The use of left ventricular assist device (LVAD) has become an essential therapy for persons with advanced heart failure to improve the survival and the quality of life. However, LVAD is commonly associated with neurologic complications such as ischemic stroke and intracranial hemorrhage, which are the leading cause of mortality along with multiorgan failure.1,2 In particular, intracranial hemorrhage is known to carry a high mortality rate regardless of the presence of LVAD.3–5
A recent systematic review showed a high prevalence of intracranial hemorrhage in LVAD population, suggesting additional LVAD-specific risk factors playing a role in pathophysiology of this devastating disease.6 Previously, few risk factors have been suggested aside from coagulopathy because of the use of warfarin in addition to antiplatelet therapy. An association between infection, especially, bloodstream infection with LVAD-associated intracranial hemorrhage was suggested.2,7,8 However, the timing of infection and its relation to hemorrhage is unclear given that infections including bloodstream infection are common in patients in intensive care unit after intracranial hemorrhage.9 A clear understanding of temporal relationship and causal effect between infection and intracranial hemorrhage is necessary. Infectious intracranial aneurysm with subarachnoid hemorrhage has been reported in only few cases.10,11 Acquired von Willebrand disease because of shearing stress and endothelial dysfunction has been established as a risk factor for bleeding complications in LVAD12 but its relation to intracranial hemorrhage is uncertain. Also, the nonpulsatile blood flow is believed to trigger the formation of gastrointestinal arteriovenous malformations (AVM)13,14 but there is no reported case of intracranial AVM in relation to intracranial hemorrhage.
We previously identified risk factors and their associations with intracranial hemorrhage.2 Herein, in a case-crossover design, we tested our hypothesis that active infection and high international normalized ratio (INR) at the time of hemorrhage affect the acute risk of intracranial hemorrhage. We also explore to investigate the different characteristics in three types of intracranial hemorrhage: intracerebral hemorrhage (ICH), subdural hematoma (SDH), and subarachnoid hemorrhage (SAH).
Materials and Methods
Study Design and Population
We reviewed prospectively collected data of 477 persons with LVAD (HeartMate II and HeartWare) in a single, tertiary center from October 2004 to December 2016. We included all adult patients (age >18 years) with LVAD-associated intracranial hemorrhages. Intracranial hemorrhages include ICH, SAH, and SDH. This study was approved by the local institutional review board.
We used a case-crossover study design to assess the risk of intracranial hemorrhage with active infection and coagulopathy. The presence of active infection within 2 weeks of acute intracranial hemorrhage and the INR value at the time of acute intracranial hemorrhage were compared with the presence of active infection and the INR values at 1, 3, and 6 months before and after intracranial hemorrhage as controls. Because of progressive and indolent nature of some infectious diseases, we allowed 2 weeks before and after (hazard period) the time of intracranial hemorrhage to collect the infection variables. The same principle was applied to the controls. International normalized ratios were collected at the time of hemorrhages and the closest INRs at 1, 3, 6 month-marks before and after the hemorrhage were collected. The INRs after intracranial hemorrhage were not used as controls because of the cessation of anticoagulation after the hemorrhage. The total number of patients at each time point varied based on the status of LVAD implantation and the timing of intracranial hemorrhage–related deaths.
All intracranial hemorrhage patients were extracted from a local, prospective database (Electronic Data Interface for Transplantation [EDIT]) which included preimplant demographic, medical history, social history, type of device, and clinical status variables, as well as postimplant clinical status variables and adverse event variables. Additional data were retrospectively reviewed and collected from the hospital electronic medical record. Information on infection (date, types of infection, and microorganism) and INR values at the time of intracranial hemorrhage, and 1 month (±2 weeks), 3 months (±2 weeks), 6 months (±2 weeks) before and after intracranial hemorrhage as controls were collected. Active infection was defined as any infectious disease that was being treated with antibiotics within 2 weeks (pre- or post-) from the time of acute intracranial hemorrhage diagnosis. Bloodstream infection was defined as a persistent infection evidenced by two positive blood cultures. Device infection (driveline or pocket infection) was defined as a culture-positive specimen from any part of the device. All infections were treated with appropriate antibiotics with infectious disease consultation. History of gastrointestinal bleeding (GIB) was gathered in all patients to investigate its association with intracranial hemorrhage. Mean arterial pressure (MAP) values were collected at the time of intracranial hemorrhage and also obtained the average of most recent three MAP values from outpatient office visits before the intracranial hemorrhage. In addition, exploratory univariate analyses of 477 patients were done to investigate the association between GIB, infection, and LVAD-associated intracranial hemorrhage.
