT underwent frailty assessment. Frailty was defined as ≥ 3 physical domains of the Fried's Frailty Phenotype (FFP) or ≥ 2 physical domains of the FFP plus cognitive impairment on the Montreal Cognitive Assessment (MoCA).
No difference in mortality at 360 days was observed in frail (n = 6/38, 15.8%) vs non-frail (n = 4/58, 6.9%) LVAD supported patients, p = 0.19. However, there was a significant excess mortality in frail BiV (n = 4/5) vs non-frail BiV (n = 0/6) supported patients, p = 0.013. In all patients, frail patients compared to non-frail patients experienced longer intensive care unit stay, 12 vs 6 days (p < 0.0001) and hospital length of stay, 48 vs 27 days (p < 0.0001). There was no difference in hemocompatibility and infection related adverse events. The majority (n = 22/29, 75.9%) of frail patients became non-frail following MCS; contrastingly, a minority (n = 3/42, 7.1%) became frail from being non-frail (p = 0.0003).
Abnormal markers of frailty are common in patients undergoing BTT-MCS support and those used herein predict mortality in BiV-supported patients, but not in LVAD patients. These findings may help us better identify patients who will benefit most from BiV-BTT therapy.
Long-Term Neurocognitive Outcome in Patients With Continuous Flow Left Ventricular Assist Device
2021, JACC: Heart Failure
Citation Excerpt :
In our multivariable analysis models for cognitive decline, 3 factors—male sex, younger age, and HVAD device—were consistently present as independent risk factors for most neurocognitive domains (except clock drawing), especially for patients with impaired cognition at baseline (Table 3). As both ischemic and hemorrhagic strokes were more common with the HVAD (vs. HMII), it is not surprising that the odds of cognitive decline were higher with the HVAD device (13,26). The association of greater decline in younger patients is somewhat counterintuitive, and we suspect that this relationship arises, in part, because younger patients had better cognitive performance at baseline and thus had more “room to decline” (Supplemental Figures 1 and 2).
The authors sought to examine the long-term cognitive outcome of patients with continuous flow left ventricular assist device (CF-LVAD).
Data on long-term neurocognitive outcome in LVAD are limited. We examined the neurocognitive outcome of patients who received a CF-LVAD as destination therapy.
Patients with HeartWare (HVAD) and HeartMate II who were enrolled in the ENDURANCE and ENDURANCE Supplemental trials were eligible. Cognition was evaluated with neuropsychological testing preoperatively and at 6, 12, and 24 months after implantation. General linear models identified demographic, disease, and treatment factors that predicted decline on each neurocognitive measure.
Of 668 patients who completed baseline testing and at least 1 follow-up evaluation, 552 were impaired at baseline on at least 1 cognitive measure. At each follow-up, approximately 23% of tested patients declined and 20% improved relative to baseline on at least 1 cognitive measure. Of those who were intact at baseline, only 10%-12% declined in delayed memory and 11%-16% declined in executive function at all 3 follow-ups. For patients impaired at baseline, delayed memory decline was associated with the HVAD device and male sex, whereas executive function decline was associated with the HVAD device and stroke during CF-LVAD support. For patients intact at baseline, male sex and history of hypertension were associated with decline in immediate memory and executive function, respectively.
Neurocognitive function remained stable or improved for most patients (∼80%) with CF-LVAD at 6, 12, and 24 months after implantation. Male sex, hypertension, HVAD, and stroke were associated with cognitive decline.
Postoperative care of 14 patients with left ventricular assist devices: a case series
2024, Journal of International Medical Research
Implications of Causes of Intracranial Hemorrhage During Left Ventricular Assist Device Support
2022, Neurocritical Care

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ORIGINAL CLINICAL SCIENCEUnderstanding risk factors and predictors for stroke subtypes in the ENDURANCE trials

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

Section snippets

Methods

Results

Discussion

Conclusions

Disclosure statement

J Heart Lung Transplant

J Heart Lung Transplant

J Am Coll Cardiol

Ann Thorac Surg

J Heart Lung Transplant

J Card Fail

JACC Heart Fail

J Am Coll Cardiol

Chest

ORIGINAL CLINICAL SCIENCE
Understanding risk factors and predictors for stroke subtypes in the ENDURANCE trials