Patients were routinely followed from the time of implant until death with mandatory follow-up visits at 1 week, 1, 3, 6, and 12 months postimplant. Patients were routinely placed on aspirin (either 81 or 325 mg) plus warfarin (with a target INR 2.0–3.0) within the first week following LVAD implant.
All patients with intracranial hemorrhage had computed tomography (CT) imaging of brain. Review of CT imaging studies was performed by a neuroradiologist and both CT images and reports of all patients were reviewed by a single neurologist (S.M.C.). Cerebral angiogram studies were also reviewed to investigate the presence of infective intracranial aneurysm. Intracranial hemorrhage was defined as ICH (±intraventricular hemorrhage [IVH]), SAH ± IVH, or SDH seen on CT images. When more than one intracranial hemorrhage type was present, the predominant hemorrhage was coded. This study expands the existing database that was utilized to investigate the risk factors for LVAD-associated stroke.2
The results are presented as median ± interquartile range (IQR). Comparisons on demographic and clinical characteristics were performed using Student’s t-test, Fisher’s exact test or Mann–Whitney U test. The relative risks of the observed active infection exposure frequency at the time of acute intracranial hemorrhage to the infection frequency at the control periods were calculated. A paired t-test was used to compare the INR values at the time of acute hemorrhage to each control period at 1, 3, and 6 months. A p value less than 0.05 was considered significant. All analyses were conducted using NCSS 10 statistical software 2015 (Kaysville, UT).
Of 477 persons with LVAD implanted between October 2004 and December 2016, 47 (10%) developed intracranial hemorrhage (27 ICH, 14 SAH, and six SDH). The median age was 58 years (IQR: 47–67) and 39 (83%) were male. HeartMate II device was implanted in 35 (74%) persons, and HeartWare device was implanted in 12 (26%) persons. The median days from LVAD implant to intracranial hemorrhage was 210 days (IQR: 61–545) and the median INR at the time of hemorrhage was 2.7 (IQR: 1.3–3.3). The patient characteristics and medical history are described in Table 1 and Table I (Supplemental Digital Content, http://links.lww.com/ASAIO/A349).
Of 47, 27 (54%) persons had active infection at the time of intracranial hemorrhage. Fewer patients had preceding infections with seven (21%) at 1 month, five (14%) at 3 months, and four (11%) at 6 months before intracranial hemorrhage (Figure 1). The relative risk of intracranial hemorrhage because of active infection compared with the infections at 1, 3, and 6 months were 2.3 (95% CI: 1.5–3.4; p < 0.0001), 2.2 (95% CI: 1.5–3.1; p = 0.0001), and 2.0 (95% CI: 1.4–2.9; p = 0.0001), respectively (Table 2). A sensitivity analysis was performed to investigate the relative risk of active infections at 1, 3, and 6 months after acute intracranial hemorrhage. The relative risks were still high with 1.9 (95% CI: 1.5–2.7; p = 0.0004), 1.9 (95% CI: 1.3–2.7; p = 0.0002), and 1.9 (95% CI: 1.3–2.7; p = 0.0002), respectively. Also, the results did not change when the infection at the time of acute intracranial hemorrhage was restricted to definite infections before the hemorrhage, excluding infections that happened after the diagnosis of hemorrhage to minimize possible confounding. This analysis showed 21 (45%) persons had acute infections before intracranial hemorrhage with the relative risk of 1.8 (95% CI: 1.3–2.6; p = 0.001) compared with the infections at 1 month.
The mean INRs at the time of intracranial hemorrhage were compared by using a paired t-test (Table 3). The INRs were also significantly higher at the time of hemorrhage compared with those at 1 month (2.6 ± 1.9 vs. 1.8 ± 0.8; p = 0.01), 3 months (3.0 ± 2.3 vs. 2.0 ± 1.1; p = 0.01), and 6 months (3.0 ± 2.5 vs. 1.9 ± 0.6; p = 0.046) (Figure 1). The number of patients who had supratherapeutic INR (>3.0) was higher at the time of hemorrhage (11 of 47; 23%) compared with those at 1 (1 of 39; 3%; p = 0.005), 3 (4 of 32; 13%; p = 0.26), and 6 months (3 of 25; 12%; p = 0.35).
Additional analysis was performed including certain types of infections such as bloodstream infection, driveline infection, and pump pocket infection, which were previously identified as the predictors of intracranial hemorrhage2 to investigate if these infections have a higher impact on the risk of intracranial hemorrhage. The relative risks were similarly significant with 2.2 (95% CI: 1.6–3.0; p < 0.0001), 1.8 (95% CI: 1.3–2.5; p = 0.0002), and 1.7 (95% CI: 1.3–2.3; p = 0.0003) at 1, 3, and 6 months before the hemorrhage.
When the type of infection was restricted to bloodstream infection only (n = 17 vs. 1 at 1 month), the relative risk was similarly elevated at 2.4 (95% CI: 1.8–3.2; p < 0.0001). The most common types of infection identified in this study at any time points (within 6 months from the hemorrhage) were bloodstream infection (N = 29) followed by driveline infection (N = 10) and urinary tract infection (N = 8). Other infection types included lung, gastrointestinal, meninges, eye, pump pocket, and other soft tissue infections (see Table II, Supplemental Digital Content, http://links.lww.com/ASAIO/A350).
Also, the median MAP at the time of acute intracranial hemorrhage was not different from the average of most recent three MAP values from office visits (83 vs. 82; p = 0.79).
The exploratory univariate analyses of 477 LVAD patients were performed to study the association between GIB, infection, and intracranial hemorrhage. Five (11%) of 47 LVAD-associated intracranial hemorrhages had a history of GIB, which was not associated with acute intracranial hemorrhage (p = 0.09) or any subtypes of intracranial hemorrhage. Having had GIB more than once was also not associated with the presence of intracranial hemorrhage (p = 1.0). The presence of acute infection (p = 0.005), bloodstream infection (p = 0.009), and multiple infections (p = 0.03) during any time during LVAD support was associated with intracranial hemorrhage (see Table I, Supplemental Digital Content, http://links.lww.com/ASAIO/A349).
Having any infection was associated with intracranial hemorrhage (odds ratio: 2.6, 95% CI: 1.3–5.1; p = 0.005). In the subgroup analyses, only SAH (N = 9, 64%) was related to acute infection at the time of bleed (odds ratio: 11.9, 95% CI: 1.5–91; p = 0.002), but not in ICH (N = 14, 52%) and SDH (N = 1, 17%).
Of 47, 13 persons underwent cerebral angiogram (seven SAH and six ICH). Most common reason for not doing cerebral angiogram was because of an early fatality and withdrawal of life-sustaining treatment in intracranial hemorrhage. Four (57%) infectious intracranial aneurysms were identified only in SAH patients who also had acute infections. In contrast, none of the patients with ICH had infectious intracranial aneurysms. Subdural hematomas were thought to be exclusively caused by either trauma or high INR values. Different presumptive etiology for the subtypes of acute intracranial hemorrhage is listed in Table 4.
In this study, both active infection and higher INR were associated with an increased risk of acute intracranial hemorrhage. The relative risk of acute intracranial hemorrhage was 2.4 times higher in the presence of active infection than the risk at 1 month before the hemorrhage. Similarly, INR was also higher at the time of acute intracranial hemorrhage compared with those at 1 month before the hemorrhage. These findings still held true when compared with the number of active infection and the INR values at 3 and 6 months. Coagulopathy is a well-known risk factor for spontaneous intracranial hemorrhage. Anticoagulant-associated intracranial hemorrhage leads to high mortality and worse functional outcome compared with nonanticoagulant-associated hemorrhage and the risk of hemorrhage increases with increasing INR.15–17 Also, concomitant use of antiplatelet therapy and warfarin, which is the most common antithrombotic therapy in LVAD, further increases the risk of intracranial hemorrhage.18 Our finding confirms, in a case-crossover design, that not only INR plays a significant role in the occurrence of acute intracranial hemorrhage but infection also has a firm association. Other clinical variables were self-matched based on each patient’s own medical history and demographics, which minimizes confounding by the case-crossover study design.
Few studies suggested that infection, especially bloodstream infection, is related to intracranial hemorrhage in LVAD. However, the timing of infection and its relation to hemorrhage was unclear. In a cohort of 87 patients with HeartMate II, bloodstream infection was associated with both ischemic and hemorrhagic strokes when looking at any strokes that occurred ≤6 months after bloodstream infection, which is a relatively wide window of time interval.7 Another cohort of 149 patients with HeartMate II also demonstrated that persistent bloodstream infection was associated with an increased risk of both ischemic and hemorrhagic strokes but the timing of blood cultures in relation to strokes is not clear.8 We previously described that infection is a predictor of stroke and particularly, pump infection and bloodstream infection were the independent predictors for hemorrhagic stroke but any history of pump or bloodstream infection was included for the analyses.2 Our results suggest that acute infection is a significant risk factor for acute intracranial hemorrhage. It is important to note that majority of patients with infection (17/27, 63%) initially presented with active bloodstream infection and developed acute intracranial hemorrhage subacutely.
Additionally, an association between SAH and infectious intracranial aneurysm in LVAD population has been uncertain. Few case reports have reported an association between SAH and infection (device, driveline) in LVAD,10,11 and there has been no report in our knowledge regarding ICH and infectious intracranial aneurysm in LVAD population. Our results show that there is a clear association between LVAD-associated SAH and the presence of infectious intracranial aneurysm, but not in ICH. Looking closely at the patients with infectious intracranial aneurysms, all four IIAs with SAH had acute bloodstream infection at the time of hemorrhage providing a strong association of SAH and infectious intracranial aneurysms in LVAD. The reported prevalence of IIA were 10–18% in infective endocarditis19,20 and the observed frequency of IIA in LVAD was 29% (4/14 SAHs). With a clear association between bloodstream infection and SAH, the early and aggressive intervention such as LVAD device exchange might increase the likelihood of survival. A close neurovascular follow-up with surveillance cerebral angiography studies is warranted for patients with intracranial hemorrhage given the natural history of IIA in LVAD is unknown and known to be unpredictable in endocarditis.
Despite this clear association with infection and coagulopathy, questions remain regarding the etiology of LVAD-associated intracranial hemorrhage. Most likely, LVAD-associated intracranial hemorrhage has multifactorial etiology. We speculate that other risk factors may include acquired von Willebrand disease, cerebrovascular hemodynamic change, autoregulatory dysfunction, and breakdown of the blood–brain barrier related to blood flow changes with LVAD, but these speculations require further investigations and research. Nevertheless, our results help to establish a clear association of infection and coagulopathy with acute intracranial hemorrhage when other factors were controlled by the case-crossover design.
There are some limitations in our study. Since the case-crossover design study uses own case as their controls, there can be no confounding by factors that are stable over time. However, there can be confounding by time-varying cofounders. Also, an obvious limitation such as selection bias with choosing accurate and consistent comparison time point is unavoidable because of the nature of the study design. We tried to minimize this bias by performing sensitivity analyses at different random time points. This was a retrospective review of prospectively collected data from a single center. Also, several risk factors such as the use of antiplatelet therapy, the types of LVAD (HeartMate II versus HeartWare), von Willebrand factor deficiency, or the duration of the device support that could have affected the risk of intracranial hemorrhage were not accounted. Finally, we cannot exclude the possibility that some ICHs may have been hemorrhagic conversion of ischemic strokes because of inability to perform magnetic resonance imaging (MRI) studies in LVAD.
Active infection and elevated INR were associated with LVAD-associated intracranial hemorrhage. The occurrence of both bloodstream infection and subarachnoid hemorrhage may indicate the presence of infectious intracranial aneurysm in LVAD.
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